NEOPLASTIC    DISEASES 

A    TREATISE   ON   TUMORS 


By 

JAMES  EWING,  A.  M.,  M.  D.,  Sc.  D. 

Professor  of  Pathology  at  Cornell  University  Medical  College,  New  York  City; 
Pathologist  to  the  Memorial  Hospital 


SECOND  EDITION, 
REVISED  AND  ENLARGED 

WITH  514  ILLUSTRATIONS 


PHILADELPHIA  AND  LONDON 

W.  B.  SAUNDERS  COMPANY 

1922 


Copyright,  1919,  by  W.  B.  Saunders  Company.     Revised,  entirely 
reset,  reprinted,  and  recopyrighted  January,  1922 


Copyright,  1922,  by  W.  B.  Saunders  Company 


MADE     IN     U.     S.     A. 


»RESS     OF 


PHILADELPHIA 


To  the  memory  of 

JAMES   DOUGLAS 

A  man  of  ideas,  ideals,  and  affairs 

In  token  of  the  deep  respect  of  the  author 

This  work  is  dedicated 


526S05 


PREFACE  TO  THE  SECOND  EDITION 


THE  early  call  for  a  reprinting  of  this  work  has  given  a  welcome  oppor- 
tunity to  revise  and  enlarge  certain  chapters  and  to  add  many  new  refer- 
ences and  data  that  have  been  contributed  or  collected  during  the  past  two 
yeirs. 

Few  portions  of  the  work  have  passed  without  minor  addenda,  while  the 
chapters  on  tumors  of  bone  and  on  neurofibromatosis  have  been  extensively 
recast.  No  reason  has  appeared  for  distrusting  the  reliance  on  photographs 
for  illustrations,  of  which  thirty-three  have  been  added. 

The  writer  wishes  to  acknowledge  with  thanks  the  great  assistance  he  has 
received  from  many  sources,  through  reviews,  correspondence,  case  records, 
and  material,  all  of  which  have  been  gladly  received  and  freely  employed. 

January,  1922. 


PREFACE 


IT  is  the  object  of  this  work  to  present  within  reasonable  space  and  in 
accessible  form  the  main  features  of  the  origin,  structure,  and  natural  history 
of  tumors. 

Up  to  a  very  recent  time  it  has  been  the  prevailing  impression  that 
tumors  fall  into  a  limited  number  of  grand  classes  in  which  the  forms  occur- 
ring in  the  several  organs  are  so  nearly  related  as  to  be  virtually  identical. 
Hence  the  practical  physician  or  surgeon  has  been  content  to  regard  all 
fibromas,  sarcomas,  or  cancers  as  equivalent  conditions  without  regard  to 
the  organ  involved,  and  on  this  theory  to  treat  the  members  of  each  class 
alike.  Upon  this  theory  also  it  was  legitimate  to  conceive  of  a  universal 
causative  agent  of  malignant  tumors  and  thus  to  subordinate  many  very 
obvious  differences  which  clinical  experience  has  established  in  the  origin 
and  behavior  of  different  related  tumors. 

I  believe  that  this  point  of  view  has  greatly  retarded  the  progress  of  the 
knowledge  of  tumors,  and  it  has  been  the  writer's  effort  to  combat  such  a 
conception,  so  far  as  present  knowledge  permits.  He  has  endeavored  to 
analyze  the  numerous  etiologic  factors  which  meet  in  such  diverse  fashions 
in  the  inception  of  tumors,  to  emphasize  the  general  dependence  of  clinical 
course  upon  histologic  structure,  to  trace  the  histogenesis  to  the  last  de- 
gree, impressing  its  essential  importance  when  known,  and  to  enumerate 
and  contrast  the  more  striking  clinical  features  which  are  often  highly 
characteristic  of  different  tumors. 

No  one  would  think  of  confusing  lobar  pneumonia  .with  pneumonic 
plague,  although  both  are  examples  of  acute  exudative  pneumonitis,  but  it  is 
quite  the  rule  to  identify  for  statistical  studies  several  equally  different  forms 
of  mammary  cancer.  The  former  diseases  are  related  only  as  forms  of 
inflammation,  the  latter  only  as  types  of  neoplasia.  From  this  point  of 
view  it  may  safely  be  said  that  there  are  more  distinct  clinical  and  pathologic 
entities  within  the  groups  of  neoplasms  than  exist  outside  of  them. 

While  a  great  volume  of  information  regarding  the  clinical  phenomena  of 
the  main  forms  of  tumors  is  available  in  special  works  on  medicine,  surgery, 
and  the  specialties,  the  task  of  unraveling  their  separate  varieties,  tracing 
their  mode  of  origin  and  growth,  and  establishing  the  nature  of  the  less  com- 
mon forms,  falls  to  the  lot  of  the  pathologist.  For  the  final  classification 
of  tumors  must  depend  chiefly  on  histogenesis  and  structure.  Present-day 
oncology  is  chiefly  concerned  with  these  topics  and  the  space  devoted 
to  them  can  safely  be  reduced  only  when  our  knowledge  is  much  further 
advanced. 

In  spite  of  several  laborious  years  spent  in  the  task  the  writer  acknowl- 
edges disappointment  with  the  results  attained  in  many  departments,  but 
can  only  claim  that  the  effort  to  present  tumors  as  specific  diseases  is  in  the 
right  direction.  He  first  undertook  to  write  a  book  on  the  general  principles 
of  oncology,  but  soon  found  that  the  significant  facts  about  tumors  are  not 
of  general  application,  but  are  best  revealed  in  the  study  of  special  tumor 
groups  or  even  of  special  cases. 

In  the  compilation  of  the  work  the  writer  has  endeavored  to  consult  with 

11 


12  PREFACE 

due  respect  all  the  standard  authorities,  and  as  far  as  possible  the  original 
contributions  in  the  literature.  The  rather  extensive  bibliographic  lists 
seem  necessary  for  the  guidance  of  the  reader  who  desires  complete  informa- 
tion and  to  whom  the  work  is  chiefly  addressed.  The  recent  rapid  increase 
in  original  contributions  from  the  United  States  has  made  it  impossible  to 
do  full  justice  to  American  literature. 

It  is  a  pleasure  to  acknowledge  the  valuable  assistance  received  from 
many  friends  and  colleagues  here  and  abroad.  The  author  acknowledges 
especially  his  indebtedness  to  Messrs.  W.  B.  Saunders  Company  for  under- 
taking the  publication  of  a  highly  specialized  work.  Through  the  pains- 
taking assistance  of  Mr.  William  Dunn  it  has  been  possible  to  rely  almost 
entirely  upon  photographs  for  illustrations. 

While  confessing  a  deep  interest  in  the  theoretic  problems  which  render 
oncology  the  most  complex  and  fascinating  field  in  pathology,  the  chief 
object  and  hope  of  the  author  have  been  that  by  rendering  more  accessible 
to  English  readers  the  knowledge  of  tumors  he  may  contribute  something 
toward  the  reduction  of  the  mortality  from  cancer. 

JAMES  EWING. 


CONTENTS 


GENERAL  ONCOLOGY 


CHAPTER   I  PAGE 

HISTORICAL 17 

CHAPTER  II 
DEFINITION.     CLASSIFICATION.    GENERAL  PATHOLOGY 25 

CHAPTER  III 
MALIGNANCY  AND  ITS  EFFECTS  ON  THE  ORGANISM 62 

CHAPTER  IV 

METASTASIS 76 

CHAPTER  V 
CHEMISTRY  OF  TUMORS;  SEROLOGY 89 

CHAPTER  VI 
THEORIES  OF  THE  NATURE  OF  CANCER 94 

CHAPTER  VII 
THE  SPECIAL  ETIOLOGY  OF  TUMORS;  TRAUMA '. 109 

CHAPTER  VIII 
THE  PARASITIC  THEORY 113 

CHAPTER  IX 
EXPERIMENTAL  CANCER  RESEARCH..  .   126 


SPECIAL  ONCOLOGY 


CHAPTER  X 
FIBROMA 149 

13 


14  CONTENTS 

CHAPTER  XI  PAGE 

MYXOMA I7° 

CHAPTER  XII 
LIPOMA X78 

CHAPTER  XIII 
CHONDROMA 1 85 

CHAPTER  XIV 

OSTEOMA I96 

CHAPTER  XV 
MYOMA 203 

CHAPTER  XVI 
ANGIOMA 223 

CHAPTER  XVII 
SARCOMA 240 

CHAPTER  XVIII 
CLINICAL  TYPES  OF  SARCOMA 249 

CHAPTER  XIX 
SARCOMAS  OF  BONE  AND  BONE-MARROW ; 269 

CHAPTER  XX 
ENDOTHELIOMA 299 

CHAPTER  XXI 
LYMPHOMA  AND  LYMPHOSARCOMA 348 

CHAPTER  XXII 
TUMORS  OF  THE  BRAIN 393 

CHAPTER  XXIII 
TUMORS  OF  NERVE  TRUNKS 427 

CHAPTER  XXIV 
TUMORS  OF  SPINAL  CORD  AND  MEMBRANES 436 

CHAPTER  XXV 
GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS 446 


CONTENTS  15 

CHAPTER  XXVI 

PAGE 

EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST.  . 484 

CHAPTER  XXVII 
CANCER  OF  UTERUS,  VULVA,  VAGINA 543 

CHAPTER  XXVIII 
CHORIOMA  (CHORIONEPITHELIOMA) 566 

CHAPTER  XXIX 
CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY 582 

CHAPTER  XXX 
THE  OVARIAN  TERATOMA : 613 

CHAPTER  XXXI 
CARCINOMA  OF  STOMACH 625 

CHAPTER  XXXII 
CARCINOMA  OF  INTESTINE 661 

CHAPTER  XXXIII 
EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER 675 

CHAPTER  XXXIV 
TUMORS  OF  PANCREAS 702 

CHAPTER  XXXV 
MAXILLARY  TUMORS  OF  DENTAL  ORIGIN 707 

CHAPTER  XXXVI 
EPITHELIAL  TUMORS  OF  THE  SALIVARY  GLANDS 725 

CHAPTER  XXXVII 
TUMORS  OF  KIDNEY 738 

CHAPTER  XXXVIII 
TUMORS  OF  THE  ADRENAL 768 

CHAPTER  XXXIX 
TUMORS  OF  PROSTATE 779 

CHAPTER  XL 
TUMORS  OF  TESTIS 790 


16  CONTENTS 

CHAPTER  XLI  PAGE 

TUMORS  OF  Luxe 807 

CHAPTER  XLII 
EPIDERMOID  CARCINOMA 818 

CHAPTER  XLIII 
EPIDERMOID  CARCINOMA  (Continued) 857 

CHAPTER  XLIV 
MELANOMA 871 

CHAPTER  XLV 
TUMORS  OF  THE  THYROID 891 

CHAPTER  XLVI 
THE  THYMUS  AND  ITS  TUMORS 912 

CHAPTER  XLyil 
TUMORS  OF  THE  HYPOPHYSIS 924 

CHAPTER  XLVIII 
THE  PINEAL  GLAND  AND  ITS  TUMORS 948 

CHAPTER  XLIX 
TERATOLOGY 954 


BIBLIOGRAPHY 987 

INDEX 1033 


NEOPLASTIC    DISEASES 


GENERAL  ONCOLOGY 

CHAPTER  I 
HISTORICAL 

The  Ancients  knew  cancer  well.  They  treated  it  by  excision  and  by  a 
variety  of  escharotics,  including  the  Egyptian  arsenical  ointment.  Cancer 
is  mentioned  in  the  Papyrus  Ebers  (B.  C.  1500)  and  in  the  oldest  remnants  of 
the  literature  of  India  and  Persia. 

Hippocrates  (B.  C.  460  to  375)  received  from  earlier  days  a  considerable 
body  of  descriptive  facts  regarding  cancer  of  the  skin,  breast,  uterus,  and 
internal  organs,  and  he  first  employed  the  terms  xapxfyx?  for  all  indolent 
ulcers,  and  xapxivuifta  for  progressive  malignant  tumors.  The  humoral  path- 
ology then  disseminated  conceptions  of  the  origin  of  cancer.  Deficiency 
or  excess  of  blood,  mucus,  or  bile  formed  the  basis,  of  all  disease.  Herodotus 
mentions  that  Democedes  (B.  C.  520)  cured  Atossa,  the  daughter  of  Darius 
Hystaspis,  of  breast  cancer,  and  Hippocrates  burnt  out  a  carcinoma  of  the 
neck,  the  earliest  record  of  diathermia. 

Celsus  (B.  C.  30  to  A.  D.  38)  distinguished  several  gross  varieties  of  cancer, 
and  he  excised  breast  cancer,  advising  against  removal  of  the  pectoralis  major. 
Treatment  by  charcoal  was  employed  by  Cato,  and  a  variety  of  crude  internal 
remedies  are  mentioned  by  Pliny. 

Galen  (A.  D.  131  to  203),  the  founder  of  experimental  physiology  and 
pathology,  failed  to  make  any  significant  advance  in  the  conception  of  cancer, 
but  the  presentation  of  the  humoral  doctrine  of  atra  bills  in  his  writings  formed 
a  scripture  which  dominated  medical  thought  for  more  than  a  thousand 
years.  Swellings  were  secundam  naturam  (gravid  uterus),  supra  naturam 
(callous  formations),  or  prater  naturam  (true  tumors).  The  pneuma,  com- 
posed of  solid  parts  and  four  fluids,  blood,  mucus,  yellow  and  black  bile, 
ruled  the  processes  of  the  body.  Cancer  developed  from  the  concentration 
of  black  bile. 

Suppression  of  menses  and  hemorrhoids,  preventing  the  discharge  of 
black  bile,  were  chiefly  responsible  for  cancer,  which  appeared  where  the 
bile  gravitated  in  face,  lips,  breast,  etc.  No  modern  writer  has  been  able 
to  reflect  the  thought  of  that  period  or  to  explain  the  firm  entrenchment 
of  the  crude  humoral  theories.  Since  capable  logic  could  not  have  been  lack- 
ing, one  must  suppose  that  religious  and  esthetic  tendencies  in  the  race  unfitted 
the  human  mind  for  natural  thought  regarding  the  structure  and  functions 
of  the  human  body.  For  internal  cancer,  of  which  little  was  known,  a  diet 
chiefly  vegetable  was  recommended.  Walnuts  were  specifically  forbidden. 

Diagnosis  rested  chiefly  on  the  cause  of  the  disease,  while  treatment  by 
excision,   ligation   of   vessels,    and   cautery   was   comparatively   successful. 
2  17 


18  NEOPLASTIC  DISEASES 

Leonides  of  Alexandria  (A.  D.  180)  broke  away  from  Hippocrates'  conserva- 
tism, dissected  out  breast  cancer  extensively,  cutting  through  healthy  tissue 
with  knife  and  cautery,  and  approached  closely  to  the  modern  technics  of 
this  operation. 

In  the  Byzantine  period  (475  to  1500)  considerable  progress  was  made 
in  the  description  of  various  tumors.  Paulus  of  ^Egina  (625  to  690)  separated 
chronic  metritis  from  uterine  cancer.  In  Arabia,  Avicenna  (980  to  1037) 
introduced  the  internal  use  of  arsenic,  and  Avenzoar  (1070  to  1162)  employed 
the  esophageal  sound  and  the  nutrient  enema.  The  i3th  to  i5th  centuries 
were  the  Dark  Ages  for  medicine,  and  especially  for  surgery.  At  the  Council 
of  Tours  (1162),  and  later,  at  the  Fourth  Lateran  Conference,  the  ban  of  the 
Church  was  laid  upon  the  free  pursuit  of  surgery.  The  fact  that  surgery 
could  be  studied  only  in  private  and  practised  only  by  nomads  was  possibly 
both  cause  and  effect  of  these  ecclesiastic  orders.  At  the  Universities  of 
Salerno  and  Montpellier  (1150)  the  Church  designated  what  books  should 
be  used.  The  Monks  jealously  dominated  medical  speculation  and  concerned 
themselves  mainly  with  translations  of  the  classics.  Walsh  would  defend 
the  influence  of  the  Popes  of  this  period  on  science,  and  refers  to  publications 
on  anatomy  and  surgery  from  Catholic  schools  where  these  branches  of  learn- 
ing were  undoubtedly  cultivated.  Lanfranchi,  of  Lyons,  an  exile  from  Mai- 
land,  established  scientific  surgery  in  France  (1290)  with  two  notable  works. 
He  strongly  urged  the  radical  operation  for  cancer  with  free  bleeding  of  the 
affected  part.  Henri  de  Mondeville  and  Guy  de  Chaulliac  (1300  to  1368), 
physician  to  Clemens  VII,  wrote  text-books  on  surgery,  excised  cancer  with 
the  knife,  and  developed  to  a  high  degree  extirpation  by  caustic  arsenic. 
Yet  the  Medicine  of  the  Monks  must  be  rated  as  unfruitful  and  as  incom- 
patible with  the  progress  achieved  shortly  thereafter  in  the  Renaissance. 

The  Renaissance  (1500  to  1700),  bringing  the  discovery  of  the  printing 
press  and  the  circulation  of  the  blood  (Harvey,  1628),  greatly  facilitated  the 
spread  of  knowledge  and  aided  the  more  accurate  diagnosis  and  better  treat- 
ment of  cancer,  but  threw  little  light  on  etiology.  Andreas  Vesal  (1514  to 
1564)  began  the  attack  on  many  of  the  concepts  of  Galen,  identifying  deep- 
seated  with  ulcerating  cancer.  Fabricius  (1537  to  1619)  separated  many 
inflammatory  swellings  from  cancer,  warned  rigidly  against  incomplete  removal, 
extirpated  the  uterus,  and  experimented  with  internal  remedies. 

Marcus  Aurelius  Severinus  (1580  to  1656)  described  myxosarcoma,  sepa- 
rated cancer  from  benign  tumors  of  the  breast,  and  extirpated  the  axillary 
nodes. 

In  Prag,  Sennert  (1572  to  1637),  and  in  Lisbon,  Lusitanus  (1642)  first 
claimed  that  cancer  was  contagious,  a  doctrine  which  prevailed  extensively 
and  with  little  dissent.  Paracelsus  (1413  to  1541)  stands  out  as  the  first 
successful  opponent  of  Galen's  theory  of  atra  bilis  as  the  cause  of  cancer. 
He  claimed  that  the  disease  was  due  to  mineral  salts  in  the  blood.  He  seemed 
to  think  that  cancer  developed  where  various  animal  salts  became  concen- 
trated and  sought  an  outlet.  At  this  period  it  is  interesting  to  note  that  the 
decline  of  Galen's  authority  and  distrust  of  even  his  crude  theories  of  etiology 
led  to  complete  demoralization  in  the  treatment  of  cancer,  encouraged  great 
abuse  of  arsenic  and  other  internal  and  external  remedies,  permitted  the 
faith  cure  career  of  Queen  Elizabeth  (1602),  and  developed  many  fantastic 
theories  regarding  the  nature  of  cancer. 

The  Lymph  Theory. — In  the  i7th  century  Galen's  doctrine  was  com- 
pletely demolished  by  the  discovery  of  the  circulation  by  Harvey  (1628), 
of  the  lymph-vessels  by  Olens  (1652),  and  of  the  red  blood-cells  by  Malpighi 
(1661). 


HISTORICAL  19 

Malpighi  used  the  microscope  which  had  been  in  existence  since  1592. 
The  black  bile  was  nowhere  to  be  found,  but  everywhere  was  blood  and  lymph. 
Lymph  coagulated  and  foamed  on  boiling,  hence  cancer  was  composed  of 
lymph  varying  in  density,  alkalescence,  or  acidity,  and  in  malignant  tumors 
fermenting  and  degenerating.  Louis  (1723  to  1792)  distinguished  gelatinous 
lymph  (goiter)  and  albuminous  lymph  (scirrhus).  LeDran  (1685  to  1770) 
studied  cancer  by  many  autopsies,  emphasized  the  local  nature  of  cancer 
of  the  skin,  and  the  internal  origin  of  breast  cancer.  He  conceived  that  if  a 
drop  of  cancer  lymph  passed  the  adjacent  nodes  it  contaminated  the  entire 
system. 

Astruc  (1684  to  1766)  separated  cysts  from  true  tumors,  showed  that 
scirrhus  and  soft  cancer  were  of  the  same  nature,  pointed  out  important 
differences  in  prognosis  of  different  types  of  carcinoma,  and  by  incineration 
proved  that  cancer  and  muscle  tissue  contained  the  same  salts.  Yet  he  likened 
the  growth  of  cancer  from  lymph  to  the  heating  and  swelling  of  gypsum  in 
water. 

Morgagni  (1682  to  1772)  established  the  importance  of  the  pathological 
anatomy  of  cancer,  describing  many  internal  tumors  studied  at  autopsy, 
and  separating  gumma,  struma,  exostosis,  and  lipoma  from  cancer.  He 
distrusted,  without  replacing,  the  lymph  theory. 

A  notable  event  in  the  history  of  cancer  research  was  the  essay  of  Peyrilhe 
(1735  to  1804)  submitted  to  the  Academy  of  Lyons  in  answer  to  the  ques- 
tion, Qu'  est  ce  que  le  cancer?  This  was  the  first  systematic  investigation  of 
the  whole  subject  and  dealt  with  the  cancer  toxin,  the  nature  of  the  disease, 
the  manner  of  growth,  and  the  treatment. 

He  spoke  of  the  local  origin,  the  production  of  a  specific  virus  from  degenera- 
tion of  the  tumor,  and  the  development  of  cachexia  from  this  source. 

He  endeavored  to  demonstrate  the  virus  by  injecting  tumor  emulsion 
beneath  the  skin  of  a  dog,  but  an  abscess  resulted  and  his  servant  drowned 
the  animal.  He  treated  ulceration  effectively  with  the  newly  discovered 
carbonic  acid.  His  imagination  was  satisfied  by  the  Cartesian  lymph  theory 
of  the  times. 

In  Germany 'the  i7th  century  was  occupied  by  the  exploitation  of  many 
personal  views  of  the  origin  of  cancer  and  other  diseases. 

Chemical  conceptions  held  sway,  and  cancer  was  attributed  usually  to 
excess  of  acid,  to  be  treated  by  alkali  (Helmont,  Ettmuller). 

Stahl  (1660  to  1734)  supposed  that  stasis  and  thickening  of  the  blood 
were  the  essential  factors.  Hoffmann  held  that  life  and  health  depended 
on  normal  movements  of  the  tissues,  cancer  and  other  diseases  resulting 
from  atony,  stasis,  and  abnormal  fermentation  of  blood  and  lymph.  He 
constructed  his  anodyne  as  a  panacea  to  restore  tissue  tone. 

In  England,  John  Hunter's  (1728  to  1793)  conception  of  the  lymph  theory 
represented  a  distinct  advance  toward  the  cellular  pathology.  He  held  that 
tumors  grew  from  the  coagulable  lymph  constantly  thrown  out  of  the  blood, 
that  tumor  tissue  like  normal  tissue  was  nourished  by  the  organism,  and 
developed  according  to  the  same  biological  laws.  In  1802  The  Society  for 
Investigating  the  Nature  and  Cause  of  Cancer  was  formed  in  London,  and 
formulated  the  problems  of  the  disease  as  they  stand  today.  The  society,, 
dissolved  in  1806. 

The  pathological  anatomy  of  malignant  tumors  chiefly  interested  the 
English  observers,  and  Hey  (1736  to  1819)  described  in  detail  the  structure 
of  certain  vascular  tumors  which  he  found  to  be  composed  of  organized  blood- 
fluid  and  a  large  proportion  of  lymph,  and  for  which  he  employecf  the  term 
"fungus  hematodes."  Wardrop,  1809,  described  in  great  detail  miscella- 


<SW 


20  NEOPLASTIC  DISEASES 

neous  tumors  of  this  gross  type,  attempting  to  separate  them  from  cancer. 
Many  of  his  cases  occurred  in  children,  some  involved  the  eye,  and  one  arose 
from  a  wart. 

Abernethy,  1804,  attempted  to  define  the  old  term  "sarcoma"  by  applying 
it  to  various  soft  tumors,  and  he  called  Key's  fungus  hematodes  medullary 
sarcoma.  Maunoir,  1820,  showed  the  beneficent  result  of  anatomical  study 
by  announcing  that  each  tumor  is  the  result  of  a  morbid  change  of  the  fluid 
or  tissue  from  which  it  arises,  and  retains  the  original  characters  of  this  tissue. 
He  employed  many  crude  chemical  and  physical  tests  to  support  this  claim. 

The  close  attention  then  being  given  to  clinical  data  led  Pott  (1775)  to 
recognize  and  describe  chimney-sweeps'  cancer  and  to  point  out  its  etiology. 
The  English  contributions  of  this  period  were  completed  "by  Home,  who, 
using  the  microscope,  described  and  depicted  rounded  bodies  which  he  regarded 
as  lymph  corpuscles. 

In  France,  Bichat's  studies  of  tissue  structure  opened  a  new  era  with  the 
appearance  of  his  Anatomie  generate  in  1801.  He  first  distinguished  the  stroma 
from  the  parenchyma  of  tumors,  deriving  the  former  from  the  originating 
tissue  and  the  latter  by  proliferation  from  the  stroma.  Without  reliance 
upon  the  microscope  he  regarded  the  stroma  as  cellular  and  conceived  of 
its  growth  by  proliferation. 

Following  Bichat,  Laennec  made  a  systematic  study  of  the  gross  features 
of  cancer  in  thin  slices,  and  introduced  the  term  "encephaloid"  for  the  soft 
parts.  Dupuytren  attempted  to  prove  the  infectiousness  of  the  disease  by 
ingestion  and  intravenous  inoculation  of  cancer  tissue.  Bayle  and  Cayol 
argued  in  favor  of  the  constitutional  nature  of  the  disease  and  fully  pointed 
out  the  difference  between  chronic  mastitis  and  cancer. 

Broussais'  doctrine  that  cancer  was  the  sequel  of  recurrent  inflammation 
had  made  some  influence  on  the  thought  of  this  period.  Based  on  chemical 
observation,  his  claim,  that  cancer  never  arises  in  normal  tissues  but  only 
after  inflammatory  alterations,  found  many  adherents  and  is  of  interest  in 
connection  with  later  theories. 

Lobstein  used  the  term  "plastic  lymph"  and  formulated  the  view  that 
the  tumor-forming  lymph  was  not  under  control  of  the  biological  laws  of 
the  organism.  Recamier  studied  especially  the  infiltration  of  cancer,  observed 
the  destruction  of  veins,  and  applied  the  term  "metastases"  to  nodules  in 
the  brain  in  cases  of  mammary  cancer.  He  recognized  the  importance  of 
supernumerary  organs  and  nevi  as  sources  of  cancer.  Andral  reflected  the 
confusion  of  ideas  then  prevailing  by  offering  his  theory  that  products  of 
secretion  became  organized  into  cancer.  Cruveilhier  regarded  cancer  as  a 
malignant  degeneration  which,  like  inflammation,  affected  all  the  organs. 
Its  chief  pathognomonic  feature  was  the  cancer  juice  exuded  on  pressure. 
Andral  thought  tumor  masses  floating  in  the  veins  were  derived  from  the 
fibrin,  but  Velpeau,  in  a  case  of  intravenous  tumor,  searched  the  blood  in 
vain  for  cancerous  elements.  Such  questions  as  the  identity  of  encephaloid 
or  soft  cancer  with  brain  tissue  were  hardly  settled.  Tubercle  was  commonly 
confused  with  cancer  and  gummata  imperfectly  distinguished  from  it.  Cancers 
were  classified  upon  crude  gross  characters,  as  in  Jager's  Handworterbuch, 
Leipsic,  1837,  where  they  were  divided  into  four  types,  hard,  soft,  pigmented, 
and  blood-cancer. 

Thus,  during  the  sway  of  the  lymph  theory,  English  and  French  students 
while  adding  important  contributions  to  the  descriptive  history  and  gross 
pathology  of  malignant  tumors,  failed  to  pass  beyond  the  limits  of  the  pre- 
vailing theoretical  conceptions  of  the  time.  It  was  the  great  period  of  indi- 
vidual surmises  which  in  some  instances,  notably  with  Hunter,  Home,  Lobstein 


HISTORICAL  21 

and  Recamier,  approached  closely  toward  and  prepared  the  way  for  modern 
conceptions. 

In  Germany,  Richter,  Walther,  and  others  engaged  in  the  current  dis- 
cussions without  adding  essentially  new  data. 

It  was  the  general  conception  that  the  elements  of  cancer  were  fluid  and 
traveled  in  the  veins. 

Great  significance  was  attached  to  the  observation  of  tumor  masses  in 
the  vessels.  A  special  variety  of  "blood-cancer"  supposed  to  come  from 
irritating  elements  was  described  by  Langstaff,  1817,  and  Carswell,  1834. 

Histological  Period. — With  the  construction  of  the  achromatic  micro- 
scope in  Paris,  1824,  a  new  era  opened  in  cancer  research.  Wolf  finds  that 
the  first  fruitful  studies  of  the  structure  of  vegetable  and  animal  tissues  by 
this  instrument  were  made  by  Raspail  in  1826,  who  showed  that  the  growth 
of  tissues  resulted  from  the  multiplication  of  cells.  He  clearly  stated  the 
doctrine  of  the  cell,  finding  that  tissues  were  composed  of  microscopic  vesicles. 
The  structure  and  growth  of  fat  tissue  he  described  in  detail.  Collard,  1828, 
also  described  rather  clearly  the  stages  in  the  embryonal  development  of 
tissues,  assuming,  however,  that  the  cells  originated  from  plastic  lymph. 
Schwann,  1838,  established  this  doctrine  of  cellular  structure  as  a  universal 
principle  and  discovered  the  nucleus  and  nucleolus  of  the  cell. 

In  the  same  year  J.  Miiller  published  his  classical  study  of  malignant 
tumors.  He  found  them  all  to  be  composed  of  groups  of  cells,  each  contain- 
ing nuclei  and  nucleoli.  The  various  current  types  of  cancer  he  found  to  be 
distinguished  only  by  different  proportions  and  groupings  of  cell  masses  and 
stroma.  Certain  elongated  or  racquet-shaped  cells,  "geschwanzten  Korper- 
chen,"  he  regarded  as  on  the  way  to  fiber  formation,  but  not  as  specific  cancer 
elements,  which  he  was  unable  anywhere  to  detect.  Hence  his  diagnosis 
of  cancer  rested  on  clinical  signs  and  the  anatomical  grouping  of  the  cells. 
He  held  the  interesting  view  that  cancer  developed  not  from  normal  tissue, 
but  from  germ  cells  which  as  a  "seminium  morbi"  lay  scattered  between  the 
tissue  elements. 

In  regard  to  the  origin  of  the  cells  it  was  held  that  most  of  them  developed 
from  the  plastic  lymph  or  blastema  by  a  process  of  budding.  Others  resulted 
from  division  of  nuclei  and  cell  bqdy,  or  by  the  transformation  of  intracellular 
blastema  lying  in  spaces  within  the  cell  body  (Virchow's  Brutraume).  The 
originating  tumor-cells  were  not  derivatives  of  the  normal  tissue  cells,  but 
came  from  the  seminium  morbi,  hence  there  were  urgent  demand  and  search 
for  specific  characters  in  the  tumor-cells.  Lebert  especially  described  such 
specific  cells  and  designated  as  pseudocancer  all  tumors,  as  rodent  ulcer, 
which  failed  to  contain  them.  Following  this  principle,  Hannover  care- 
fully described  the  group  of  tumors  arising  from  stratified  squamous  epithe- 
lium and  separated  them  from  cancer  under  the  term  "epithelioma." 

Hannover  believed  that  cancer-cells  circulated  in  the  blood  and  produced 
metastases  as  pus-cells  produced  pyemia. 

The  doctrine  of  the  specific  cancer-cell  now  became  the  chief  topic  of  dis- 
cussion and  was  supported  by  many  writers.  It  was  opposed  by  Bruch,  who 
added  many  details  to  Miiller's  work;  by  Virchow,  who  found  the  tailed  cor- 
puscles in  the  normal  bladder  epithelium;  and  by  Velpeau,  who,  with  Hannover, 
established  the  microscopical  diagnosis  of  tumors.  Endogenous  cell  forma- 
tion then  took  the  place  denied  the  "tailed  corpuscle"  as  the  pathognomonic 
sign  of  cancer,  Bruch,  Virchow,  Remak  and  many  others  accepting  the  impor- 
tance of  this  supposed  type  of  cell  growth.  The  significance  of  tumor  stroma 
also  attracted  new  attention,  especially  from  Rokitansky,  who  explained 
many  of  the  gross  features  from  variations  in  this  element.  He  also  studied 


22  NEOPLASTIC  DISEASES 

the  secondary  degenerations  of  cancer  tissue,  including  inflammation,  necrosis, 
and  saponification,  and  considered  the  possibility  of  a  spontaneous  cure  by 
these  processes. 

In  spite  of  their  very  careful  histological  studies  of  tumor  tissue  in  the 
fresh  condition  all  the  authoritative  writers  of  this  period  including  Virchow 
were  led  to  believe  in  the  origin  of  cancer  from  a  fluid  blastema.  Cancer 
was  defined  as  an  organized  exudate  from  the  blood  with  overnutrition  and 
overgrowth.  Much  controversy  arose  concerning  the  various  types  of 
blastemas  supposed  to  exist  and  the  changes  in  the  blood  from  which  they 
were  all  necessarily  derived.  Vogel  thought  there  were  as  many  blastemas 
as  tissues,  different  tumors  arising  in  different  tissues  according  to  the  type 
or  analogy  of  the  tissue  involved  (law  of  analogous  blastemas).  These  views 
led  directly  to  the  conception  of  cancer  as  a  constitutional  dyscrasia 
(Rokitansky),  a  belief  that  gained  wide  acceptance  and  seemed  to  be  sup- 
ported by  the  anemia  of  the  disease.  The  help  of  the  chemists  was  sought 
to  separate  from  the  blood  the  different  blastemas,  and  Fiihrer  was  able  to 
distinguish  albuminous,  chondrinous,  and  glutinous  varieties,  each  of  which 
gave  a  suitable  color  reaction  with  nitric  acid,  and  which  were  offered  as 
sources  of  the  corresponding  tumors.  The  idea  that  exuded  elements  of  the 
blood  could  become  organized  into  cancer  was  vigorously  opposed  by  Cruveil- 
hier,  who  urged  that  extravasated  blood  never  became  organized,  but  had 
lost  all  claim  to  vitality.  Cancer  could  therefore  develop  only  in  the  vessels. 
This  reasoning  led  Langenbeck  to  study  cancerous  masses  in  the  veins  which 
he  found  to  be  composed  of  fibrin,  pus-cells,  and  cancer-cells.  He  therefore 
drew  the  important  conclusion  that  cancer-cells  possess  a  remarkable  capacity 
for  independent  existence  and  that  they  were  carried  through  the  veins,  pro- 
ducing secondary  tumors  or  metastases.  After  Peyrilhe,  Alibert,  1806,  and 
Dupuytren,  1817,  produced  only  suppuration  by  intravenous  injections  of 
tumor  emulsion,  but  Langenbeck,  Follin  and  Velpeau  claimed  to  have 
observed  tumor  nodules  in  the  lungs  of  dogs  receiving  intravenous  injections. 
These  results,  although  failing  to  receive  confirmation,  seemed  then  to  prove 
not  only  the  origin  of  metastases,  but  the  contagiousness  of  cancer.  Yet 
Bruch  at  once  interpreted  them  as  transportation  of  cancer-cells  and  not  as 
infection.  He  held  the  lymph-vessels  to  be  the  chief  channels  of  transport 
and  with  Meckel  described  backward  transport  in  lymphatics. 

While  still  burdened  by  the  blastema  theory  of  origin  the  study  of  cancer 
had  succeeded  up  to  1860  in  rather  accurately  describing  and  classifying 
the  main  classes  of  tumors  chiefly  according  to  microscopical  structure.  The 
description  of  the  benign  tumors,  the  existence  of  various  types  of  carcinoma, 
the  malignancy  of  epithelioma  and  the  separate  position  of  sarcomas,  were 
generally  accepted  facts.  Correct  conceptions  of  the  histogenesis,  however, 
were  impossible  until  Virchow  founded  the  cellular  pathology  upon  the  doc- 
trine of  Omnis  cellula  e  celMa.  There  had  been  several  opponents  of  the 
idea  that  cells  could  be  formed  from  exuded  lymph,  notably  Cruveilhier, 
while  Remak  at  the  same  time  with  Virchow  claimed  that  cells  grew  exclu- 
sively from  other  cells  by  endogenous  reproduction;  but  Virchow  applied 
the  new  principle  rigidly  to  all  departments  and  especially  to  the  origin  and 
growth  of  tumors.  Coincidently  with  this  memorable  service  he  fell  into 
two  grave  errors.  He  failed  to  correctly  interpret  the  deceptive  evidence  of 
endogenous  cell  formation  and  he  was  led  to  believe  that  cancer-cells  originated 
from  connective-tissue  cells.  The  latter  error  he  never  fully  relinquished 
and  possibly  on  this  account  his  monumental  work  "Die  krankhaften  Gesch- 
wulste"  was  never  extended  over  the  field  of  cancer. 

Remak  immediately  attacked  the  connective  tissue  theory  which  had 


HISTORICAL  23 

become  very  popular,  but  which  conflicted  with  the  significant  principle  of 
the  immutability  of  the  three  separate  germ  layers  which  he  with  His  had 
already  established.  Remak  insisted  that  epithelial  cells  could  arise  only 
from  epithelium.  The  appearance  of  such  cells  in  abnormal  places  he  referred 
to  the  misplacement  of  embryonal  cell  groups. 

Virchow's  authority,  however,  prevented  the  general  acceptance  of  Remak's 
views  for  many  years,  until  the  appearance  of  Thiersch's  famous  monograph 
on  epithelial  cancer. 

Although  many  authors  opposed  the  theory  of  the  connective  origin  of 
cancer,  and  Meckel  in  1857  had  traced  the  origin  of  a  buccal  tumor  directly 
from  the  lining  epithelium,  it  remained  for  Thiersch  to  present  convincing 
evidence  of  the  invariable  derivation  of  epithelioma  from  lining  epithelium. 
By  improvements  in  hardening,  cutting  and  staining  the  tissues  in  serial 
sections  he  traced  the  growth  of  several  epitheliomas  from  the  Malpighian 
layer  or  glandular  structures  of  the  skin  and  demonstrated  the  principle, 
omnis  cellula  e  cellula  ejusdem  generis.  He  also  placed  great  importance  upon 
previous  changes  in  the  epithelial  connective  tissue  as  precipitating  the  down- 
ward growth  of  epithelium. 

By  a  process  of  involution  associated  with  diminished  nutrition,  functional 
capacity,  and  mechanical  resistance  the  histogenetic  equilibrium  between 
stroma  and  epithelium  became  disturbed  and  overgrowth  of  epithelium 
resulted.  This  was  the  first  competent  physiological  conception  of  the  patho- 
genesis  of  cancer  and  with  it  Thiersch  introduced  the  modern  era  of  our  knowl- 
edge of  the  nature  of  the  disease.  Waldeyer  extended  Thiersch's  observa- 
tions to  the  internal  organs  and  traced  the  origin  of  cancer  of  stomach,  liver, 
and  kidney  to  the  epithelial  cells  of  these  organs.  He  first  described  the 
isolation  of  these  cells  by  indurated  connective  tissue  and  held  that  tkimors 
developed  from  these  isolated  cells.  The  formation  of  secondary  tumors 
he  demonstrated  to  be  the  result  of  continuous  growth  through  blood-  and 
lymph-vessels  as  well  as  of  cell  emboli. 

The  acceptance  of  the  epithelial  theory  was  briefly  delayed  by  the  studies 
of  Recklinghausen  and  Koster,  who  brought  forward  evidence  to  show  that 
many  cancers  arose  from  the  endothelium  of  lymph  spaces.  The  outcome 
of  this  controversy  was  the  establishment  of  the  group  of  endothelioma. 
That  true  cancer  has  no  connection  with  lymphatic  endothelium  was  shown 
by  Carmalt,  who  in  Waldeyer's  laboratory  shook  thin  sections  of  fresh  cancer 
in  silver  solution,'  thereby  removing  the  cancer-cells  from  the  lymph  spaces 
and  leaving  the  silvered  endothelium  intact.  Yet  Virchow's  influence  still 
predominated  and  led  to  the  assumption  that  cancer  developed  from  almost 
any  mesoblastic  cell,  as  from  sarcolemma  (Popper),  perimysium  (R.  Volk- 
mann),  cartilage  (Weber),  vessel  wall  (Gussenbauer),  and  leukocytes  (Classen, 
Rollett). 

Through  the  untiring  industry  of  himself  and  his  pupils  Waldeyer  slowly 
forced  the  acceptance  of  his  views  of  the  origin  of  cancer.  Billroth  slowly 
abandoned  much  of  his  early  allegiance  to  the  connective  tissue  doctrine. 
It  was  of  great  assistance  when  the  regeneration  of  epithelium  over  wounds 
was  shown  to  advance  from  the  edges  of  intact  skin.  By  the  minute  study 
of  a  large  number  of  cancers  of  many  varieties  Waldeyer  eventually  estab- 
lished the  principle  of  the  exclusive  epithelial  origin  of  cancer  and  of  its  growth 
from  its  own  resources,  and  demolished  the  former  belief  that  normal  tissues 
could  become  transformed  into  cancer. 

The  classification  of  tumors  upon  the  histogenetic  basis  was  accomplished 
with  the  data  furnished  by  the  studies  of  this  period.  The  theory  of  a  can- 
cerous dyscrasia  necessarily  lost  ground  with  the  demonstration  that  the 


24  NEOPLASTIC  DISEASES 

disease  has  a  local  origin  and  that  secondary  tumors  arise  from  transported 
cells.  Likewise  it  became  evident  that  the  parasitic  theory  which  had  enjoyed 
a  general  acceptation  must  be  set  aside  as  an  inadequate  explanation  of  the 
new  facts  of  tumor  origin  and  growth. 

Further  than  this  the  cellular  pathology  seemed  incapable  of  carrying 
progress  in  the  etiological  explanation  of  cancer.  Irritation,  trauma,  and 
infection  seemed  to  be  connected  with  the  origin  of  the  disease,  but  the  obscure 
nature  of  the  relation  of  any  of  these  factors  was  fully  recognized. 

The  last  decades  of  the  nineteenth  century  were  thus  occupied  with  the 
detailed  study  of  the  morphology  of  tumors,  the  separation  of  varieties  of  the 
disease,  the  elucidation  of  histogenesis,  and  the  writing  of  the  natural  history 
of  malignant  diseases.  The  twentieth  century  opens  as  the  experimental 
era  with  the  systematic  study  of  tumors  throughout  the  animal  kingdom, 
and  it  seems  likely  to  become  noteworthy  as  the  period  of  specific  etiological 
investigation  which  promises  to  widely  separate  many  neoplastic  diseases 
formerly  held  to  be  closely  related.  It  may  thereby  prove  to  be  the  era  of 
successful  therapeutics  and  prophylaxis. 


CHAPTER   II 

DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY 

Definition. — A  tumor  is  an  autonomous  new  growth  of  tissue. 

Among  most  authors  there  is  virtual  agreement  regarding  the  essential 
parts  of  the  definition  of  tumors,  v.  Rindfleisch  says  briefly:  "A  tumor  is 
a  localized  degenerative  excess  of  growth."  Ziegler  defines  a  tumor  as  a  new 
growth  of  tissue  which  apparently  originates  and  grows  spontaneously, 
possesses  an  atypical  structure,  does  not  subserve  the  uses  of  the  organism, 
and  reaches  no  definite  termination  of  its  growth.  According  to  Birch- 
Hirschfeld,  tumors  are  progressive  new  growths  of  tissue  arising  sponta- 
neously from  cells  of  its  own,  and  separated  from  normal  tissue  both  in  mor- 
phology and  in  function.  Ribbert  states  that  tumors  are  new  growths  of 
tissue,  self-centered,  largely  or  wholly  uncontrolled  by  the  organism  which 
supplies  only  their  nutrition,  with  a  structure  never  entirely  normal,  and 
reaching  no  definite  termination  of  growth. 

Lubarsch  includes  among  tumors  all  spontaneously  arising  tissue  growths 
which,  while  typical  in  form,  differ  in  histology  from  the  originating  tissue, 
and  in  spite  of  organic  connection  with  the  body  pursue  an  autonomous 
course  rarely  to  the  benefit  of  the  whole  body.  Borst  emphasizes  in  the  tumor 
process  the  unknown  etiology,  the  local  overgrowth,  the  peculiar  autonomy, 
the  purposeless  and  endless  course,  and  the  atypical  morphology  and  biology 
of  the  tumor  product.  Adami  accepts  White's  descriptive  definition:  "A 
tumor  proper  is  a  mass  of  cells,  tissues,  or  organs,  resembling  those  normally 
present  but  arranged  atypically.  It  grows  at  the  expense  of  the  organism 
without  at  the  same  time  subserving  any  useful  function." 

I  believe  with  Prudden  that  beyond  the  autonomy  of  tumor  growth  it 
is  difficult  to  add  any  element  to  our  definition  which  may  apply  to  all  true 
blastemas.  The  more  descriptive  definitions  are  doubtless  more  readily 
applied  but  with  increasing  knowledge  the  unknown  etiology,  progressive 
growth,  and  even  the  atypical  morphology,  may  become  less  significant, 
while  the  physiological  conception  of  autonomy  grows  more  substantial. 
Certain  obvious  features  of  tumor  growth  emphasize  the  importance  of  their 
autonomy. 

The  nature  of  tumor  growth  is  different  from  that  of  the  normal  tissues 
and  from  inflammatory  hyperplasia,  and  is  something  new  and  foreign  to  the 
organism  in  which  it  occurs. 

In  most  tumors  growth  is  progressive,  and  no  natural  termination  is  real- 
ized, the  tumor  growing  most  rapidly  at  the  death  of  the  patient.  Yet  the 
progressive  quality  is  not  invariable,  as  some  tumors  spontaneously  regress; 
others,  as  scirrhous  cancer,  long  remain  practically  quiescent,  and  others 
degenerate  or  necrose  or  become  extruded,  while  fibrosis  overtakes  a  few. 

The  growth  of  tumors  is  new  to  the  organism  in  that  it  is  usually  expansive, 
emanating  from  an  isolated  group  of  cells  and  pushing  contiguous  tissue 
before  it.  Such  tumors  are  more  or  less  encapsulated,  appearing  as  isolated 
or  parasitic  organoid  structures.  In  some  tumors  the  growth  is  infiltrative, 
single  cells  or  cell  groups  pushing  their  way  through  and  destroying  adjacent 
tissues.  In  many  tumors  growth  is  extensive,  beginning  in  a  small  focus  and 
gradually  precipitating  the  contiguous  normal  cells  into  the  tumor  process. 

25 


26  NEOPLASTIC  DISEASES 

Tumor-cells  acquire  new  and  greatly  increased  powers  of  growth  often 
exceeding  those  possessed  by  any  parallel  normal  tissue. 

Ribbert  claims  that  tumor-cells  do  not  reveal  any  abnormal  capacity 
for  growth  since  these  are  determined  in  the  ovum,  but  merely  exhibit  their 
innate  capacities  because  the  restraints  to  growth  have  been  lost.  It  is  true 
that  the  organized  regenerative  properties  of  tissue  cells  are  determined  in 
the  fertilized  ovum,  but  the  power  of  multiplication  without  organization  is 
subject  to  great  variations  from  the  environment,  and  observation  and  experi- 
ment show  that  tumor-cells  have  acquired  in  this  sense  abnormal  capacity 
for  proliferation.  The  growth  of  tumor-cells  is  peculiar  in  that  it  proceeds 
under  abnormal  conditions  when  the  cells  have  been  separated  from  their 
natural  connections,  and  even  when  they  are  transferred  to  other  animals  of 
the  same  species.  In  transplanted  tumors  the  cells  often  grow  with  increased 
activity,  when  normal  cells  rapidly  necrose  or  undergo  slow  regression,  or 
adjust  themselves  to  the  organization.  Thus  in  many  particulars  the  growth 
of  tumors  differs  from  the  organized  regeneration  of  normal  tissues. 

These  physiological  peculiarities  will  later  be  considered  in  detail. 

CLASSIFICATION  AND  NOMENCLATURE 

There  are  three  obvious  and  useful  plans  for  the  classification  of  tumors: 
histological,  regional,  and  etiological. 

1.  A  thorough  etiological  classification  of  tumors  cannot  with  our  present 
knowledge  be  accomplished  with  sufficient  detail  for  most  practical  purposes. 
Yet  many  useful  terms,  which  have  more  or  less  etiological  significance, 
are  employed  to  designate  tumors.     Most  tumors  are  post-natal  in  origin; 
many  are  congenital,  as  the  multiple  chondromas  of  the  spinal  column,  sarcoma 
of  the  kidney,  and  angioma  of  the  skin. 

There  are  some  notable  tumors  which  show  a  striking  hereditary  character, 
as  glioma  of  the  retina.  A  large  class  of  tumors  of  many  varieties  are  appar- 
ently of  traumatic  origin.  Partly  etiological  is  the  grouping  of  tumors  into 
adult  and  embryonal,  arising  from  adult  or  embryonal  cells  and  reproducing 
adult  or  embryonal  cells  and  structures. 

The  list  of  known  specific  causes  of  tumors  is  small  but  enlarging,  includ- 
ing the  cancers  of  pipe-smokers,  chimney-sweepers,  and  workers  in  paraffin, 
oj-ray  cancers,  Kangri  cancer  and  that  of  chewers  of  betelnut  among  Africans. 
Some  tumors  probably  result  from  exaggerated  response  to  functional  stimuli, 
as  the  thyroid  tumors  of  fish;  others  from  prolonged  mechanical,  chemical 
or  thermal  irritation;  some  are  closely  related  to  tuberculous,  syphilitic  and 
other  infectious  processes.  As  knowledge  advances  it  seems  probable  that 
a  much  wider  extension  of  etiological  classification  along  these  and  other 
lines  will  be  accomplished. 

2.  The  regional  classification  of  tumors  is  of  great  practical  utility,  but 
as  a  rule  it  only  deals  with  superficial  characters  of  neoplasms  and  usually 
resolves  itself  into  a  grouping  of  distinct  histological  varieties  occurring  in 
different  organs.     Yet  there  are  exceptions  to  the  rule.     Hypernephroma 
is  a  regional  term  referring  to  tumors  chiefly  of  the  head  of  the  kidney,  but 
including  several  histological  and  structural  types.    Multiple  myeloma  varies 
in  structure,  but  is  practically  the  sole  primary  tumor  of  bone-marrow.    Ter- 
atoma  of  the  testis  and  adamantinoma  of  the  maxillae  are  almost  the  only 
tumors  arising  in  these  regions  and  both  cover  such  a  wide  variety  of  struc- 
tures that  it  is  convenient  to  employ  regional  terms  to  designate  such  tumors. 
Moreover,  the  marked  peculiarities  in  the  origin  and  course  of  similar  his- 
tological tumors  in  different  organs  often  render  it  advisable  to  emphasize 


DEFINITION.     CLASSIFICATION.    GENERAL  PATHOLOGY  27 

the  organ  involved  rather  than  the  structure  of  the  tumors.  The  morphologist 
speaks  of  cancer  of  mamma,  larynx,  uterus,  etc.,  as  one  and  the  same  disease, 
while  the  clinician  properly  conceives  of  mammary  cancer,  laryngeal  cancer, 
uterine  cancer,  etc.,  as  quite  distinct  clinical  entities.  There  is  much  practical 
value  in  emphasizing  the  regional  point  of  view,  and  as  knowledge  advances 
it  may  well  prove  that  the  strictly  histological  grouping  of  many  tumors 
is  based  on  structural  resemblances  which  are  less  significant  than  are  now 
supposed. 

3.  The  histological  structure  of  tumors  offers  the  simplest  means  of 
classification. 

A  tumor  receives  a  name  and  position  according  to  the  tissue  which  it 
most  resembles.  Yet  this  plan  meets  difficulties  at  once  and  applies  readily 
only  to  simple  and  benign  tumors.  Many  malignant  tumors  do  not  resemble 
any  normal  tissue  and  terms  drawn  from  gross  pathology,  sarcoma  and  carci- 
noma, have  been  drafted  to  designate  the  microscopical  structure  of  the  two 
main  classes  of  tumors. 

Moreover,  to  name  a  tumor  according  to  its  microscopical  structure  often 
conveys  very  little  information  about  it. 

Tumor  nomenclature  aims  to  be  more  specific  and  there  is  a  constant 
tendency  to  replace  histological  with  histogenetic  terms  wherever  possible. 
The  main  classes  of  tumors  are  therefore  named  from  their  histology,  while 
the  specific  forms  are  designated,  if  possible,  by  their  histogenesis,  as  neuro- 
fibroma,  adenoma  sebaceum,  etc. 

Where  structure  varies,  histogenesis  dominates  the  nomenclature,  as 
with  adamantinoma,  hypernephroma,  etc. 

HISTOLOGICAL  CLASSIFICATION 
GROUP  I.— TYPE:  CONNECTIVE  TISSUE 

(a)  Fibroma,  composed  of  connective  tissue. 
(V)  Chondroma,  composed  of  cartilage. 

(c)  Chordoma,  composed  of  tissue  of  chorda  dorsalis. 

(d)  Osteoma,  composed  of  bone. 

(e)  Myxoma,  composed  of  mucous  tissue. 
(/")  Lipoma,  composed  of  fat  tissue. 

(g)  Angioma,  composed  of  blood-vessels. 
(Ji)  Lymphoma,  composed  of  lymphatic  tissue. 

(i)  Sarcoma,  a  cellular  tumor  composed  of  anaplastic  tissue  of  any  of 
the  above  types. 


GROUP  H.— TYPE:  MUSCLE  TISSUE.    MYOMA  AND  MYOSARCOMA 

(a)  Leiomyoma,  composed  of  smooth  muscle  tissue. 

(b)  Rhabdomyoma,  composed  of  striated  muscle. 

GROUP  m.— TYPE:  THE  ELEMENTS  OF  THE  NERVOUS  SYSTEM 

(a)  Neuroma,  composed  of  nerve-fibers. 

(ft)  Neuroma  ganglionare,  composed  of  nerve-fibers  and  ganglion  cells. 

(c)  Glioma,  composed  of  glia  tissue. 

(d)  Neuro-epithelioma,  composed  of  neuro-epithelium. 

GROUP  IV.— TYPE:  ENDOTHELIUM.    ENDOTHELIOMA 


28  NEOPLASTIC  DISEASES 

GROUP  V.— TYPE:  EPITHELIUM,  PAVEMENT  OR  GLANDULAR 

(a)  Papilloma,  a  tumor  of  pavement  epithelium,  with  supporting  tissues 
in  normal  arrangement. 

(6)  Adenoma,  a  benign  tumor  of  glandular  epithelium,  with  supporting 
tissue,  in  normal  arrangement. 

(c)  Epithelioma,  or  epidermoid  carcinoma,  epithelium  in   atypical   ar- 
rangement. 

(d)  Carcinoma,  a  tumor  of  glandular  epithelium  in  atypical  arrangement. 

GROUP  VI.— TYPE:  COMPLEX  TISSUES 

(a)  Simple  mixed  tumors,  composed  of  more  than  one  type  of  neoplastic  tis- 
sue— named  according  to  composition :  as  chondro-epithelioma,  adenosarcoma. 

(b)  Teratoma,  composed  of  tissues  and  organs  of  one,  two,  or  three 
germinal  layers,  as  monodermal,  bidermal,  or  tridermal  types. 

(c)  Embryoma,  composed  of  tissues  from  three  germinal  layers  in  more 
or  less  orderly  imitation  of  a  fetus. 

The  variable  structure  of  many  simple  tumors  requires  complex  terms 
for  the  accurate  designation  of  structure.  A  fibroma  with  many  neoplastic 
blood-vessels  is  called  an  angiofibroma,  while  a  tumor  chiefly  composed  of 
blood-bessels  with  much  new  connective  tissue  is  called  a  fibro-angioma. 

A  sarcomatous  quality  is  indicated  as  fibro-,  chondro-,  or  osteosarcoma. 
So  fibre-adenoma  and  adenofibroma  indicate  predominance  of  one  or  another 
structure.  Histioid  tumors  are  composed  of  a  simple  tissue,  organoid  growths 
reproduce  the  structure  of  organs.  Homologous  tumors  resemble  the  tissue 
in  which  they  arise,  as  adenoma  mammae;  heterologous  tumors  present  a 
structure  foreign  to  the  tissue  in  which  they  grow,  as  chondroma  mammae. 

A  strictly  embryologic  classification  of  tumors  presents  many  advantages  over  others, 
but  for  good  reasons  has  never  gained  general  adoption. 

The  early  segmenting  embryo  first  consists  of  a  mass  (morula,  blastula)  of  large  un- 
differentiated  cells  (blastomeres).  Soon  these  cells  form  two  distinct  layers,  epiblast  and 
hypoblast,  both  of  which  have  the  characters  of  lining  membranes,  the  pavement  qual- 
ity being  more  marked  in  the  former.  Next  the  hypoblast  gives  rise  to  a  group  of  cells 
forming  the  mesoblast  and  lying  intermediate  between  the  other  two  layers.  The  meso- 
blast  cells  lose  their  pavement  qualities  and  appear  in  an  undifferentiated  cell  mass, 
but,  later,  certain  of  its  cells  grow  out  between  the  epiblast  and  hypoblast  in  modified 
pavement  form  and  enclose  the  body  cavity  (ccelom).  Thus  the  mesoblast  comes  to 
possess  a  lining  portion,  mesothelium,  and  a  pulp  portion,  mesenchyme. 

The  coelom  with  its  mesothelial  lining  eventually  becomes  the  pleura,  pericardium 
and  peritoneum.  From  a  portion  of  the  mesothelium  is  also  developed  the  parent 
tissue  of  the  striated  muscles,  and  later  modified  mesoblastic  cells  form  the  lining  cells 
of  the  blood  and  lymphatic  vessels.  Thus  the  lining  cells  of  the  great  serous  cavities, 
and  the  vessels,  and  the  striated  muscles,  are  derived  from  mesoblastic  cells  which  have 
at  one  time  lost  their  pavement  quality  while  merged  in  the  mesoblast. 

At  the  same  period  with  these  changes,  the  epiblast  proliferates  in  the  region  of  the 
primitive  groove  and  forces  inward  a  mass  of  cells,  which  become  isolated  and  modified, 
going  to  form  the  central  nervous  system.  Coincidently,  a  portion  of  hypoblast  retain- 
ing some  of  its  pavement  qualities  arises  to  form  the  notochord. 

Adami  points  out  that  these  early  embryological  processes  lead  to  the  development 
of  two  main  classes  of  tissue  which  permanently  retain  their  early  characters,  viz. : 
lining  membrane  tissues  and  pulp  tissues,  and  which  he  proposes  to  call  lepidic  (XeTrtj, 
membrane)  and  hylic  (11X17,  crude  matter).  Lepidic  tissues  are  composed  of  groups  of 
specific  cells  which  are  not  penetrated  by  blood-vessels  and  possess  no  intercellular 
stroma.  The  epiblast  and  hypoblast  are  primary,  the  mesothelium  and  endothelium 
are  secondary  lepidic  tissues.  Hylic  or  pulp  tissues  of  which  the  mesenchyme  is  the 
type,  are  composed  of  cells  separated  by  a  homogeneous  fibrillar  stroma  which  may  or 
may  not  be  penetrated  by  vessels. 

Upon  this  basis  Adami  has  divided  the  blastemas  into  two  main  groups:  Lepidoma 
and  Hyloma. 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY  29 

I.  LEPIDOMATA 

A.  Primary,     (i)  Epilepidomata,  typical  (papilloma  and  adenoma),  and  atypical 
(carcinoma),  all  from  epiblast.     (2)   Hypolepidomata,  typical  (adenoma)  and  atypical, 
(carcinoma)  all  from  hypoblast. 

B.  Secondary.    (3)  Mesolepidomata,  typical  (adenoma  of  kidney,  etc.)  and  atypical 
carcinoma  of  kidney,  etc.),  all  from  mesothelium.     (4)  Endothelial  lepidomata. 

II.  HYLOMATA,  OR  PULP  TUMORS 

1.  Epihylomata,  typical  (neuroma,  glioma)  and  atypical  (gliosarcoma). 

2.  Hypohylomata,  chordoma. 

3.  Mesohylomata,  typical  (fibroma,  lipoma,  etc.)  and  atypical  (sarcoma)  from  mesen- 
chymal  tissues.     Mesothelial  hylomata  or  rhabdomyomata. 

There  is  no  doubt  that  in  the  above  scheme  Adami  has  accomplished  a  successful 
classification  and  legitimate  nomenclature  for  tissues  and  tumors,  based  upon  accredited 
data.  In  several  directions  this  classification  is  of  value  in  the  interpretation  of  many 
peculiarities  of  tumor  growth.  Thus  the  essential  distinctions  between  lepidic  or  pave- 
ment tissues  and  hylic  or  pulp  tissues  established  in  the  early  embryo  have  a  strong 
influence  upon  tumors  derived  from  these  tissues.  The  degrees  and  types  of  the  pave- 
ment quality  observed  in  embryonal  epiblast,  hypoblast,  and  mesothelium  reappear  in 
much  of  the  history  of  tumors  derived  from  such  tissues,  especially  the  mesenchymal 
relations  of  endothelium.  To  a  less  extent,  I  think,  the  reversionary  tendencies  of  tumor- 
cells  show  the  influence  of  embryological  relations. 

Yet  there  appear  to  me  to  be  two  main  objections  to  the  adoption  of  this  most  suc- 
cessful embryological  classification  and  nomenclature: 

First,  the  behavior  of  tumor-cells  is  very  much  more  influenced  by  the  acquired  char- 
acters of  the  cells  of  origin  than  by  their  embryological  derivation. 

Second,  the  neoplastic  process  does  not  consist  in  retracing  the  steps  of  embryological 
development,  but  probably  in  a  progressive  loss  of  original  cell  potencies,  so  that  the 
cells  become  a  prey  to  all  manner  of  new  external  conditions  which  control  their  nutri- 
tion, greatly  influence  their  form  and  render  them  significant  chiefly  as  pathological 
parasitic  cells  and  tissues. 

Embryology  has  been  of  great  value  in  clearing  up  many  of  the  disturbances  of  de- 
velopment, which  lead  to  the  growth  of  heterologous  tumors  and  teratomas,  it  aids  in 
the  interpretation  of  many  phenomena  of  tumor  growth,  especially  of  teratomas,  and 
will  likely  be  of  further  aid  in  this  field,  but  with  the  main  element  in  the  neoplastic 
process,  anaplasia,  it  has  nothing  to  do. 

Oncology  is  not  a  department  of  embryology,  but  a  separate  chapter  in  the  biology 
of  the  cell.  Hence  strictly  embryological  classification  and  nomenclature  have  never 
gained  great  favor,  because  they  do  not  serve  the  largest  needs  of  the  student  of  tumors. 
The  generally  accepted  plan  of  classification  and  terminology  which  is  based  on  his- 
tology, modified  as  much  as  possible  by  histogenesis,  is  a  natural  product  which  has 
become  very  firmly  established  and  probably  deserves  to  prevail  against  the  varying 
prominence  of  embryology,  chemistry,  and  etiology. 

GENERAL  MORPHOLOGY  OF  TUMORS 

The  external  appearances  of  tumors  present  extremely  wide  variations 
far  exceeding  those  of  normal  structures.  Yet  these  gross  features  are  as  a 
rule  distinctive,  so  that  the  recognition  of  a  tumor  may  usually  be  made 
by  inspection  and  palpation  of  the  tissue. 

The  terms  "sarcoma"  and  "carcinoma"  refer  to  the  exuberant  fleshy  char- 
acter of  connective  tissue  growths  and  the  rough  similarity  of  cancer  to  the 
crab. 

The  local  circumscription  of  many  tumors  is  a  sufficient  gross  sign  of 
many  blastemas,  but  fails  to  separate  miliary  or  nodular  granulomas  from 
many  forms  of  multiple  tumors.  There  are  some  cases  of  diffuse  carcinoma, 
as  of  the  breast,  or  carcinosis,  as  of  the  meninges,  in  which  no  visible  tumor 
is  produced,  and  only  a  minute  attention  to  color,  consistence,  and  distribu- 
tion saves  the  gross  diagnostician  from  error. 

The  color  of  tumor  tissue  is  often  distinctive. 

The  normal  color  of  tissues  is  almost  invariably  altered,  becoming  opaque, 
lighter  and  often  with  a  tinge  of  yellow  or  white,  where  groups  of  cancer-cells 


30  NEOPLASTIC  DISEASES 

are  growing.  Virchow  used  to  emphasize  three  zones  in  a  cancer  nodule,  a 
central  light  or  yellowish  area  of  degeneration  or  cicatrization,  a  middle, 
firm,  opaque,  cellular  zone,  and  a  peripheral  reddish  area  of  congestive  re- 
action. The  congestion  which  marks  the  advance  of  many  cancers  in  the 
skin  may  simulate  a  bacterial  process. 

Blood  content  and  hemorrhage  chiefly  determine  the  color  of  most  tumors 
as  of  other  tissues.  Most  cancers  are  comparatively  bloodless  while  sarcomas 
are  usually  more  vascular  and  often  contain  extravasated  blood.  Angiomas 
and  angiosarcomas  can  usually  be  recognized  in  the  gross  from  the  congeries 
of  blood-vessels  composing  them.  Some  sarcomas  of  bone  are  traversed  by 
wide  blood  sinuses  surrounded  by  little  tumor  tissue,  and  deserve  the  name 
of  bone  aneurism.  Multiple  hemorrhagic  sarcoma  of  the  skin  (Kaposi)  is 
marked  by  frequent  hemorrhages  and  pigmentation.  Certain  types  of  car- 
cinoma, as  chorioma,  and  teratoid  cancer  of  the  testis  usually  produce  notably 
hemorrhagic  tumors. 

The  fungus  hematodes  of  older  writers  is  a  cauliflower-like  growth  rich 
in  blood  sinuses.  Hemorrhagic  infarction  may  overtake  many  tumors  caus- 
ing them  to  assume  a  very  dark  red  or  rusty  color.  Secondary  pigmentation 
of  large  portions  of  tumors  may  result  from  altered  extravasated  blood.  Car- 
cinoma of  the  breast  in  dogs  is  nearly  always  pigmented  from  this  source. 

Melanoma  of  the  skin  and  choroid  is  a  brown  or  black  tumor  containing 
autochthonous  pigment,  but  in  rapidly  growing  metastases  it  may  progres- 
sively lose  its  pigment.  The  greenish  yellow  color  of  chloroma  is  a  distinctive 
feature  possibly  caused  by  lipochromes. 

A  pearl  gray  color  is  seen  in  chondroma,  myxoma,  and  some  scirrhous 
cancers.  Hypernephroma,  except  in  its  highly  embryonal  types  and  in  rapidly 
growing  metastases,  has  an  ochre  yellow  tint. 

The  consistence  yields  significant  indications  of  the  nature  of  many 
tumors.  Osteoma  and  chondroma  reveal  themselves  at  once  by  stony  hard- 
ness, but  hard  fibroma  may  simulate  chondroma. 

The  peculiar  density  of  many  carcinomatous  nodules  in  the  breast  and 
of  the  bases  and  borders  of  carcinomatous  ulcers  is  their  chief  diagnostic 
feature.  There  are  few  organs  in  which  the  density  of  carcinoma  is  equaled 
by  any  other  process,  but  gumma  of  the  testis  is  usually  firmer  than  the  em- 
bryonal cancer  of  this  organ. 

Many  tumors  are  softened  by  edema,  hemorrhage,  necrosis,  mucous 
degeneration  and  cyst  formation,  and  some  become  very  hard  from  fibrosis 
or  calcification.  In  each  organ  carcinoma  is  usually  firmer  than  adenoma 
and  sarcoma,  which  have  less  fibrous  tissue  and  more  vessels.  Rapidly  grow- 
ing and  embryonal  cancers  fail  to  show  the  density  of  older  types,  and  from 
this  and  other  characters  are  difficult  to  distinguish  in  the  gross  from  sarcoma. 
The  soft  elasticity  of  lipoma  and  especially  of  myxoma  and  colloid  tumors 
is  somewhat  characteristic.  Glioma  is  usually  softer  and  more  vascular  than 
adjacent  brain  tissue. 

Cystic  tumors  are  tense,  but  yielding  or  fluctuating.  Angiomas  may 
be  compressible.  Lymphosarcoma  is  rather  less  firm  than  Hodgkin's 
granuloma,  leukemia,  or  slow  tuberculosis  of  lymph-nodes. 

Mucous  carcinoma  of  peritoneum  produces  jelly-like  infiltration  or  huge 
intraperitpneal  masses,  and  endothelioma  of  pleura  may  yield  peculiar  dry 
crumbly  material.  The  "sand  tumors"  of  the  dura  (endothelioma)  and 
ovary  (adenoma)  are  easily  recognized  on  palpation,  and  the  waxy  plates 
of  cholesteatoma  and  sebaceous  contents  of  dermoids  are  equally  characteristic. 

The  texture  and  markings  revealed  by  inspection  of  the  surface  and 
section  of  tumors  often  disclose  their  true  nature. 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY  31 

The  firm  translucent  surface  of  a  fibroma,  the  glistening  homogeneous 
luster  of  a  chondroma,  the  intertwined  fascicles  of  muscle  fibers  in  a  myoma, 
and  the  branching  twigs  of  a  papillary  tumor,  are  readily  recognizable  naked- 
eye  features.  Likewise  the  jelly-like  material  in  myxoma  and  colloid  cancer, 
the  whorls  of  many  endotheliomas  of  the  dura,  the  vascular  twigs  of  angio- 
sarcoma,  and  the  lobules  of  fat  tissue  in  lipoma  furnish  a  ready  basis  for  gross 
diagnosis. 

In  dealing  with  cellular  tumors  there  are  many  criteria  which  lead  one 
to  a  correct  conclusion. 

Very  cellular  tumors  without  much  stroma  are  invariably  soft  and  fragile 
or  pultaceous  (encephaloid).  Soft  but  coherent  tumor  masses  usually  show 
abundant  stroma.  Cellular  tumors  whether  sarcoma  or  carcinoma  are  usually 
lighter  colored  and  more  opaque  than  the  surrounding  normal  tissues.  As 
a  rule,  sarcomas  are  more  uniform  in  texture  than  carcinomas.  The  former 
may  produce  wide  areas  of  new  tissue  unbroken  by  bands  of  connective  or 
areas  of  necrosis  although  frequently  interrupted  by  hemorrhages.  The 
latter  exhibit  the  tendency  of  carcinoma  to  excite  the  growth  of  connective 
tissue  and  to  undergo  focal  fatty  degeneration  which  produce  points  and 
masses  of  yellowish  or  whitish  material.  The  necrosis  of  sarcoma  is  usually 
more  massive. 

Vertical  section  through  an  acanthoma  shows  compact  columnar  masses 
or  whorls  of  cells,  of  pearly  white  luster  which  even  when  infiltrating  are  well 
banked  against  the  surrounding  tissue.  Early  ulceration  is  also  character- 
istic of  this  common  tumor,  but  it  rarely  produces  bulky  masses,  either 
primary  or  secondary. 

There  are  peculiar  forms  of  carcinoma,  as  in  the  pylorus  and  rectum, 
marked  by  mucous  degeneration  and  fibrosis,  which  are  sometimes  more 
safely  identified  in  the  gross  than  by  the  microscope.  They  produce  annular 
constrictions,  or  wide  infiltrations  of  the  submucosa,  but  most  of  the  cells 
may  be  lost  by  mucous  degeneration. 

By  naked  eye  inspection  one  can  frequently  recognize  the  main  characters 
of  tumor  structure  many  of  which,  from  too  exclusive  reliance  on  the  micro- 
scope, have  come  to  possess  chiefly  a  histological  significance. 

The  growth  of  a  tumor  may  be  mainly  central  so  that  it  displaces  the 
surrounding  tissue  by  lateral  pressure,  as  in  myoma  uteri. 

Central  growth  is  well  shown  in  some  angiosarcomas  in  which  actively 
growing  blood-vessels  sheathed  with  tumor-cells  compose  the  central  por- 
tions, while  in  the  periphery  the  growth  is  solid  and  grades  into  a  firm  fibrous 
capsule.  Or  the  growth  may  be  peripheral,  in  which  case  the  central  portions 
are  apt  to  be  fibrosed  or  degenerated  and  depressed. 

Infiltratwe  growth  is  revealed  by  lack  of  capsule  or  other  demarcation 
and  by  opaque  cords  of  tumor-cells  stretching  out  into  the  lymph  spaces 
or  vessels.  Extensive  intravascular  growth  characterizes  hypernephroma, 
adenoma  of  liver,  and  chorioma.  Polypoid,  papillary  and  dendritic,  and 
cystic  architectures  reveal  themselves  best  to  the  naked  eye,  while  more 
minute  structures  designated  as  fascicular,  plexiform,  and  alveolar  can  usually 
be  detected  by  careful  inspection. 

Soft  cellular  tumors  are  often  called  medullary,  or  encephaloid,  from 
resemblance  to  brain  tissue,  to  which  the  counterpart  is  the  hard  scirrhus. 

Thrombosis  of  blood-vessels,  edema,  fatty,  hyaline,  mucoid  and  colloid 
degeneration,  calcification  and  ossification,  are  all  encountered  in  extreme 
degrees  in  the  gross  anatomy  of  tumors. 

Cysts  of  varying  origin,  form,  and  content  are  notable  gross  features  of 
rrjany  tumors. 


32 


NEOPLASTIC  DISEASES 


Retention  cysts  filled  with  retained  secretion  develop  in  many  adenomas 
especially  of  the  ovary,  some  of  which  are  the  largest  tumors  ever  observed. 
Originating  in  a  closed  group  of  alveoli  whose  secreting  function  is  active 
dilatation  of  alveoli  is  accompanied  by  complex  systems  of  papillary  in- 
growths which  constantly  add  their  quota  of  secretion.  Eventually  inflam- 
matory exudate  and  hemorrhage  are  added  with  rapid  increase  in  volume. 
The  contents  of  such  cysts  are  therefore  serous  fluid  with  much  nucleo-albumin 
and  mucus,  or  with  pus  and  disintegrated  chocolate  colored  blood.  The 
walls  are  lined  with  varying  quantities  of  papillary  tumor  growth. 

Liquefaction  cysts  with  smooth  walls  form  in  fibromyomas,  sarcomas,  etc., 
from  local  edema,  necrosis,  and  autolysis  of  solid  elements.  Their  contents 


m 


FIG.   i. — Fibrosing  epidermoid  carcinoma.     Spindle-shaped  tumor-cells.     Illustrating 

infiltrative  growth. 

are  thin  and  serous  or  mingled  with  granular  or  fatty  detritus,  blood  or  pus; 
or  the  fluids  are  removed  by  absorption.  Extravasation  cysts  form  after 
hemorrhages  and  exhibit  all  stages  of  alteration  and  absorption  of  blood. 
Dilated  lymph-  or  blood-vessels  contribute  to  the  structure  of  some  cystic 
sarcomas  of  bone  and  other  tissues.  Cystosarcoma  phylloides  is  an  old  term 
sometimes  applied  to  tumors  showing  a  branching  system  of  more  or  less 
parallel  cysts  recalling  the  veins  of  a  leaf. 

It  is  often  difficult  to  distinguish  between  true  cystic  blastemas  and  simple 
cysts  with  inflammatory  overgrowth  of  lining  cells. 

In  most^  simple  retention  cysts  there  is  a  tendency  for  the  epithelium 
to  grow  up  into  papillary  projections,  as  in  chronic  mastitis,  and  with  several 
forms  of  encysted  animal  parasites.  Such  inflammatory  overgrowth  may 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY  33 

reach  a  considerable  grade,  but  usually  lacks  the  distinctive  morphology 
of  a  tumor,  and  regresses  when  the  cyst  is  evacuated.  Yet  some  of  them  may 
go  on  to  produce  genuine  neoplasms. 

Ulceration  overtakes  most  tumors  of  the  skin  and  mucous  membranes. 
The  inadequacy  and  fragility  of  blood-vessels,  degeneration  and  autolysis 
of  tumor-cells,  trauma,  mechanical  pressure  and  tension,  contact  with  irri- 
tants causing  inflammation,  and  bacterial  infection,  are  the  chief  factors  in 
its  origin. 

In  ulcerating  acanthoma  the  base  is  formed  of  dense  eroded  tumor  tissue; 
the  secretion  is  scanty  or  abundant  pus,  serum  and  opaque  particles  of  tumor- 
cells;  the  edges  are  raised,  very  hard,  in  mucous  membranes  often  under- 
mined, rounded,  irregular,  or  serpiginous;  and  the  vicinity  is  indurated  and 
inflamed  according  to  the  extent  of  infiltration  and  infection.  Erosion  of 
bone  and  cartilage  with  pain,  and  of  blood-vessels  with  hemorrhage  may 
occur,  and  perforation  into  adjoining  hollow  viscera.  Considerable  masses 


FIG.  2. — Fungating  carcinoma  of  neck.     A  recurrence  from  the  lip. 

may  slough,  and  new  skin  or  mucous  membrane  may  replace  portions  of  the 
ulcer.  Extensive  tracts  of  suppuration  may  follow  invasion  of  cellular  tissues. 

In  adenocarcinoma  of  mucous  membranes  thrombosis  and  infection  com- 
monly leads  to  the  formation  of  large  sloughing  excoriated  ulcers  with  much 
hemorrhage.  Flat,  indurated,  annular  ulcers  with  extensive  infiltration  of 
the  vicinity  and  construction  of  the  lumen  form  in  carcinoma  of  the  rectum. 
Necrosis  of  large  portions  of  the  tumor  together  with  the  distended  overlying 
skin  in  carcinoma  of  the  breast  and  other  cancers  produces  extensive  ulcers 
hi  which  the  sloughing  tumor  may  protrude  or  suffer  deep  excavation.  In 
sarcoma,  ulceration  is  usually  marked  by  massive  necrosis  and  hemorrhage. 

The  onset  of  ulceration  frequently  transforms  a  comparatively  harmless 
tumor  into  a  rapidly  fatal  process  through  local  or  general  infection,  suppura- 
tion, absorption  of  toxic  products  and  hemorrhage,  to  which  chiefly  must 
be  attributed  the  cachexia  of  cancer. 

In  general  it  may  be  said  that  the  outward  morphology  of  tumors  con- 
3 


34 


NEOPLASTIC  DISEASES 


stitutes  an  important  and  very  practical  chapter  in  their  study  since  it  not 
only  reveals  the  general  architecture  of  neoplasms,  but  allows  their  separa- 
tion in  most  cases  from  other  processes,  and  usually  permits  an  accurate 
diagnosis  of  their  histological  structure. 

HISTOPATHOLOGY 

The  study  of  tumor  growth  must  begin  with  its  earliest  stages. 

In  one  large  group  this  study  leads  to  the  scrutiny  of  misplaced  and 
chiefly  embryonal  cells,  or  even  to  the  consideration  of  single  cells,  giving 
rise  to  the  large  group  of  tumors  to  which  Cohnheim's  theory  applies.  In 
another  equally  important  class  the  initial  changes  affect  cells  which  so  far 


FIG.  3. 


Precancerous  changes  in  breast.    Atypical  epithelial  proliferation  in  ducts  and 
acini  found  in  a  small  portion  of  the  breast. 


as  we  know  are  normal  and  here  a  series  of  preliminary  changes  occurs,  be- 
longing to  the  so-called  precancerous  stage,  which  is  of  importance  in  the 
origin  and  growth  of  tumors. 

Precancerous  Stage  of  Tumor  Growth.  —  Processes  occasionally  followed 
by  neoplastic  growth  are  observed  in  syphilitic  leukoplakia,  tuberculosis, 
Hodgkin's  granuloma,  chronic  eczema,  chronic  mastitis,  ulcer  of  the  stomach, 
cirrhosis  of  liver,  tf-ray  dermatitis,  and  the  chronic  processes  associated  with 
mechanical,  chemical  and  thermal  irritation. 

It  is  impossible  to  analyze  all  the  factors  acting  in  such  processes.  Upon 
their  interpretation  have  been  built  many  theories  of  the  nature  of  tumor 
growth.  Yet  it  is  possible  to  enumerate  several  very  constant  morphological 
changes  which  in  certain  combinations  seem  to  be  most  effective  in  exciting 
the  subsequent  autonomous  growth. 


DEFINITION.     CLASSIFICATION.    GENERAL  PATHOLOGY 


35 


In  a  study  of  precancerous  changes  in  several  situations  Bonney  finds 
constant  loss  of  elastic  tissue,  and  usually  hyaline  changes  in  the  collagen, 
lymphocytic  exudate,  and  fraying  of  the  edges  of  the  epithelium. 

In  multiple  epithelioma  of  the  skin  Janeway  has  observed  that  the  tumors 
are  often  preceded  by  a  period  of  local  erythema  which  may  slowly  disappear 
or  be  followed  by  cancer.  Sections  of  the  skin  show  focal  dilatation  of  the 
blood  capillaries  adjacent  to  the  basal  epithelium  about  which  the  epithe- 
lium is  hypertrophied,  hyperplastic,  and  with  hyperchromatic  nuclei. 

In  leukoplakia,  hyperkeratosis,  thickening  of  the  Malpighian  layer,  hyper- 
trophy of  the  epithelium,  round-cell  infiltration,  increased  vascularity  and 
edema  long  precede  epithelioma  of  the  tongue. 

In  ulcer  of  the  stomach  disordered  gland  alveoli  are  drawn  into  new  cellu- 
ar  connective  tissue,  detached  from  their  normal  relations,  pass  through 


FIG.  4. — Atypical  epithelial  hyperplasia  on  edge  of  a  beginnnig  carcinoma  of  skin. 

stages  of  proliferation,  hypertrophy  of  cells  and  nuclei,  and  gradually  or 
suddenly  assume  neoplastic  characters.  Here,  as  in  cancer  following  cir- 
rhosis of  the  liver,  it  is  sometimes  difficult  to  determine  just  when  a  true 
neoplastic  process  exists. 

In  chronic  mastitis  single  small  cancer  nodules  may  appear  and  I  believe 
their  preliminary  stages  may  be  traced  in  other  portions  of  the  breast,  chiefly 
in  the  ducts.  Here  one  finds  hyperplasia  of  lining  cells  with  hypertrophy 
and  increased  eosin  stain,  cyst  formation  and  papillary  outgrowths  into  them, 
in  which  condition  they  seem  usually  to  be  diverted  from  further  dangerous 
tendencies.  Yet  other  cells  show  more  active  proliferation,  increase  in  size 
and  in  nuclear  chromatin;  their  polarity  is  lost  by  growth  of  round-cells  and 
connective  tissue,  and  it  is  possible  to  trace  such  cells  into  types  closely 
approaching  those  seen  in  early  carcinoma. 


36  NEOPLASTIC  DISEASES 

It  may  be  true,  as  Ribbert  asserts,  that  no  one  has  ever  seen  the  beginning 
of  cancer  of  the  breast,  but  the  changes  just  enumerated  seem  to  form  a  com- 
mon preliminary  to  the  onset  of  true  cancer,  which  on  such  a  basis  develops 
rapidly  and  is  accompanied  as  a  rule  with  fatty  degeneration  in  the  affected 
cells. 

In  rare  cases  of  Hodgkin's  granuloma  the  proliferation  of  large  mono- 
nuclear  cells  and  of  giant-cells,  originally  of  inflammatory  origin,  takes  on 
more  autonomous  and  sarcomatoid  qualities.  The  cells  become  more  numer- 
ous, the  stroma  less,  the  nuclei  larger,  mitoses  more  abundant,  metatases 
composed  of  large  round-cells  without  stroma  occur,  and  the  process  has 
many  of  the  qualities  of  a  blastema.  Yet  the  true  neoplastic  properties  of 
these  cases  must  be  doubted,  although  they  exhibit  a  certain  progress  toward 
a  genuine  autonomous  new  growth. 

The  abnormal  physiology  associated  with  the  precancerous  state  will  be 
discussed  under  General  Etiology. 

Beginning  thus  either  in  isolated  embryonal  cell  groups  or  in  tissues  long 
subjected  to  the  influences  of  the  precancerous  stage,  tumors  grow,  always 
chiefly,  sometimes  exclusively,  from  their  own  resources,  i.  e.,  from  the  original 
cells  involved  in  the  process. 

Modes  of  Origin. — Four  modes  of  the  origin  and  extension  of  tumors  may 
be  discerned: 

1.  Growth  is  unicentric  and  exclusively  from  the  original  cell  group  in- 
volved in  the  tumor  process.     In  the  large  class  of  blastomas  arising  from 
embryonal  cell  groups,  the  originating  cells  are  isolated  from  the  first,  and 
the  tumor-cells  remain  isolated  during  their  entire  history.     Thus  hyper- 
nephroma  may  begin  in  a  small  group  of  cells  misplaced  in  the  renal  cortex, 
produce  a  large  tumor  of  the  kidney,  invade  the  renal  vein   and  produce 
metastases  in  many  organs,  the  cells  in  all  situations  being  the  direct  descend- 
ants of  those  composing  the  original  cell  complex. 

2.  Multicentric  growth  is  observed  in  many  tumors.     In  multiple  epithe- 
lioma  of  the  skin,  x-ray  cancers,  cancers  of  the  gastro-intestinal  tract  follow- 
ing multiple  polypi,  fibrosarcoma  of  nerve  trunks,  and  others,  several  centers 
originating  tumor-cells  appear  simultaneously  or  at  intervals.    These  centers 
may  gradually  coalesce,  producing  one  large  tumor  area,  or  they  may  long 
remain  discrete. 

Petersen  by  reconstruction  in  wax  has  shown  that  certain  cancers  of  the 
breast  arise  from  several  discrete  centers  of  proliferation,  and  a  similar  multiple 
origin  in  an  adrenal  tumor  is  described  by  Woolley;  and  for  carcinomatosis 
of  the  liver,  by  Von  Heukelom  and  Oertel. 

A  remarkable  case  of  multiple  angiosarcoma  or  endothelioma,  involving 
nearly  the  entire  skeleton,  is  described  by  Marckwald. 

Of  such  cases  some  must  be  referred  to  the  wide  diffusion  of  the  inciting 
factors,  as  in  x-ray  cancers;  others  to  multiple  foci  of  embryonal  displaced  or 
superfluous  cells  as  Hauser  would  explain  the  multiple  cancers  of  the  intes- 
tine; while  the  conditions  in  a  few  cases  suggest  some  complex  influence  of 
an  existing  tumor  upon  neighboring  cell  groups  predisposed  to  tumor  growth. 

Multiple  tumors  of  the  same  type  in  paired  organs  is  a  special  case  of 
multicentric  growth.  Carcinoma  arises  in  both  breasts,  teratoma  in  both 
ovaries,  lymphosarcoma  in  both  testes.  In  each  such  case  different  influ- 
ences seem  to  be  concerned,  but  in  all  the  influence  both  of  local  and  of  con- 
stitutional factors  is  suggested. 

The  occurrence  of  multiple  tumors  of  different  types  in  the  same  organ 
or  in  different  organs  of  the  same  subject  is  also  observed. 

In  some  instances  a  second  tumor  may  result  from  conditions  brought 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY  37 

about  by  the  presence  of  the  first,  as  when  a  submucous  fibromyoma  causes 
ulceration  followed  by  cancer  of  the  uterine  mucosa. 

Tumors  have  been  observed  simultaneously  in  the  uterus,  ovaries,  and 
breast,  a  combination  suggesting  the  influence  of  the  functional  relation 
existing  between  these  organs.  The  rather  common  occurrence  of  two  or 
more  tumors  in  different  organs  of  the  same  subject  suggests  nothing  more 
than  the  accidental  coincidence  in  several  organs  of  the  general  etiological 
factors  in  the  genesis  of  tumors. 

Many  cases  illustrating  several  groups  of  multiple  tumors  have  been 
collected  by  Walter  and  Woolley.  Among  1000  autopsies  on  tumor  cases 
Hansemann  found  5  with  multiple  primary  growths,  and  in  1225  cases 
collected  by  Redlich  14  showed  more  than  one  primary  tumor.  When  a 
minute  search  is  carefully  conducted  and  all  forms  of  tumor  growth  included, 
the  proportion  of  multiple  tumors  is  much  greater. 

Symmers  in  215  autopsies  found  tumors  in  55,  in  22  of  which  more  than 
one  type  existed.  .  Getting  observed  3  cancers  of  different  organs,  several 
adenomas  of  bile-ducts,  and  an  angioma  of  liver,  in  a  man  of  58  years. 

3.  The  question  whether  a  tumor  process  may  gradually  extend  from  an 
originating  focus  over  the  surrounding  normal  cells  cannot  at  present  be 
determined.  Such  a  possibility  is  commonly  denied.  Borst  argues  that 
it  is  impossible  to  conceive  how  such  an  influence  can  be  transferred  from 
one  cell  to  another.  Ribbert,  after  strongly  opposing  the  idea  of  transference 
of  the  tumor  tendency  from  a  tumor-cell  to  normal  cells,  admits  that  there 
may  be  wide-spread  multiple  foci  of  origin  which  exhibit  neoplastic  growth 
one  after  the  other,  thus  simulating  the  lateral  diffusion  of  the  tumor  process. 
Unless  one  assumes,  as  White  actually  does,  that  tumors  develop  from  single 
cells,  it  is  necessary  to  assume  some  such  gradual  implication  of  the  several 
cells  in  the  originating  group,  so  that  Ribbert  has  practically  admitted  the 
gradual  extension  of  a  tumor  by  progressive  involvement  of  normal  cells, 
not  by  transfer  of  influence  from  one  cell  to  another,  yet  by.  the  effects  of 
underlying  factors  upon  one  cell  after  another.  It  is  not  necessary  to  attribute 
this  influence  to  the  mere  contact  of  tumor-cells  or  to  suppose  that  it  involves 
a  parasite. 

Increased  vascularity,  mechanical  displacement,  disordered  function, 
chemical  stimuli,  and  toxic  agents  may  all  be  included  among  the  factors 
resulting  from  the  presence  of  tumor-cells.  There  is  also  a  certain  complex 
tropism  observed  in  the  growth  of  tissues  in  lower  animals,  whereby  processes 
at  work  in  one  tissue  induce  similar  tendencies  in  contiguous  cells.  There 
appears  to  be  adequate  theoretical  basis  for  the  extension  of  a  tumor  process 
over  normal  cells,  and  observation  indicates  that  in  some  cases  such  extension 
actually  occurs. 

First,  in  the  neighborhood  of  many  epithelial  tumors  the  contiguous 
cells  show  a  peculiar  increase  in  number,  size,  and  chromatin  content. 

This  collateral  hypertrophy  is  more  common  about  primary  tumors,  but 
may  be  seen  in  metastases.  Usually  it  does  not  reach  a  neoplastic  grade, 
but  it  is  sometimes  difficult  to  distinguish  from  an  advance  of  the  tumor. 

In  adenoma  of  the  sigmoid  such  transformations  may  occur,  the  outlying 
cells  first  increasing  in  size,  then  becoming  opaque  and  granular,  while  the 
nuclei  become  hyperchromatic.  Some  extensive  superficial  adenomas  of  the 
sigmoid  appear  to  have  developed  in  this  manner. 

Hauser  depicts  definite  stages  in  the  transformation  of  normal  glands 
into  hypertrophic  forms  which  he  believes  precede  the  development  of  cancer. 
Haaland  has  described  a  neoplastic  transformation  of  the  pulmonary  cells 
in  metastatic  carcinoma  in  the  mouse,  an  observation  which  needs  to  be 


38  NEOPLASTIC  DISEASES 

confirmed,  but  the  sarcomatous  transformation  of  the  stroma  of  trans- 
planted cancers  of  the  mouse,  if  genuine,  is  probably  a  sufficiently  attested 
instance  of  the  tropism  exerted  by  tumor  epithelium  upon  adult  connective 
tissue. 

In  adenocarcinoma  of  the  human  ovary  is  sometimes  seen  a  sarcomatoid 
proliferation  of  the  stroma. 

Yet  these  instances  of  lateral  extension  of  tumor  processes,  if  they  eventu- 
ally stand  the  test  of  criticism,  are  rare,  and  it  should  be  emphasized  that 
the  great  majority  of  tumor-cells  are  isolated  in  origin  and  throughout  their 
history. 

4.  The  systemic  round-cell  sarcomas  present  a  difficult  problem  in  the 
analysis  of  their  mode  of  origin  and  extension.  Multiple  myeloma  arises 
simultaneously  at  numerous  widely  distant  foci  in  the  bone-marrow  and 
may  early  show  a  diffuse  tumor  process  throughout  many  bones.  Hence 
one  must  assume  the  existence  of  so  many  foci  of  origin  as  to  suggest  the 
simultaneous  involvement  of  the  entire  bone-marrow  system. 

Multiple  metastases  cannot  satisfactorily  explain  the  course  of  these 
tumors,  and  it  would  seem  probable  that  there  occurs  a  lateral  extension 
of  the  tumor  process  over  adjacent  normal  areas  as  well  as  infiltrative  growth 
from  the  multiple  foci.  In  the  group  of  lymphocytomas  there  are  examples 
very  strongly  indicating  simultaneous  tumor  growth  originating  in  a  large 
portion  of  the  lymphatic  system.  In  some  intestinal  cases  (Wells,  Symmers) 
there  is  a  diffuse  lymphadenomatous  hyperplasia  involving  the  entire  lym- 
phoid  apparatus,  from  the  cardiac  orifice  to  the  anus,  the  superficial,  the 
thoracic  and  the  abdominal  nodes,  and  the  bone-marrow.  Leucocytosis  is 
absent  and  the  spleen  is  little  affected.  A  rapid  lateral  extension  from  very 
many  foci  or  a  primary  involvement  of  the  entire  system  seems  to  be  the 
only  reasonable  explanation  of  such  cases.  There  are  systemic  highly  malig- 
nant large-cell  sarcomas  of  equal  extent.  Chloroma,  with  or  without  leukemia, 
occurs  as  a  multiple  or  diffuse  tumor  process  affecting  wide  areas  of  marrow 
and  lymphatic  system  for  which  a  lateral  extension  from  many  foci  or  a  primary 
diffuse  origin  seems  a  necessary  assumption.  In  thyroid  tumors  of  fish  the 
hyperplasia  which  seems  to  result  from  exaggerated  response  to  functional 
stimulus  is  felt  in  all  the  widely  disseminated  alveoli  of  the  gland.  Some 
of  these  hyperplastic  glands  may  regress  (Marine),  but  beyond  a  certain 
stage  they  become  autonomous. 

Cell  Division  in  Tumors. — Normal  and  many  abnormal  types  of  cell 
division  occur  in  tumors,  including  mitosis,  direct  nuclear  division,  and  direct 
and  indirect  fragmentation. 

This  subject  has  been  very  fully  investigated  by  Stroebe,  Vit.  Miiller, 
Cornil,  Arnold,  Pianese,  Galeotti,  Hansemann,  and  many  others,  who  agree 
that  the  chief  mode  of  cell  division  in  tumors  is  by  mitosis.  In  the  benign 
tumors  in  which  the  growth  is  comparatively  slow  the  scanty  mitotic  figures 
usually  appear  normal,  but  degeneration,  inflammation,  and  very  rapid  growth 
are  marked  by  increasing  irregularity  in  the  mitotic  process. 

Pianese  classifies  the  irregularities  occurring  in  cancer  as  follows: 

A.  Relatively  typical  mitosis,  which  may  be  bipolar  and  symmetrical, 
hyper-  or  hypochromatic,  and  giant. 

B.  Atypical  mitosis,  either  asymmetrical  or  multipolar. 

C.  Abortive  mitoses,  marked  by  suppressed  or  atypical  polarization  of 
chromosomes,  by  aberration  of  chromosomes,  by  loss  of  polar  bodies,  and  by 
degeneration  of  cytoplasm. 

As  a  rule  he  found  the  first  two  types  in  comparatively  intact  cells,  while 
abortive  mitoses  occurred  chiefly  in  degenerating  cells.  Irregularities  in 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY  39 

all  the  phases  and  elements  of  the  mitotic  process  occur  in  malignant  tumors 
and  bear  a  certain  relation  to  the  morphological  and  physiological  variation 
of  the  tissue  from  the  normal  (Hansemann).  The  number  and  size  of  the 
chromosomes,  the  structure  of  the  spindles,  the  coordination  of  the  division 
phases,  the  position  of  the  elements  in  the  cell,  contribute  numerous  abnor- 
malities in  the  process.  Hyperchromatic  cells  may  arise  from  asymmetric 
mitosis.  Hypochromatism  results  from  asymmetric  mitosis  and  loss  of 
chromosomes. 

Asymmetric  mitosis  has  been  referred  to  secondary  subdivision  of  cen- 
trosomes,  one  of  which  may  divide  into  as  many  as  four  parts,  each  forming 
attraction  spheres.  Under  these  conditions  the  migration  of  chromosomes 
is  often  delayed  and  unequal  (Galeotti). 

The  results  of  abortive  mitosis  give  rise  to  a  great  variety  of  structures 
which  have  been  elaborately  illustrated  by  Pianese.  In  this  class  of  struc- 
tures have  been  found  many  of  the  pseudoparasites  of  cancer.  Thus  abnor- 
malities in  the  mitotic  process  have  been  observed  rather  more  abundantly 
in  carcinoma  than  in  sarcoma,  but  many  of  them  have  been  seen  in  inflam- 
matory and  regenerative  hyperplasia  (Stroebe). 

Striking  peculiarities  in  such  a  fundamental  process  as  cell  division  may 
well  suggest  that  here  is  disclosed  the  essential  nature  of  tumor  growth. 
Hansemann  has  interpreted  the  studies  in  this  field  in  such  a  manner,  hold- 
ing that  asymmetrical,  multipolar  and  abortive  mitoses  mean  unequal  dis- 
tribution of  cell  potencies,  loss  of  cell  differentiation,  freedom  from  normal 
restraints  to  growth,  and  exaggeration  of  growth  over  functional  capacities. 
These  physiological  properties  he  includes  in  the  conception  of  anaplasia, 
the  morphological  side  of  which  is  illustrated  in  resting  and  dividing  tumor- 
cells.  To  a  considerable  extent  this  interpretation  may  be  valid,  and  yet 
the  majority  of  tumor-cells  divide  by  normal  mitosis  (Pfitzner,  Hauser), 
and  the  minute  study  of  the  conditions  favoring  abnormal  mitoses  indicates 
that  these  changes  are  secondary  results  of  tumor  growth  and  not  primary 
and  essential. 

Abnormal,  asymmetric,  and  multipolar  mitoses  are  readily  produced 
experimentally  by  heat  and  by  many  chemicals  (Galeotti,  O.  Hertwig). 

Gametoid  Mitosis. — In  the  maturation  of  sex  cells  the  mitotic  nucleus 
exhibits  only  one-half  the  number  of  chromosomes  of  the  somatic  or  general 
body  cells,  and  these  chromosomes  instead  of  assuming  a  V  shape  and  radial 
arrangement  and  splitting  lengthwise  in  the  monaster,  are  ring-like  or  loop 
shaped,  or  composed  of  coarse  granules  arranged  in  the  long  axis  of  the 
spindle.  This  type  of  division  with  reduction  of  chromosomes  is  called  game- 
togenous  or  heterotype. 

Farmer,  Moore  and  Walker  have  found  that  this  type  of  division,  here 
called  gametoid,  is  common  in  the  growing  edges  of  epithelioma  and  other 
tumors.  On  this  ground  they  at  first  assumed  that  tumor-cells  possess  the 
physiological  significance  of  sexual  cells,  but  this  view  has  been  abandoned 
since  gametoid  mitosis  is  by  no  means  constant  in  tumors,  and  the  peculiar 
mitoses  may  not  signify  the  properties  of  sex  cells.  Yet  I  think  the  observa- 
tion remains  suggestive,  since  tumor-cells  may  show  three  properties  of  sex 
cells,  gametoid  mitosis,  increased  growth  capacities,  and  remarkable  altruistic 
relations. 

Amitosis  is  frequently  observed  in  rapidly  growing  tumors  and  in  some 
cases  it  may  be  the  chief  mode  of  cell  division.  Accordingly  to  Nedjelsky 
it  begins  with  swelling  of  the  nucleolus  followed  by  elongation,  budding  or 
cleavage  of  the  nucleus.  It  results  in  the  formation  of  giant-cells  with  pale 
nuclei  which  may  later  undergo  budding  or  mitotic  division,  or  by  division 


40  N EOF  LA  STIC  DISEASES 

of  the  cell  body  it  often  leads  to  rapid  regeneration  of  viable  tumor-cells 
(V.  Miiller). 

Flemming  and  Trambusti  hold  that  amitosis  always  results  from  degenera- 
tive changes  in  the  cell  and  may  yield  giant-cells,  but  not  fully  viable  tumor- 
cells.  Marchand  and  most  observers  believe  that  mitosis  contributes,  as 
does  amitosis,  to  the  rapid  regeneration  of  tumor-cells,  but  fails  to  convey 
to  the  progeny  all  the  properties  of  the  parent  cells.  Pianese  in  his  elaborate 
study  of  cancer-cells  could  not  find  that  amitosis  was  ever  followed  by  cell 
division,  but  was  always  abortive,  leading  to  the  formation  of  multinucleated 
giant-cells. 

Howard  has  endeavored  to  trace  in  the  nuclear  changes  of  tumor-cells 
many  processes  parallel  to  those  observed  in  the  protozoon  nucleus. 

The  impression  that  tumor-cells  must  owe  their  exaggerated  growth 
capacities  to  some  form  of  fertilization  has  led  to  an  interpretation  of  certain 
nuclear  changes  suggested  by  this  point  of  view,  but  now  abandoned.  Klebs 
once  thought  that  the  nuclei  of  englobed  leukocytes  fused  with  the  nuclei  of 
tumor-cells.  Recklinghausen  saw  appearances  suggesting  the  fusion  of  the 
nuclei  of  endothelium  and  fibroblast. 

Auerbach  and  Bashford  pictured  the  fusion  of  the  nuclei  of  adjoining 
tumor-cells,  and  Schleich  thought  that  endogenous  cell  formation  consti- 
tuted a  form  of  cell  infection  which  accounted  for  overgrowth. 

Neoplastic  vs.  Inflammatory  Hyperplasia. — Neoplastic  hyperplasia  is 
usually  more  rapid  than  the  multiplication  of  cells  in  inflammation,  or  re- 
generative growth.  Lymphosarcoma  of  a  few  months'  growth  may  reach 
a  bulk  constituting  a  large  portion  of  the  body  weight.  Carcinoma  of  the 
liver  may  largely  replace  the  tissue  of  this  organ  in  a  brief  period.  In  the 
terminal  stages  of  many  malignant  tumors  growth  is  much  accelerated  so 
as  to  divert  much  nutriment  from  the  other  tissues.  This  rapid  growth  is 
associated  with  a  great  abundance  of  mitotic  nuclei  in  the  tumor-cells  which 
often  far  exceeds  that  seen  in  any  inflammatory  process. 

Yet  rapidity  of  growth  is  not  an  essential  distinguishing  feature  of  tumor 
processes.  Few  tumors  grow  as  rapidly  as  the  fetus  in  utero. 

Leucocytes  multiply  with  great  rapidity  in  pneumonia;  and  epithelium 
covers  denuded  skin  far  more  actively  than  the  growth  of  such  cells  in  many 
epitheliomas. 

A  more  important  distinction  of  tumor  growth  is  found  in  its  progressive 
tendencies.  Tumors  commonly  grow  to  a  bulk  far  exceeding  the  limits  of 
any  inflammatory  or  physiological  process  affecting  the  same  area,  and  they 
continue  to  grow  to  whatever  extent  nutrition  is  provided.  Physiological 
regeneration  observes  a  certain  adaptation  to  the  function  of  the  organ; 
inflammatory  overgrowth  is  measured  by  the  intensity  and  duration  of  cer- 
tain irritants  and  ceases  when  these  irritants  are  removed;  tumor  growth 
ignores  all  these  limitations  and  ceases  only  with  the  death  of  the  patient 
or  the  curtailment  of  blood-supply.  Yet  there  are  cyclic  variations  in  the 
growth  of  tumors,  periods  of  activity  being  followed  by  standstill  or  regression. 

Indeed,  there  appears  to  be  a  natural  limit  to  the  growth  of  some  tumors 
in  some  subjects.  Progressive  fibrosis  brings  some  cancers  of  the  breast 
to  comparative  quiescence  in  an  innocuous  scirrhus  form,  and  the  meno- 
pause marks  the  acme  of  growth  of  some  uterine  myomas,  and  has  been  fol- 
lowed by  the  spontaneous  regression  even  of  cancer  of  the  breast  (Watson- 
Cheyne). 

The  frequency  of  tumor  regression  in  lower  animals,  the  increasing  number 
of  spontaneous  regressions  in  human  tumors  (Czerny),  and  observations  of 
the  unhindered  growth  of  tumors  over  many  years  in  old  persons,  indicate 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY 


41 


that  limitless  growth  is  not  a  power  possessed  by  all  malignant  tumors.  The 
universal  employment  of  surgical  measures  renders  this  fact  less  obvious 
than  it  might  be. 

The  morphology  of  neoplastic  hyperplasia  differs  from  inflammatory  over- 
growth and  physiological  regeneration.  A  productive  inflammation  is  usually 
a  diffuse  process  involving  a  whole  organ  or  tissue  area  and  it  grades  off  in- 
sensibly into  normal  tissue  (chronic  mastitis),  while  a  neoplasm  is  usually 
circumscribed  on  account  of  its  origin  from  an  isolated  group  of  cells  (fibroma 
mammaae).  Productive  inflammation  involves  all  the  elements  of  a  tissue; 
tumor  processes  usually  reside  in  a  single-cell  type.  Inflammatory  neoplasia 
is  confined  by  narrow  limits,  which  in  tumors  are  very  wide. 


FIG.  5. — Mammary  cancer.     Spontaneous  local  regression,  with  formation  of  fibrous 
tissue,  calcine  granules,  and  fatty  crystals. 

Tumor-cells  .show  the  features  of  anaplasia,  loss  of  specific  form,  and  of 
polarity,  variation  in  size,  nuclear  hyper chromatism,  multiformed  nuclei 
and  atypical  mitoses,  all  of  which  are  absent  or  less  marked  in  inflammatory 
hyperplasia. 

Yet  inflammatory  overgrowth  passes  by  insensible  gradations  into  neo- 
plastic hyperplasia.  This  significant  principle  of  pathology  has  an  important 
and  yet  a  limited  application.  As  a  rule  tumor  growth  differs  sharply  from 
any  inflammatory  hyperplasia  affecting  the  same  tissue,  but  there  are  excep- 
tions to  this  rule. 

(a)  There  are  inflammatory  hyperplasias  of  the  bone-marrow  cells, 
leukemic  processes  with  some  of  the  features  of  a  neoplasm,  and  chloromas 
which  are  true  tumors  of  marrow-cells.  Most  cases  fall  clearly  into  one  of 
these  categories,  but  others  are  intermediate  in  type  and  it  is  difficult  to  deter- 
mine whether  they  are  strictly  inflammatory  or  truly  neoplastic.  Similar 


42  NEOPLASTIC  DISEASES 

intermediate  grades  of  hyperplasia,  difficult  to  classify,  are  occasionally 
encountered  with  nearly  every  tissue  cell  in  the  body. 

(b)  A  process  beginning  as  a  simple  inflammatory  hyperplasia  may  in 
the  same  individual  gradually  assume  neoplastic  properties. 

In  the  thyroid  gland  of  goiter,  especially  in  fish,  in  the  prostate  gland  of 
hypertrophic  prostatitis,  in  the  uterine  mucosa  of  a  glandular  endometritis, 
in  the  mammary  gland  of  chronic  mastitis,  and  in  the  lymph-nodes  of  Hodg- 
kin's  granuloma,  are  occasionally  seen  transformations  of  a  functional  or 
inflammatory  hyperplasia  into  a  more  or  less  typical  neoplasm.  Here  it 
would  appear  that  a  hyperplastic  process  incited  by  external  irritants  may 
continue  and  increase  long  after  the  removal  of  the  irritant.  As  with  certain 
chemical  reactions  so  with  pathological  processes  the  importance  of  momen- 
tum must  be  recognized. 

It  may  be  objected  that  when  a  neoplasm  appears  in  the  course  of  inflam- 
matory hyperplasia  something  new  is  added. 

This  objection  may  be  valid  for  certain  cases  where  the  neoplasm  appears 
suddenly  and  in  widely  different  form  from  that  exhibited  by  the  preexisting 
hyperplasia,  but  not  for  other  cases  in  which  observation  shows  the  change 
to  be  gradual.  Since  with  every  increase  in  quantity  there  is  a  change  in 
quality  it  is  reasonable  to  expect  that  gradually  accumulating  tendencies 
in  the  life  of  the  cell  may  express  themselves  at  times  in  quite  sudden  and 
radical  changes  in  morphology  and  behavior.  All  these  considerations 
strengthen  the  view  that  the  "precancerous  condition"  is  of  wide  occurrence 
and  of  much  theoretical  and  practical  importance  in  oncology.  In  this  condi- 
tion one  finds  tissues  and  cells  in  a  state  of  overgrowth  intermediate  between 
inflammatory  and  neoplastic  hyperplasia,  exhibiting  certain  tumor  characters 
which  must  be  judged  from  different  standards  for  each  tissue,  and  which 
experience  shows  are  often  followed  by  genuine  and  usually  malignant  tumors. 

The  theoretical  distinctions  which  a  general  survey  establishes  between 
neoplastic  and  inflammatory  hyperplasia  are  sharp  and  fundamental,  but 
these  distinctions  fail  us  when  we  have  to  search  for  them  in  processes  of 
doubtful  nature.  Here  we  assume  them  to  exist  from  our  general  knowledge, 
but  we  cannot  prove  their  presence. 

Thus,  as  Borst  assumes,  inflammatory  overgrowth  results  from  exagger- 
ated response  to  external  irritants  while  neoplastic  growth  arises  from  loss  of 
normal  restraints  to  growth.  The  one  is  purposeful,  organized,  self-limiting, 
typical,  accelerated  hyperplasia,  while  the  other  is  baneful,  lawless,  progres- 
sive, atypical  degenerative  growth  excess.  But  this  is  a  composite  picture 
and  the  practical  problem  is  to  decide  how  much  it  is  reflected  in  individual 
doubtful  cases.  Virchow  recognized  this  difficulty  and  some  observers,  find- 
ing it  insurmountable,  have  concluded  that  there  is  only  a  difference  in  degree 
between  healing  of  wounds,  inflammatory  hyperplasia,  and  tumor  formation 
(Brosch,  Fabian). 

This  view  cannot  be  accepted.  Inflammatory  hyperplastic  processes 
pass  by  insensible  gradation  into  neoplastic  growth  according  to  our  present 
analysis.  Syphilitic  leukoplakia  becomes  epithelioma,  and  Hodgkin's  gran- 
uloma may  take  on  a  sarcomatoid  character.  Yet  these  are  complex  processes 
and  although  we  cannot  detect  when  growth  from  external  stimulation  is 
succeeded  by  growth  from  loss  of  growth  restraints,  yet  theoretical  considera- 
tions require  us  to  assume  that  at  some  point  such  a  change  actually  occurs. 
I  have  elsewhere  suggested  that  some  hyperplastic  processes,  owing  their 
inception  to  the  influence  of  parasites,  become  at  length  established  and 
progress  without  the  stimulus  of  the  parasite.  Here  one  may  suppose  that 
the  declining  stimulus  is  replaced  by  progressive  loss  of  growth  restraints, 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY  43 

but  the  reasoning  would  still  show  that  inflammatory  hyperplasia  passes 
into  neoplastic  growth. 

On  the  other  hand,  I  do  not  believe  that  growth  restraints  are  fully  main- 
tained in  some  inflammatory  hyperplasias.  In  proud  flesh  mechanical  re- 
straints seem  obviously  defective  and  in  hypertrophic  endometritis  several 
signs  of  lowered  tissue  tension  are  visible.  External  stimulus  and  loss  of 
growth  restraints  are  here  combined,  and  it  cannot  be  said  that  neoplastic 
hyperplasia  is  wholly  different  in  nature  from  inflammatory  overgrowth. 

Thus,  however  closely  the  processes  are  analyzed,  the  conclusion  remains 
that  inflammatory  hyperplasia  passes  into  neoplastic. 

Regressive  Changes  in  Tumor-cells. — Tumor-cells  in  general  suffer  the 
same  degenerative  changes  as  occur  in  other  tissues,  but  some  special  interest 
attaches  to  this  field  on  account  of  the  frequency  and  extent  of  these  changes 
in  tumors,  and  also  from  the  very  minute  analysis  which  has  been  required 
because  of  the  former  interpretation  of  many  intracellular  structures  as 
parasites.  The  presence  of  degenerative  changes  in  tumors  is  the  direct  result 
of  the  activity  of  growth,  the  accelerated  metabolism,  and  the  uncertainty 
of  blood-supply. 

Fatty  degeneration  is  nearly  constant  in  cancer,  less  common  in  sarcoma. 
It  contributes  a  light  opaque  color  to  tumor  cords  which  is  one  of  the  earliest 
gross  diagnostic  signs  of  many  cancers.  It  seldom  reaches  an  extreme  degree, 
the  fat  being  commonly  limited  to  fine  droplets  which  first  appear  about  the 
nucleus. 

It  is  most  prominent  in  tumors  of  glands  which  normally  secrete  fatty 
substances  as  in  adenoma  sebaceum,  adrenal  tumors,  and  cancer  of  the  breast. 
In  rapidly  growing,  well-nourished  tumors  the  active  metabolism  is  unfavor- 
able to  the  deposit  of  visible  fat,  which  appears  chiefly  in  areas  of  necrosis. 

The  chemical  nature  of  the  lipoids  of  tumors  is  no  better  known  than  is 
that  of  the  fats  in  other  conditions.  In  a  series  of  cancers  Pianese  could  find 
no  fat  blackening  with  osmic  acid. 

Stains  by  Sudan  III  and  Scharlach  R  commonly  reveal  many  fine  fat 
droplets  in  such  tumors.  To  what  extent  the  fatty  degeneration  of  tumors 
belongs  in  the  class  of  lipoid  or  myelinic  degenerations  has  not  been  deter- 
mined, but  Kaiserling  and  Orgler  found  myelin  droplets  in  the  cells  of  many 
cancers  and  sarcomas. 

White  has  described  several  varieties  of  fatty  crystals  occurring  in  frozen 
sections  in  and  about  the  cells  of  carcinoma,  sarcoma,  and  adenoma.  Some 
of  these  were  large  plates  or  needles  which  did  not  melt  readily  and  which 
he  regarded  as  cholesterin. 

Smaller  needles  which  melt  and  solidify  into  globules  on  cooling  he  identi- 
fied as  fats.  Other  small  needles  and  anisotropic  crystals  were  classed  as 
mixtures  of  cholesterin  with  lecithin  and  as  myelin  forms.  The  crystals 
seem  to  be  associated  with  cell-growth  rather  than  with  degeneration,  and 
White  suggests  that  they  are  in  some  way  concerned  in  the  regulation  of 
cell  growth. 

Hydropic  degeneration  occurs  in  the  edematous  portions  of  both  benign 
and  malignant  tumors,  and  affects  both  nuclei  and  cell  bodies. 

It  is  seen  in  marked  degree  in  the  lining  cells  of  cystic  adenoma  and  in  the 
cells  of  any  tumor  that  is  constantly  bathed  in  fluids  as  in  papillary  epithe- 
lioma  of  the  bladder.  Exfoliated  cells  lying  in  tissue  spaces  are  commonly 
ballooned  out  with  imbibed  fluids.  Virchow's  "physaliden"  were  in  part 
hydropic  vacuoles  in  nuclei  or  cytoplasm  which  in  the  fresh  condition  ap- 
peared hyaline,  but  on  hardening  yielded  a  central  granular  or  homogeneous 
mass. 


44  NEOPLASTIC  DISEASES 

Glycogenic  degeneration  of  tumors  has  been  carefully  studied  by  several 
observers.  According  to  Gierke  it  appears  in  tumors  under  the  same  condi- 
tions as  in  other  cells.  These  are  mainly  as  a  primary  physiological  con- 
stituent of  actively  growing  or  embryonal  cells  and  as  a  secondary  result  of 
disturbed  nutrition  and  degeneration.  In  the  former  class  it  would  naturally 
characterize  malignant,  rapidly  growing  and  embryonal  tumors,  and  in  the 
latter  it  would  be  associated  with  and  have  much  the  same  significance  as 
fatty  changes.  Observation  has  shown  that  glycogen  is  commonly  found  in 
most  rapidly  growing  tumors  (Best),  but  in  very  variable  quantities,  and 
some  malignant  growths,  as  breast  cancer,  are  usually  free  from  it.  In  endothe- 
lioma  it  is  very  constant  and  abundant  (Gierke).  In  1544  tumors  Lubarsch 
found  glycogen  in  477,  2Q  per  cent.  Fibroma,  osteoma,  glioma,  and  heman- 
gioma  were  constantly  glycogen  free;  lipoma  and  lymphangioma  and  ade- 
noma nearly  always  so.  The  more  certain  the  embryonal  nature  of  the  tumor, 
the  more  constant  was  the  presence  of  glycogen.  Thus  in  teratomas,  hyper- 
nephromas,  and  choriomas  it  was  present  in  all  cases  and  usually  abundant. 
It  was  about  equally  common  in  sarcomas  (50.7  per  cent.)  and  carcinomas 
(43.6  per  cent.);  in  squamous  cell  epithelioma  70  per  cent. 

Four  factors  seemed  to  Lubarsch  to  chiefly  determine  its  occurrence. 

1.  An  origin  of  the  tumor  from  embryonal  cells. 

2.  An  origin  from  cells  normally  containing  glycogen. 

3.  The  absence  of  mucous  and  colloid  degeneration,  and  frequent  presence 
of  fatty  changes. 

4.  The  presence  of  numerous  delicate  blood-vessels  in  intimate  relation 
to  the  parenchyma. 

Secondary  glycogen  deposits  appear  in  necrotic  areas  and  about  the 
inflamed  edges  of  tumors  which  are  elsewhere  free  from  it  (Best).  Brault 
thought  that  glycogenic  degeneration  sometimes  preceded  mucous  changes 
in  mucoid  carcinoma. 

Miiller  concluded  that  actively  growing,  well-nourished  cells  contain 
no  glycogen,  which  appears  in  cells  with  feeble  metabolism.  The  relation 
of  glycogen  content  to  the  prognosis  of  tumors  was  considered  by  Brault, 
who  states  that  in  sarcomas  there  is  no  parallel  between  glycogen  content 
and  malignancy,  while  with  carcinoma  the  glycogen-holding  tumors  are 
regularly  the  more  malignant.  Best  and  Gierke,  however,  did  not  find  this 
rule  to  hold. 

Mucous  degeneration  is  a  wide-spread  and  important  regressive  change 
in  many  tumors.  It  may  be  a  primary  and  essential  feature  of  the  neoplasms, 
arising  from  exaggerated  development  of  the  mucous  constituents  or  from 
increased  secretion,  or  it  may  overtake  tumors  wrhose  cells  have  no  original 
tendency  toward  its  production. 

It  represents  the  matrix  of  primary  myxoma,  the  secretion  of  many 
adenomas,  and  a  degenerative  product  in  chondroma,  sarcoma,  and  carci- 
noma. It  is  readily  recognizable  by  the  homogeneous  luster  and  viscid  quality 
which  it  imparts  to  the  tissue.  True  mucin  is  found  chiefly  in  connective- 
tissue  tumors,  pseudomucin  in  epithelial  growths.  Certain  tumors  are  char- 
acterized by  a  remarkable  production  of  mucus.  Primary  myxoma  of  the 
skin  consists  of  spindle-  and  star-shaped  cells  lying  in  a  matrix  of  homogeneous 
finely  fibrillated  material  which  infiltrates  the  surrounding  tissues  and  doubt- 
less contributes  to  the  local  recurrence  of  these  growths.  Some  gelatinous 
cancers  of  the  colon  early  invade  the  peritoneum,  spread  through  the  cavity, 
and  produce  immense  quantities  of  firm  gelatinous  material  which  distends 
the  abdomen.  In  such  cases  it  may  be  difficult  to  discover  any  remnants 
of  living  tumor-cells,  and  some  such  tumors  seem  to  reach  a  standstill  through 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY  45 

excessive  production  of  mucus.  Cancer  of  the  stomach  may  yield  a  localized 
growth  or  diffuse  infiltration  of  the  stomach  wall  in  which  are  found  scanty 
groups  of  tumor-cells  widely  distended  by  mucus. 

Adenoma  of  the  ovary  may  yield  cystic  tumors  of  very  large  dimensions 
composed  of  cysts  distended  by  fluid  containing  large  quantities  of  pseudo- 
mucin.  Mixed  chondroma  of  the  parotid  commonly  shows  areas  of  cartilage 
verging  into  myxoma,  and  recurrences  of  the  tumor  may  eventually  assume 
the  type  of  pure  myxoma.  Actively  growing  lipomas  are  occasionally  over- 
taken by  diffuse  mucoid  degeneration. 

In tra  cellular  mucous  globules  are  observed  in  a  wide  variety  of  tumors 
in  which  the  process  fails  to  make  headway.  As  a  rule,  when  mucous 
degeneration  overtakes  a  tumor,  while  a  rapid  increase  in  size  may  follow, 
the  tumor  has  reached  the  acme  of  its  cellular  activity  and  its  malignancy 
is  reduced.  Since  the  nuclear  constituents  of  the  cell' are  chiefly  concerned 
in  mucus  production,  the  appearance  of  intracellular  mucous  degeneration 
usually  indicates  a  process  intimately  affecting  the  vitality  of  the  cell. 

Hyaline  changes  in  cells,  vessels,  and  stroma  are  the  most  common  forms 
of  regressive  process  occurring  in  tumors.  Firm,  homogeneous,  acidophile 
material  arises  from  the  connective-tissue  elements  and  vessels  of  the  stroma, 
from  the  tumor-cell  cytoplasm,  and  from  exu dates  and  secretions.  Pro- 
nounced grades  of  the  first  type  are  seen  in  keloids,  fibroma,  fibrocarcinoma, 
endothelioma,  and  angiosarcoma. 

It  may  strongly  influence  the  course  of  the  neoplasm,  usually  appearing 
in  slowly  growing  or  regressing  tumors,  to  which  qualities  it  contributes. 
Atrophy  of  cells  usually  keeps  pace  with  the  progress  of  hyaline  changes, 
so  that  large  tumors  may  be  converted  into  nearly  stationary  growths  com- 
posed largely  of  hyaline  masses. 

In  some  angiosarcomas  the  walls  of  vessels  are  converted  into  hyaline 
rings  sheathed  by  ill-nourished  tumor-cells.  Calcification  of  these  hyaline 
vessels  produces  the  sand  grains  of  psammoma. 

Intracellular  hyalinosis  produces  a  wide  variety  of  intracellular  structures 
which  have  been  studied  and  elaborately  depicted  by  Pianese.  A  some- 
what special  variety  is  the  keratinization  of  squamous-cell  epitheliomas, 
in  which  group  the  appearance  of  hyaline  globules,  rings,  and  vacuolated 
bodies,  within  or  about  the  nucleus,  in  the  cytoplasm,  or  involving  the  cell 
borders,  produces  bizarre  structures,  many  of  which  were  once  interpreted 
as  parasites.  Exudates  and  secretions  becoming  inspissated  contribute  a 
large  portion  of  the  hyaline  material  in  some  tumors.  "Mulberry  cells" 
containing  small  nuclei  and  many  large  acidophile  globules  resembling  red 
blood-cells  occur  in  certain  tumors  and  in  other  conditions.  Their  appear- 
ance suggests  an  origin  from  englobed  red  cells  or  from  intracellular  hyaline 
degeneration.  Weber  depicts  them  in  a  case  of  myeloma,  and  I  have  found 
them  very  abundant  in  cancer  of  the  stomach.  True  amyloidosis  has  been 
described  by  many  authors  in  a  variety  of  tumors,  as  carcinoma  of  esophagus 
by  Wagner,  tumor  of  the  bladder  (Billroth),  carcinoma  and  sarcoma  of 
larynx  (Burow),  carcinoma  of  lung  (Langhans),  chondroma  of  lung  (Siegert), 
carcinoma  of  breast  (Aoyama),  and  endosteal  sarcoma  (Hildebrandt).  Some 
fibromas  or  sarcomas  of  the  larynx  are  characterized  by  the  development  of 
large  masses  of  amyloid.  Usually  the  amyloid  masses  have  a  concentric  or 
radial  striation. 

Colloid  Degeneration. — Homogeneous,  semisolid,  acidophile  material  occurs 
in  many  tumors  in  large  intercellular  masses  and  in  small  intracellular 
globules.  The  largest  collections  are  seen  in  ovarian  adenomas,  in  which  the 
ordinary  mucin  may  present  the  qualities  of  firm  colloid.  Thyroid  tera- 


46  NEOPLASTIC  DISEASES 

tomas  containing  little  else  than  thyroid  tissue  with  distended  alveoli  are 
frequent  in  the  ovary,  and  some  ovarian  adenomas,  not  of  thyroidal  nature, 
may  show  considerable  masses  of  colloid  substance.  Carcinomas  in  various 
situations  may  present  cylindrical  intra-alveolar  masses  of  colloid  approach- 
ing the  appearance  of  thyroid  tissue.  Colloid  appears  in  the  cells  of  many 
tumors  in  the  form  of  globules  of  rather  dense,  strongly  acidophile  material. 
These  structures  are  one  of  the  chief  sources  of  Russell's  fuchsin  bodies. 
Colloid  droplets  may  appear  in  well-nourished  mitotic  cells  or  in  cells  showing 
advanced  stages  of  other  forms  of  degeneration. 

Miscellaneous  Peculiarities  of  Tumor-cells. — Besides  the  well-defined 
types  of  degeneration  tumor-cells  exhibit  a  wide  variety  of  alterations  which 
have  been  subjected  to  close  scrutiny,  but  which  it  is  difficult  to  interpret 
and  classify. 

These  changes  affect  both  nucleus  and  cytoplasm. 

In  the  highly  developed  tumor-cell  nucleus  may  be  distinguished  five 
elements : 

1.  Nuclein,   a   nucleoproteid,   composing   the   chromatin   which   appears 
in  densely  basic  staining  clumps,  normally  arranged  along  the  periphery  of 
the  nucleus  or  as  an  intranuclear  network. 

2.  Paranuclein,  an  acidophile  substance  composing  the  nucleoli. 

3.  Linin,  or  plastin,  an  achromatic  substance  forming  an  intranuclear 
network. 

4.  Amphipyrenin,  which  some  authors  describe  as  constituting  the  nuclear 
membrane.     It  is  distinguishable  from  linin.     According   to  Albrecht  the 
nuclear  membrane  is  a  lipoid  substance. 

5.  Nuclear  fluid,  filling  the  meshes  of  the  nuclear  network. 

As  compared  with  normal  cells  all  of  these  nuclear  structures  may  be 
much  more  abundant  in  tumor-cells.  In  giant-cells,  especially  those  of 
myogenous  origin,  and  in  various  sarcomas  and  epitheliomas,  the  nuclei 
reach  astonishing  proportions  from  hypertrophy,  chiefly  of  nuclein.  In  epi- 
theliomas great  excess  and  multiplicity  of  paranuclein  bodies  is  somewhat 
characteristic,  while  in  endotheliomas  the  nucleoli  are  relatively  small. 
Shrinkage  and  pyknosis  of  nuclei  occurs  in  degenerating  and  necrosing  areas 
of  many  tumors.  Wide  distention  from  imbibition  of  fluids  may  accompany 
hydropic  degeneration  of  the  cytoplasm.  Rarefaction  of  nuclein  masses 
may  result  in  a  pale  diffuse  stain  of  the  thickened  chromatin  network.  Or 
the  chromatin  may  appear  in  very  thin  strands,  eventually  disappearing  in 
complete  karyolysis.  A  common  appearance  in  carcinomas  is  the  presence 
of  several  discrete  blocks  of  chromatin  lying  irregularly  in  a  nucleus  devoid  of 
chromatic  membrane.  The  various  stages  of  karyorrhexis  may  be  followed 
in  degenerating  or  necrosing  cells.  The  fragments  of  chromatin  thus  result- 
ing may  be  scattered  in  the  cytoplasm  and  remain  pyknotic  or  become 
vacuolated  or  surrounded  by  cytoplasmic  vacuoles  or  become  dissolved. 
Extrusion  of  chromatin  into  the  cytoplasm  may  result  in  the  appearance  of 
many  basophile  granules  in  the  cell.  The  chromatin  or  linin  may  break  up 
into  many  fine  rings  within  the  nucleus  and  these  be  discharged  into  the 
cytoplasm,  as  observed  by  Schuller  and  interpreted  by  him  as  the  forms  of 
an  intranuclear  parasite. 

Under  the  term  "pseudo-adipose  and  cystic  degeneration  of  nucleus" 
Pianese  described  the  appearance  of  homogeneous  spheroidal,  brownish, 
achromatic  globules  in  the  nucleoplasm,  occurring  especially  in  tumors  of 
the  liver.  This  author  also  describes  a  hyalinosis  of  the  nucleoplasm  which 
results  in  a  transformation  of  part  or  the  whole  nucleus  into  a  hyaline  mass. 

Fragmentation   of   the  nucleus   with   formation   of  pseudonuclei   occurs 


DEFINITION.    GENERAL  PATHOLOGY.     CLASSIFICATION  47 

in  many  giant-cell  tumors.  In  melanoma  the  nuclei  often  contain  large 
masses  of  homogeneous  material  in  which  appear  all  stages  of  the  formation 
of  granular  pigment. 

In  the  cytoplasm  of  tumor-cells  the  early  stages  of  degeneration,  hydropic, 
mucous,  lipoid,  fatty,  glycogenic,  colloid,  hyaline,  and  calcine,  yield  a  great 
variety  of  distortions  of  the  cell  structure  and  abnormal  granules,  rings, 
globules  and  complex  masses,  most  of  which  are  identified  by  appropriate 
technics.  The  complex  morphology  of  these  products  is  illustrated  in  the 
extensive  literature  on  the  pseudoparasites  of  cancer,  especially  in  the  work 
by  Pianese.  Many  of  the  bodies,  especially  those  of  epithelioma,  I  have 
found  duplicated  by  diphtheria  toxin  necrosis  of  the  corneal  epithelium. 

Phagocytosis  by  tumor-cells  yields  many  intracellular  bodies,  as  from 
red  blood-cells,  leukocytes,  other  tumor-cells,  bacteria,  pigment,  and  foreign 
bodies,  all  in  stages  of  degeneration.  Meser  found  throughout  a  deep  cancer 
of  the  breast  lycopodium  seeds  which  had  penetrated  the  tumor  from  the 
dressing  and  had  been  englobed  in  the  cells. 

Multiplication  of  centrosomes  with  their  surrounding  archoplasm  may 
yield  a  number  of  cytoplasmic  bodies  containing  a  central  chromatic  point, 


FIG.  6.— Bird's-eye  inclusions  in  cancer-cells.     (After  Le  Count.) 

and  a  rim  of  condensed  protoplasm  more  or  less  separated  from  the  remaining 
cytoplasm.  Hansemann  found  as  many  as  twenty  centrosomes  in  one  cancer- 
cell  with  multipolar  mitosis.  In  normal  cells  the  occurrence  of  multiple 
centrosomes  has  been  abundantly  shown  by  many  histologists,  Heidenhain 
counting  as  many  as  one  hundred  in  a  giant-cell  of  the  rabbit's  marrow. 

Comparing  the  centrosomes  of  the  guinea-pig's  spermatocytes  with 
structures  in  cancer-cells,  Borrel  has  shown  that  multiple  centrosomes  are 
a  prolific  source  of  the  peculiar  bird's-eye  inclusion  of  Leyden  which  he  and 
many  others  have  regarded  as  a  parasite.  He  finds  that  the  centrosomes  of 
cancer-cells  may  appear  as  chains  or  congeries  of  chromatin  granules  without 
special  protoplasmic  mantle  or  as  multiple  chromatic  granules  with  well 
segregated  and  somewhat  differentiated  cytoplasm,  or  as  single  swollen 
chromatin  bodies  with  large  cytoplasmic  masses  lying  in  cell  vacuoles. 

LeCount's  observations  support  Borrel's  interpretation  of  a  large  class 
of  intracellular  bodies  in  cancer.  Benda  in  dissenting  from  this  view  was 
able  to  show  the  presence  of  normal  centrosomes  in  cells  containing  the  bird's- 
eye  inclusion,  possibly  from  some  other  source  than  centrosomes. 


48  NEOPLASTIC  DISEASES 

Accumulation  of  secretory  products  greatly  modifies  the  appearance  of 
many  tumor-cells  and  produces  some  structures  which  have  been  interpreted 
as  parasites.  Since  the  secretory  activities  of  glandular  epithelium  are 
closely  associated  with  that  portion  of  the  cell  containing  the  centrosome, 
the  presence  of  chromatin  in  many  cancer  bodies  is  perhaps  not  an  argument 
against  the  origin  of  these  bodies  from  secretory  processes.  That  such  an 
origin  accounts  for  many  of  the  peculiar  structures  in  cancer-cells  has  been 
maintained  by  many  observers.  Pianese  thus  explained  the  majority  of 
the  bodies  of  the  Thoma-Sjobing  type  which  were  small  perinuclear  bodies 
with  relatively  large  chromatin  granules.  According  to  Greenough  the  char- 
acteristic bird's-eye  inclusion  of  cancer-cells  is  practically  limited  to  glandular 
carcinomas  and  is  chiefly  the  result  of  secretory  processes. 

He  found  them  nearly  constantly  in  breast  cancers,  but  absent  in  sarcomas 
and  epitheliomas. 

Somewhat  similar  conclusions  have  been  reached  by  Nosske,  Honda,  and 
Klimenko.  As  a  rule  these  authors  found  the  typical  inclusions  in  slowly 
growing  cancers  in  which  secretory  function  may  be  assumed  to  persist. 
In  position  they  usually  lie  between  the  nucleus  and  the  alveolar  lumen 
(Greenough).  They  vary  in  size  from  minute  globules  to  masses  distending 
the  cell.  Stains  show  a  central  basophile  portion  which  may  be  of  large  size 
or  may  be  absent,  and  a  rim  of  protoplasm  which  may  be  granular,  or  radially 
striated,  or  surrounded  by  a  condensation  capsule.  While  Plimmer  stated 
that  these  bodies  occur  in  enormous  numbers  in  rapidly  growing  cancers, 
chiefly  in  the  growing  edges,  later  observers  have  not  confirmed  this  state- 
ment, but  have  found  them  in  moderate  numbers,  chiefly  in  slowly  growing 
tumors,  and  well  within  the  edges.  Apolant  and  Embden  noted  very  few 
inclusions  in  mitotic  cells,  an  observation  which  accords  equally  well  with 
the  secretory  origin  as  with  the  centrosome  theory. 

Thus  the  specific  bird's-eye  inclusions  of  cancer-cells,  first  described  by 
Virchow,  suggested  by  Foa  as  a  possible  parasite,  appropriated  and  variously 
described  by  Thoma,  Soudakewitsch,  Leyden,  Plimmer,  Ruffer  and  Walker, 
and  finally  defended  by  Feinberg,  must  be  ascribed  to  two  main  sources, 
multiplication  of  centrosomes  and  secretory  processes  in  which  centrosomes 
are  probably  concerned.  The  chromatin  element  of  these  bodies  favors  their 
origin  from  centrosomes,  while  the  location  in  the  cell  and  the  morphology 
and  occurrence  chiefly  in  glandular  carcinoma  support  the  theory  of  retained 
secretion. 

STRUCTURE  AND  GROWTH 

The  composition  of  tumors  and  the  characteristics  of  their  growth  present 
many  variations  from  the  normal  standards. 

Some  tumors,  called  kistioid,  reproduce  simple  tissues  and  are  composed 
of  a  single  and  uniform  parenchyma. 

Others,  called  organoid,  are  of  more  complex  architecture  consisting  of 
tumor-cells  supported  by  normal  stroma  and  blood-vessels,  and  reproduce 
the  structure  and  preserve  more  or  less  the  function  of  organs.  The  extremes 
of  these  types  are  well  defined,  as  lymphosarcoma  versus  adrenal  adenoma, 
but  the  great  majority  of  tumors  reveal  some  organoid  characters. 

Homotypic  or  homologous  tumors  reproduce  the  structure  of  the  tissue 
in  which  they  arise  (adenoma  of  breast) ;  heterotypic  or  heterologous  growths 
differ  in  structure  from  the  tissue  in  which  they  grow  (chondroma  of  breast). 
Tumors  may  reproduce  the  structures  of  adult  organs,  and  tumor  cells 
may  preserve  the  characters  of  adult  cells,  as  in  epithelioma  of  the  lip,  and 
there  may  be  termed  adult  tumors.  Others  arise  from  groups  of  embryonal 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY 


49 


cells  whose  adult  characters  they  never  reproduce  and  these  are  conveniently 
termed  embryonal.  Examples  are  the  so-called  fetal  adenoma  of  thyroid, 
and  many  teratomas  of  testicle  and  kidney.  Such  embryonal  tumors  are 
to  be  distinguished  from  those  which,  because  of  extreme  metaplasia,  differ 
widely  from  the  originating  structure.  The  organoid  homotypic  and  adult 
characters  tend  to  disappear  as  growth  proceeds  more  rapidly  and  in  metas- 
tases  and  recurrences,  or  in  different  parts  of  the  same  tumor.  In  ordinary 
cancer  of  the  breast  there  may  be  wide  variations  in  these  qualities. 

Adamantinoma  in  successive  recurrences  may  change  from  an  adult 
acanthoma  through  an  adenomatoid  growth  to  a  highly  malignant  tumor 
composed  of  closely  packed,  indifferent  round  and  polyhedral  cells. 

Chondro-epithelioma  of  the  parotid  of  comparatively  adult  type  may 
recur  as  pure  atypical  myxoma.  Recurrences  after  operation  may  differ 
widely  from  the  original  structure.  I  have  observed  typical  perithelioma 


FIG.  7. — Peritheliomatous  structure  assumed  by  adenocarcinoma  of  uterus  following 

curettage. 

after  the  removal  of  adenocarcinoma  of  testis,  and  in  a  uterus  removed  shortly 
after  curettage  for  typical  adenoma  malignum  I  have  found  a  spindle-cell 
tumor  of  perithelial  type. 

Wholly  spontaneous  changes  are  illustrated  in  adenocarcinoma  of  adrenal 
which  may  invade  the  liver  under  the  form  of  diffusely  growing  large  cell 
carcinoma. 

In  normal  growth  cells  maintain  a  certain  quantitative  relation  to  the 
other  elements  of  the  tissue  of  origin,  and  they  have  an  orderly  arrangement 
and  a  polarity  toward  each  other  and  to  contiguous  structures,  but  in  tumors 
there  is  a  progressive  loss  of  these  relations.  Even  in  benign  tumors,  as  in 
chondroma,  the  cells  are  in  excess  over  stroma  and  their  relation  and  position 
are  altered. 

Some  adenomas,  as  of  thyroid  and  stomach,  show  a  remarkable  preserva- 
tion of  normal  structure  even  while  proving  malignant,  but  in  most  pro- 
4 


50  NEOPLASTIC  DISEASES 

nounced  blastemas  cells  increase  enormously  over  stroma,  eventually  rela- 
tions between  individual  cells  and  between  cells  and  stroma  are  lost,  and 
the.  cells  grow  diffusely.  Several  notable  characters  of  tumors  are  dependent 
upon  the  gradual  development  of  these  tendencies.  Benign  tumors  retain 
much  of  the  tissue  organization,  grow  from  their  own  resources,  provide 
themselves  with  their  own  stroma  and  vessels,  and  push  surrounding  tissues 
before  them  and  remain  encapsulated. 

In  malignant  tumors  the  cells  increase  in  number  and  size,  become  dis- 
placed from  natural  connections,  lose  their  polarity,  and  invade  and  destroy 
surrounding  tissues. 

Lining  cells  grow  outward  into  polypoid  projections,  drawing  blood- 
vessels with  them,  or  downward,  forming  compressed  pearls  or  convoluted 
cords;  gland  alveoli  elongate  and  widen,  or  sacculated  projections  from  sides 
or  fundi  produce  simple  tubules,  or  cystic  or  complex  adenomas;  diffuse 
masses  of  cancer  or  sarcoma  cells  disorganize  the  normal  structure  and  force 
their  way  into  neighboring  spaces,  alveoli,  and  vessels.  The  demands  for 
nourishment  lead  to  formation  of  elongated  vessels  sheathed  with  tumor- 
cells  producing  the  arrangement  of  perithelioma,  which  may  appear  in  many 
varieties  of  tumors  where  the  cells  are  pressed  for  food. 

Necroses  arise  where  nutrition  fails.  Finally,  the  disordered  cells  pene- 
trating lymph-  and  blood-vessels,  become  loosened  and  pass  into  the  circula- 
tion, lodging  into  adjacent  lymph-nodes  or  distant  organs,  giving  rise  to 
secondary  tumors. 

Many  of  these  characters  of  tumor  growth  must  be  referred  to  mechanical 
crowding  of  cells,  and  the  demands  for  nutrition,  influenced  by  whatever 
remnant  of  tissue  organization  the  tumor  may  retain. 

The  local  extension  of  malignant  tumors  gives  rise  to  many  changes  in  the 
invaded  tissue  and  reveals  many  specific  qualities  of  tumor-cells. 

Local  extension  involves  the  passage  of  tumor-cells  first  into  tissue  spaces 
and  lymph  radicles.  Whether  tissue  spaces  directly  communicate  with  lymph 
radicles  (Recklinghausen),  or  lymph  radicles  form  a  series  of  closed  anas- 
tomosing channels  (Ranvier),  there  is  no  doubt  that  inflammatory  and 
degenerative  processes  soon  open  the  lymphatic  vessels  to  the  tumor-cells. 

From  this  point  the  ameboid  properties  of  the  cells  (Klebs,  Waldeyer), 
mechanical  pressure,  and  the  natural  course  of  fluids  facilitate  the  progress 
of  the  tumor  toward  the  larger  lymph-vessels  and  nodes.  Invasion  of  the 
terminal  vessels  occurs  through  the  communication  between  the  lymph  and 
blood  capillary  plexuses  (Sabine). 

Through  gland  ducts,  renal  tubules,  bile  ducts,  bronchioles,  and  tubular 
structures  also,  as  well  as  through  vessels,  local  extension  may  occur. 

In  muscle,  extension  of  tumor-cells  is  affected  by  the  muscular  contrac- 
tions, and  especially  in  pyloric  cancer  the  extension  may  be  wide-spread  before 
any  local  tumor  develops.  Blumenthal  attributes  the  invasive  properties 
of  tumor-cells  to  their  proteolytic  enzymes  which  he  conceived  as  dissolving 
the  tissue  barriers,  but  neither  the  histology  of  the  process  nor  the  known 
capacities  of  tumor  ferments  support  such  a  view. 

Inflammatory  reaction  frequently  meets  the  invasion  of  tumor-cells. 
This  is  usually  of  a  low  grade,  causing  the  appearance  of  lymphocytes,  large 
mononuclear  leukocytes,  plasma-cells,  and  in  certain  cases  polynuclear  leu- 
kocytes. It  is  a  highly  significant  feature  of  malignant  tumor  growth  and 
must  be  regarded  as  a  defensive  process.  Well-marked  reaction  signifies  a 
pronounced  capacity  to  limit  the  tumor  growth,  but  not  that  the  effort  will  be 
successful.  Yet  about  many  epitheliomas  which  are  making  little  progress 
one  finds  a  thick  barrier  of  lymphocytes.  In  carcinoma  of  the  breast  one 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY 


51 


may  find  islands  of  tumor-cells  inclosed  in  masses  of  lymphocytes  and 
presenting  clear  signs  of  degeneration. 

It  is  probable,  as  Orth  concludes,  that  some  degeneration  of  tumor-cells 
always  precedes  the  tissue  reaction. 

Very  actively  growing  malignant  tumors  and  their  late  metastatic 
deposits  often  fail  to  show  any  inflammatory  reaction,  but  the  majority 
of  infiltrating  growths  elicit  considerable  cellular  response  from  invaded 
tissues.  Degeneration  and  calcification  of  tumor-cells,  formation  of  macro- 
phages  from  fibroblasts,  endothelium,  and  leukocytes,  and  appearance  of 
giant  tumor-cells,  accompany  the  process. 

Besides  the  general  inflammatory  reaction,  which  fails  only  in  very  rapid 
invasion,  the  different  tissue  cells  exhibit  interesting  reactions  against  tumor- 
cells. 


Diffuse  lymphocytic  infiltration  in  a  rapidly  growing  carcinoma  of  breast. 


Striated  muscle-cells  exhibit  a  relative  immunity  to  many  cancers  which 
infiltrate  the  perimysium  wrhile  long  sparing  the  muscle-fibers.  Eventually 
the  sarcolemma  is  penetrated  and  the  tumor-cells  pass  rapidly  along  the 
sheaths,  absorbing  the  muscle  substance,  hollowing  out  central  portions  of 
fibers,  causing  fatty  and  hyaline  degeneration,  fragmentation,  swelling  of 
ends  of  fibers  with  formation  of  giant-cells,  and  exciting  proliferation  of  nu- 
clei of  sarcolemma  and  muscle-cell  (Fujinami). 

Smooth  muscle-cells  also  are  rather  resistant,  but  are  frequently  destroyed 
chiefly  with  simple  atrophy. 

Specialized  gland  epithelium  is  usually  passive  before  the  attack  of  invad- 
ing tumors.  The  cells  degenerate  and  atrophy,  the  membrana  propria  often 
persisting  to  inclose  pseudo-alveoli  of  tumor-cells.  Gland  ducts  are  often 
filled  or  distended  with  tumor-cells  which  replace  the  lining  cells  or  stimulate 
them  to  feeble  multiplication. 


52  NEOPLASTIC  DISEASES 

Squamous  epithelium  tends  to  hypertrophy  when  invaded  by  alien  cells, 
with  thickening  of  the  Malpighian  layer,  formation  of  new  papillae  and  hyper- 
keratosis.  With  melanoma  the  swollen  hyperchromatic  and  pigmented 
epithelium  is  often  difficult  to  distinguish  from  the  tumor-cells. 

Endothelium  usually  degenerates,  exfoliates  and  disappears,  or  forms 
macrophages.  In  blood-vessels  it  may  proliferate  and  assist  in  the  formation 
of  stroma. 

In  connective  tissues  where  the  changes  are  not  obscured  by  inflammation 
the  invasion  leads  to  degeneration,  compression,  and  atfophy  of  fibroblasts, 
swelling,  edema,  fragmentation  and  solution  of  fibrils  and  matrix,  and  destruc- 
tion of  elastic  fibers. 

In  many  organs  preexisting  stroma,  vessels  and  trabeculae,  may  long 
persist,  as  in  the  lung,  where  the  air  vesicles  may  be  passively  filled  with  invad- 
ing tumor-cells.  Strongly  encapsulated  organs,  as  testis,  kidney,  lymph- 
nodes,  spleen,  may  long  resist  invasion  and  rupture  by  tumor-cells. 

Reactive  growth  of  invaded  connective  tissue  plays  an  important  part 
in  the  course  of  desmoplastic  tumors.  In  scirrhous  and  metastatic  car- 
cinoma it  may  far  exceed  the  bulk  of  tumor-cells  and  may  eventually  lead 
to  complete  scarring  of  large  quescent  areas  once  the  seat  of  active  proli- 
feration. 

In  fat  tissue  cells  penetrate  readily,  replace  the  fat  in  the  tissue  cell 
envelops,  incite  mucous  degeneration,  form  foreign  body  giant-cells  about 
free  fat,  and  sometimes  induce  proliferation  of  fat-cells. 

Periosteum  and  perichondrium  may  successfully  resist  invasion  from 
without,  but  when  the  element  of  pressure  is  added  they  yield  to  the  invading 
cells.  From  within  the  attack  on  bone  is  more  rapid.  The  matrix  is 
absorbed,  the  tumor-cells  forming  lacunae  like  osteoclasts,  dissolving  cancel- 
lous  tissue,  and  in  many  cases  of  myeloma,  sarcoma  and  metastatic  hyper- 
nephroma  and  carcinoma,  perforating  the  shaft.  New  blood-vessels  accom- 
pany these  inroads  and  new  fibroblasts  act  as  osteoclasts,  facilitating  the 
absorption.  Formative  osteitis  accompanies  many  tumor  processes  in  bone. 
Located  in  periosteum  it  may  lead  to  bony  encapsulation  on  the  periphery' 
keeping  pace  with  bone  absorption  within.  Epithelial  tumor-cells  invading 
bone  are  usually  free  from  new  bone  formation,  but  in  a  group  of  carcinomas, 
especially  of  the  prostate,  bone-cells  are  excited  to  extensive  proliferation 
possibly  even  to  the  extent  of  a  secondary  tumor  growth.  Such  cases  are 
wholly  different  from  the  tumors  originating  in  bone-cells  and  yielding  the 
extensive  group  of  bone  sarcomas.  In  certain  very  vascular  tumors  the  bone 
is  passively  absorbed  and  replaced  by  large  sinuses  lined  by  giant-cells. 

Nerve-trunks  owing  to  their  rich  lymphatic  sheathing  are  extensively 
invaded,  especially  by  epithelial  tumor-cells.  The  medullary  sheaths 
atrophy  from  pressure,  the  axis-cylinders  being  the  last  element  to  disappear; 
while  the  nuclei  may  feebly  multiply. 

In  a  few  instances  the  nerve-trunks  seem  to  lead  the  way  in  local  exten- 
sions, especially  of  epidermoid  carcinoma.  Brain  tissue  is  quite  passive  to 
the  invasion  of  tumors,  suffers  pressure  atrophy  with  degeneration  of  all  the 
specific  elements,  while  necrosis  often  occurs  from  occlusion  of  vessels. 

In  the  local  extension  of  malignant  tumors  the  inherent  momentum  of 
cell  growth  is  doubtless  the  chief  factor.  As  this  property  constitutes  the 
great  distinction  between  normal  regeneration  and  malignant  neoplasia,  its 
analysis  is  of  first  importance,  and  will  be  discussed  under  general  etiology. 
Here  it  may  only  be  mentioned  that  the  histological  study  of  invaded  tissues 
leads  to  the  conclusions  above  stated,  and  offers  little  basis  for  the  theories 
of  attraxins  drawing  the  cells  deeply  into  the  tissues,  or  of  special  toxic  agents 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY  53 

preparing  the  tissues  for  invasion,  or  for  the  belief  that  inflammatory  changes 
greatly  influence  the  invasive  properties  of  the  cells  of  an  established 
tumor. 

Functional  activity  in  tumors  may  be  retained  in  part  or  exhibited  in 
exaggerated  form.  Geotropism,  the  quality  of  living  cells  to  cover  and  grow 
along  surfaces,  is  shown  in  epithelioma,  endothelioma,  and  adenoma.  Phago- 
cytosis of  bacteria,  leukocytes,  red  cells,  fragments  of  organ  cells,  other  tumor- 
cells,  even  in  mitotic  division,  bile,  fatty  material  and  foreign  bodies, 
is  exhibited  in  great  variety.  Many  tumor-cells  may  exhibit  slow  ameboid 
properties,  as  first  observed  by  Virchow  in  chondroma. 

The  abundant  matrix  in  many  osteo-  and  chondrosarcomas,  the  mucus  of 
myoma,  fat-cells  in  liposarcoma,  and  the  rigid  alveolar  structure  of  adenoma 
destruens  even  in  metastases,  are  familiar  indications  of  functional  activity. 

Clear  examples  of  overfunction  of  tumor  tissue  are  seen  in  mucous 
carcinoma  of  the  colon  and  in  melanoma  of  the  skin.  Some  tumors  of  the 
hypophysis  seem  to  be  followed  by  overactivity  of  the  influence  of  this  gland 
on  growth. 

While  tumors  destroying  the  adrenal,  pancreas,  or  thyroid  may  not  be 
followed  by  Addison's  disease,  diabetes,  or  myxedema,  yet  the  functional 
capacities  of  such  tumor  tissue  have  not  been  demonstrated  by  chemical 
and  physiological  tests,  and  the  absence  of  specific  disease  with  these  tumors 
may  be  referable  to  the  wide  limit  of  safety  of  the  organs  involved  or  the 
presence  of  aberrant  glands.  Hansemann  reports  complete  destruction  of 
the  pancreas  by  carcinoma  without  diabetes,  although  diabetes  is  common 
with  cancer  of  the  pancreas.  The  early  bilateral  adenomas  of  the  adrenal 
may  very  well  fail  to  give  Addison's  disease,  but  I  have  seen  complete  destruc- 
tion of  both  adrenals  by  diffuse  hypernephroma  with  bulky  metastases,  but 
no  signs  of  Addison's  disease.  The  disease  was  rapid  and  no  search  was  made 
for  aberrant  adrenals. 

Tetany  followed  extirpation  of  one-half  of  the  thyroid  for  cancerous  goiter 
by  v.  Eiselsberg,  but  disappeared  on  the  development  of  a  metastatic  focus. 
When  this  focus  was  removed  the  symptoms  of  tetany  recurred,  in  spite  of 
new  metastatic  growths,  these,  Hansemann  suggests,  being  more  anaplastic. 
Since  a  large  portion  of  the  thyroid  was  not  removed  and  since  the  symp- 
toms suggest  involvement  of  the  parathyroid  rather  than  the  thyroid  I 
think  the  interpretation  of  this  case  is  very  uncertain.  Many  thyroid 
adenocarcinomas  contain  colloid  and  functionate,  but  it  is  difficult  to  find 
any  histological  traces  of  functional  activity  in  true  cancer  of  the  thyroid. 

Adenoma  and  primary  carcinoma  of  the  liver  usually  fail  to  show  traces 
of  bile  formation,  yet  Heller  observed  bile  in  the  cells  of  a  pulmonary  metas- 
tasis from  liver  cancer.  Hansemann  found  bile  in  the  adenomatous  portion, 
but  none  in  the  carcinomatous  areas  of  an  adenocarcinoma  of  the  liver. 

Chemical  studies  in  general  support  the  view  that  many  tumors  retain 
some  of  the  function  of  their  parent  cells,  as  shown  by  the  high  content  and 
qualities  of  lipoids  in  hypernephroma  (Wells)  and  the  considerable  content 
of  iodin  in  thyroid  cancer  (Beebe,  Ewald).  As  a  rule,  functional  activities 
diminish  with  increasing  anaplasia,  and  original  overactivity  may  be  suc- 
ceeded by  complete  failure,  as  in  the  pigment-free  metastases  of  melanoma. 

Stroma. — -Benign  or  encapsulated  tumors  provide  themselves  with  a  new 
stroma,  while  infiltrating  growths  appropriate  and  alter  the  preexisting 
stroma  of  the  invaded  tissue.  In  sarcoma  it  is  usually  much  less  abundant 
than  in  carcinoma  and  may  consist  entirely  of  blood-vessels,  while  in  cancer 
it  is  more  abundant  and  fails  only  in  very  anaplastic  growths.  In  sarcoma 
a  fine  intercellular  stroma  is  in  some  degree  constant,  but  may  be  difficult 


54  NEOPLASTIC  DISEASES 

to  demonstrate.  In  carcinoma  the  cells  are  in  immediate  apposition  without 
intervening  fibrils.  Endothelioma  reveals  its  close  embryological  relation  to 
sarcoma  by  fine  fibrils  which  imperfectly  penetrate  the  cell  masses  (Woolley). 

In  benign  organoid  tumors  the  neoplastic  process  is  usually  limited  to 
one  type  of  cell,  in  adenoma  to  epithelial  cells,  and  the  new  stroma  results 
from  a  formative  influence  on  the  cells  of  the  connective  tissue  and  vessels 
associated  with  cells  originating  the  tumor. 

Mechanical  influences  may  be  prominent  in  the  behavior  of  this  stroma 
or  the  cells  may  show  active  mitosis,  and  even  participate  in  the  tumor  growth. 
Thus  stroma  may  have  adult  characters,  or  as  in  fibro-adenoma  it  may  be 
difficult  to  determine  whether  the  epithelium  or  the  stroma  cells  dominate 
the  neoplastic  process.  In  certain  ovarian  adenomas  the  periacinar  stroma 
may  be  extremely  cellular,  as  in  sarcoma. 

It  seems  necessary  to  sharply  distinguish  between  those  tumors  whose 
stroma  is  clearly  not  neoplastic  and  those  in  which  it  constitutes  a  part  of 
the  tumor  and  which  must,  therefore,  be  regarded  as  mixed  tumors.  In 
chondro-  and  osteosarcoma  the  stroma  is  a  combined  product,  consisting 
of  intercellular  substance  derived  from  the  tumor-cells  and  new  vessels  de- 
rived from  the  tumor  or  from  peripheral  tissues.  In  teratomatous  cancer 
of  the  testis  the  stroma  may  be  richly  infiltrated  by  lymphocytes  and  even 
contain  lymph-follicles,  yielding  a  type  of  stroma  not  seen  in  any  other  car- 
cinoma. In  veins  the  stroma  of  an  invading  tumor  may  consist  of  capillaries 
arising  from  the  vessel  wall. 

Elastic  fibers  are  seldom  reproduced  in  the  stroma  of  tumors  and  if  present 
belong  chiefly  to  the  preexisting  tissue  (Williams). 

According  to  Bonney  they  disappear  in  all  areas  of  connective-tissue 
proliferation  and  cellular  exudation,  but  in  isolated  areas  in  breast  cancer 
he  found  bulky  periacinar  masses. 

The  stroma  of  an  original  growth  may  fail  to  be  reproduced  in  metastases 
with  increasing  anaplasia,  but  often  reappears  in  typical  form,  as  in  scirrhous 
carcinoma,  or  in  the  overdeveloped  vessels  of  fungous  hematodes. 

The  stroma  of  surrounding  tissues  may  be  (i)  passive  during  the  increase 
of  tumor-cells,  or  it  may  be  incited  to  (2)  reactive  growth,  and  there  is  con- 
siderable evidence  to  show  that  this  reaction  may  reach  almost  if  not  quite 
to  a  (3)  neoplastic  grade. 

Most  highly  organized  tissues  are  passive  during  tumor  invasion,  as  the 
liver  in  cancer.  Very  active  growth  of  tumor-cells  usually  fails  to  excite  any 
reaction  even  from  simple  tissues,  as  in  lymphosarcoma  in  the  skin. 

Apart  from  collateral  hypertrophy  as  previously  discussed,  epithelial 
tumor-cells  exert  a  notable  formative  influence  on  connective  tissue;  they 
are  desmoplastic. 

So  marked  is  this  influence  that  many  carcinomas  are  composed  of  much 
new  connective  tissue  and  relatively  few  cells  both  in  primary  tumors  and 
in  metastases.  Originally  this  action  is  the  result  of  a  formative  stimulus  of 
epithelium  upon  connective  tissue,  but  eventually  it  proves  protective  and 
some  cancerous  areas  undergo  complete  regression  from  overgrowth  of  fibrous 
tissue. 

An  osteoplastic  influence  is  exerted  on  bone  tissue  by  some  cancers,  and 
active  budding  and  proliferation  of  muscle-cells  is  occasionally  seen  with  rare 
myoplastic  tumors. 

That  the  presence  of  a  tumor  may  excite  its  stroma  or  surrounding  tissue 
to  neoplastic  growth  has  never  been  demonstrated.  While  improbable,  such 
an  action  is  not  impossible,  and  has  been  suggested  by  several  appearances 
encountered  with  spontaneous  and  transplanted  tumors.  Langhans  con- 


DEFINITION.    CLASSIFICATION.    GENERAL  PATHOLOGY  55 

sidered  the  possibility  that  teratoma  testis  might  incite  the  spermatoblasts 
to  tumor  growth  in  certain  complex  tumors  of  this  organ. 

In  certain  lymphocytomas  it  is  difficult  to  distinguish  between  the  infil- 
trative  growth,  multicentric  origin,  and  the  contact  influence  of  tumor-cells. 
Haaland  thought  he  observed  the  transformation  of  pulmonary  cells  into 
tumor-cells  about  metastatic  carcinoma  in  the  mouse.  Ehrlich,  Loeb,  and 
others  have  observed  the  sudden  appearance  of  sarcoma  in  the  course  of 
transplantations  of  carcinoma  in  mice  and  rats,  and  Murray  has  strongly 
substantiated  the  belief  that  this  sarcoma  arises  from  the  stroma  and  not 
from  the  altered  cancer-cells. 

The  influence  of  transplantations  renders  these  observations  inapplicable 
to  human  tumors,  and  several  uncertainties  still  surround  the  interpretation 
of  this  remarkable  change  of  structure.  No  such  stroma  reaction  has  been 
observed  in  spontaneous  tumors,  although  the  reactive  overgrowth  of  invaded 
tissues  may  at  times  exhibit  some  of  the  qualities  of  a  neoplasm. 

Regressive  changes  occur  in  tumor  stroma  very  similar  to  those  observed 
in  the  parenchyma.  In  some  cases  these  changes  greatly  influence  the  char- 
acter and  course  of  the  tumor.  In  progressive  keloids  the  hyaline  stroma 
is  the  chief  portion  of  the  tumor. 

Cylindroma,  or  syphonoma,  are  terms  applied  to  a  tumor  structure  in 
which  the  stroma  appears  in  the  form  of  elongated,  twisted,  thickened  cords 
of  hyaline  material.  This  structure  is  most  often  seen  in  basal -cell  carcino- 
mas. In  old  regressing  carcinoma  large  areas  of  tissue  may  show  very  few 
tumor-cells  in  a  mass  of  quiescent  hyaline  stroma. 

Edema,  mucous  degeneration,  and  calcification  of  stroma  are  frequent 
factors  influencing  the  course  of  tumors. 

In  cancers,  fatty  degeneration  often  affects  not  only  the  parenchyma  but 
also  the  stroma.  Calcification  may  begin  in  the  stroma  and  gradually  involve 
the  entire  substance  of  myomas,  or  it  may  form  a  hard  shell  about  this  or 
other  growths.  Solid  or  lamellated  concretions  of  hyaline  material  of  uncer- 
tain nature  are  occasionally  seen  in  the  stroma  as  in  the  parenchyma. 

Experimental  Analysis  of  Stroma  Reactions. — Much  light  has  been  thrown 
on  the  meaning  of  the  cellular  reaction  to  invading  tumors  by  experimental 
studies  on  transplantable  tumors. 

The  inoculation  of  susceptible  animals  with  a  tumor  graft  is  usually  followed  by  a 
brief  local  polynuclear  leukocytosis  incited  by  diffusible  products  of  tumor-cells  red 
cell  detritus,  and  traumatism. 

An  excessive  degree  of  this  reaction  may  prevent  the  graft  from  surviving.  With 
successful  grafts  there  is  later  a  gathering  of  lymphocytes  in  moderate  number  and  these 
may  form  rich  foci  which  interfere  with  the  growth  of  the  tumor-cells.  The  graft  then 
becomes  successfully  implanted  by  inciting  the  growth  of  fibroblasts  and  capillaries 
about  which  the  cells  adhere.  Often  the  vessels  of  the  graft  are  appropriated  and  re- 
opened. From  this  point  the  growth  proceeds  by  multiplication  of  the  transferred  cells 
about  the  new  stroma  derived  from  the  host's  tissues.  In  its  further  progress  the  tumor 
may  become  encapsulated  and  thus  be  shielded  from  cellular  attack,  or  it  may  early 
show  infiltrative  tendencies  unopposed  by  any  cellular  reaction. 

In  some  conditions  animals  become  immunized  by  the  temporary  growth  followed 
by  spontaneous  regression  of  the  tumor  (Gaylord,  Clowes).  In  such  cases  one  of  the 
earliest  changes  observed  is  a  focal  degeneration  of  the  tumor-cells  accompanied  by  an 
accumulation,  probably  from  chemotactic  influences,  of  ameboid  large  and  small 
lymphocytes,  mononuclear  leukocytes,  and  often  many  plasma  cells.  Minute  hemor- 
rhages may  occur  in  the  tumor  about  which  eosinophile  cells  gather.  These  cells  sur- 
round the  tumor  and  penetrate  within  it,  sometimes  richly  infiltrating  the  stroma. 

Then  follows  contraction  of  the  tumor  mass,  multiplication  of  spindle-cells,  growth 
of  new  vessels,  and  encapsulation  of  the  regressing  tumor.  During  the  absorption  process 
the  endothelial  macrophages  appear  and  giant-cells  result  from  fusion  of  tumor  ele- 
ments. Even  to  a  late  stage  mitosis  may  persist  in  such  encapsulated  regressing  tumors 
and  section  of  the  capsule  may  excite  renewed  growth. 


56  NEOPLASTIC  DISEASES 

In  immune  animals  the  implantation  of  cancer  excites  a  more  active  emigration  of 
polynuclear  cells,  the  degeneration  of  parenchyma  cells  appears  earlier  and  is  more 
pronounced,  and  the  lymphocytic  reaction  is  less  marked,  plasma-cells  being  absent 
(De  Fano). 

With  a  sarcoma  of  the  hare  transplanted  into  rabbits  v.  Dungern  and  Coca  obtained 
in  the  rabbit  hypersensitization  followed  by  complete  immunity  by  successive  implan- 
tations of  the  tumor.  The  second  or  third  graft  excited  a  rich  production  of  endothelial 
macrophages  which  promptly  surrounded  and  englobed  the  degenerating  tumor-cells, 
and  formed  macrophage  thrombi  in  the  small  vessels.  Leukocytes  were  not  prominent 
in  this  reaction.  In  the  adjoining  lymph-nodes  were  many  similar  endothelial  macro- 
phages. 

With  Jensen's  mouse  cancer  Russell  found  that  grafts  in  resistant  mice  suffered  ex- 
tensive degeneration  and  the  peripheral  rim  of  surviving  cells  failed  to  excite  a  stroma 
reaction. 

Working  with  Japanese  mice  Burgess  observed  that  in  both  susceptible  and  non- 
susceptible  animals  tumor  grafts  established  themselves  by  exciting  a  stroma  reaction, 
after  which  in  the  immunized  mice  the  nutrition  of  the  tumor  was  cut  off  by  overgrowth 
of  fibroblasts  with  much  intercellular  substance. 

In  the  interpretation  of  these  results  one  may  conclude  that  in  highly  immunized 
and  hypersensitized  animals  the  reaction  is  pronounced,  immediate,  and  exudative, 
preventing  the  growth  of  new  stroma  or  by  thrombosis  (v.  Dungern-Coca)  shutting  off 
blood-supply.  In  spontaneously  immune  or  in  alien  animals  the  reaction  is  less  pro- 
nounced, new  stroma  forms,  but  later  degeneration  of  the  graft  leads  to  strangulation 
by  connective-tissue  overgrowth. 

Analyzed  in  the  light  of  experimental  studies,  the  processes  connected 
with  the  growth  of  tumors  signify  as  follows: 

Infiltrative  growth  without  stroma  or  cellular  reaction  indicates  absence 
of  protective  forces  in  the  body. 

The  development  of  vascular  stroma  from  the  host's  tissues,  up  to  a  cer- 
tain degree,  is  favorable  to  the  growth  of  the  tumor. 

Overgrowth  of  stroma  with  much  intercellular  substances  is  a  menace 
to  the  tumor. 

Polynuclear  leukocytes  gather  about  the  tumor  as  the  result  of  necrosis, 
trauma,  bacterial  processes  and  actively  chemotactic  tumor  products,  and 
signifies  a  sharp  response  against  the  tumor. 

Lymphocytes  and  large  mononuclear  leukocytes  signify  a  reaction  of 
immunity,  limiting  the  growth  of  cells,  establishing  local  tissue  immunity, 
and  conveying  immune  forces  to  a  distance.  Plasma-cells  are  a  later  factor 
in  the  same  process. 

Eosinophile  cells  gather  about  hemorrhages. 

Endothelial  proliferation,  if  slight,  figures  as  a  part  of  the  stroma  reaction, 
but  if  excessive,  macrophages  form  and  oppose  cell  growth. 

Degeneration  of  tumor  areas,  fusion  giant-cells,  and  necrosis  may  result 
chiefly  from  withdrawal  of  nutriment. 

It  is  obvious  that  most  of  these  conclusions  have  been  warranted  by  previous 
study  of  human  material,  but  it  must  be  claimed  that  the  experimental  studies 
have  rendered  them  more  precise. 

Blood-vessels. — The  relation  of  blood-vessels  to  tumor  growth  presents 
two  highly  important  aspects,  first  in  connection  with  the  beginning  of  cancer, 
and  second  in  the  channels  of  nutrition  in  the  progressive  growth  of  tumors. 

Franz  Boll  from  a  study  of  early  epithelioma  and  of  the  growing  edges 
of  such  tumors  concluded  that  changes  in  the  blood-vessels  determined  the 
proliferation  of  epithelium.  He  found  the  walls  of  capillaries  thickened, 
opaque,  and  varicose.  The  adventitia  of  veins  and  arteries  was  invaded  by 
cells,  and  the  vessels  lost  their  sharp  demarcation  from  the  surrounding  tissue 
which  took  on  an  embryonal  character. 

These  changes  were  found  throughout  the  tumor  and  preceded  the  exten- 
sion of  the  growth.  An  extensive  disease  of  the  vascular  system  of  the  whole 


DEFINITION     CLASSIFICATION.    GENERAL  PATHOLOGY  57 

area  involved  was  in  Boll's  opinion  an  essential  part  of  the  cancerous  process. 
The  later  study  of  the  vascular  system  of  malignant  tumors,  while  not  fully 
demonstrating  the  prime  influence  of  vascular  lesions,  has  yet  emphasized 
the  importance  of  the  blood-supply  in  the  origin  and  growth  of  many  neo- 
plasms. 

Theilhaber,  among  recent  writers,  has  emphasized  the  importance  of 
arteriosclerosis  in  the  origin  of  many  cancers  in  elderly  persons.  He  con- 
cludes that  the  local  predisposition  of  aging  tissues  to  cancer  results  from  a 
diminution  of  the  cellular  elements  and  a  contraction  of  the  blood-vessels 
in  the  connective  tissue.  On  the  other  hand,  Warner  reports  a  study  of  the 
blood-vessels  of  206  cancerous  organs,  finding  that  105  (51  per  cent.)  showed 
obstructive  arterial  changes,  118  (57  per  cent.)  fibrosis,  and  85  (42  per  cent.) 
lymphocytic  infiltration.  Since  normal  vessels  were  present  in  almost  half 
the  cases  endarteritis  could  not  be  considered  a  necessary  factor  in  the  pro- 
duction of  the  disease. 

Possibly  a  very  close  analysis  by  various  methods  of  the  circulatory  con- 
ditions about  beginning  carcinomas  would  show  a  more  constant  relation 
between  this  factor  and  carcinoma  in  elderly  persons.  On  the  contrary  side, 
increased  vascularity  has  been  demonstrated  in  the  beginnings  of  many 
carcinomas,  and  has  been  assumed  to  account  for  the  awakening  of  many 
cell  rests.  Evidently  the  exact  relation  between  blood-supply  and  the  incep- 
tion of  carcinoma  has  not  yet  been  elucidated. 

Since  the  demands  for  nutrition  in  tumors  exceed  those  of  normal  tissues 
the  significance  of  the  vascular  system  is  correspondingly  increased.  In  the 
older  literature  S.  von  der  Kolk  stated,  as  a  result  of  injection  experiments, 
that  only  arteries  formed  anew  in  tumors,  the  veins  being  those  which  became 
inclosed  in  the  tumor. 

Extensive  lesions  of  the  blood-vessels  have  been  described  by  many  authors 
as  a  significant  feature  of  tumor  growth  (Eberth,  Belapolsky).  Virchow 
pointed  out  that  the  circulation  in  many  tumors  is  to  some  degree  independent 
of  and  different  from  the  general  circulation,  a  fact  according  with  the  parasitic 
nature  of  tumor  growth.  The  difficulty  of  passing  injection  material  from 
arteries  through  veins  he  attributed  to  compression,  invasion,  and  thrombosis 
of  the  veins  and  to  an  indirect  connection  of  veins  with  arteries. 

The  "saber-sheath"  flat  veins  on  the  surface  of  many  tumors  result  chiefly 
from  compression.  The  turgescence  of  enlarged  veins  leading  out  from  malig- 
nant tumors  was  one  of  the  gross  features  giving  rise  to  the  term  "cancer." 
Compared  with  the  affected  organ  the  vessels  of  actively  growing  tumors 
are  more  numerous,  dichotomous  branching  of  the  arterial  system  is  absent 
or  irregular,  and  the  main  vessels  are  often  tortuous  and  spirally  wound. 

The  vascular  system  may  be  studied  by  corrosion  preparations,  by  x-ray  photographs 
of  specimens  injected  with  bismuth  and  oil,  and  by  Hill's  method  of  injection  with  India 
ink  with  subsequent  clearing  of  tissues  by  alkali  and  glycerin. 

From  results  obtained  by  the  two  latter  methods  Goldman  observed  the  marked 
increase  in  vascularity  in  the  periphery  of  growing  tumors,  while  in  quiescent  cases  the 
central  portions  were  nearly  devoid  of  vessels  and  those  of  the  periphery  reduced.  The 
new  vessels  were  usually  of  small  size,  tortuous,  irregularly  distributed,  and  the  arteries 
rapidly  broke  up  into  capillaries. 

In  the  growth  of  blood-vessels  in  tumors  one  may  distinguish  two  factors, 
direct  irritation  by  tumor  products  and  a  formative  influence  exerted  by 
tumor-cells.  Along  the  growing  edges  of  advancing  carcinoma  there  is  often 
a  zone  of  hyperemia,  and  section  shows  many  new  capillaries  and  round- 
cells,  producing  at  times  a  structure  which  is  equivalent  to  granulation  tissue. 
Such  changes,  which  soon  regress,  may  be  referred  to  inflammatory  reaction. 


58  NEOPLASTIC  DISEASES 

In  the  artificial  implantation  of  tumor  grafts,  in  the  organization  of  intra- 
vascular  tumor  thrombi,  in  the  natural  growth  of  angiomas,  and  in  the  recur- 
rence of  many  varieties  of  cellular  tumors,  new  vessels  develop  apparently 
as  a  result  of  a  formative  influence  centered  on  the  vessels  of  surrounding 
tissues. 

In  many  endotheliomas  and  some  angiomas  the  vessels  constitute  the 
unit  of  the  tumor;  elsewhere  they  are  devoid  of  neoplastic  qualities.  The 
structure  known  as  perithelioma  may  develop  solely  as  an  expression  of  a 
formative  influence  of  tumor-cells  upon  blood-vessels,  and  has  been  observed 
in  angiosarcoma,  fibroblastic  sarcoma,  hypernephroma,  epithelioma,  and 
teratoma. 

The  structure  of  the  blood-vessels  varies  greatly. 

In  some  benign  growths  the  large  arteries  exhibit  all  three  coats  in  pro- 
portions approaching  the  normal.  In  most  malignant  tumors  muscle-tissue 
is  deficient  in  walls  of  arteries,  and  the  main  type  of  vessel  is  composed  of 
adult  fibroblastic  tissue  lined  by  endothelium.  In  many  endotheliomas 
the  vessels  are  chiefly  spaces  lined  by  tumor-cells.  In  adenoma  of  thyroid 
and  some  primary  carcinomas  of  the  liver  widely  dilated  capillaries  lined  by 
endothelium  produce  highly  vascular  growths.  In  telangiectatic  sarcoma 
the  capacious  sinuses  may  be  lined  by  endothelium  backed  by  connective 
tissue.  In  bone-sarcoma  widely  dilated  sinuses  are  lined  by  tumor  giant- 
cells,  as  in  the  pulsating  sarcomas  of  tibia  and  humerus.  Finally  a  feeble 
circulation  may  be  maintained  in  intercellular  tissue  spaces  without  definite 
lining  cells. 

Lesions  of  blood-vessels  are  frequent  and  important  for  both  the  tumor 
and  the  organism.  Functional  inadequacy  or  compression  of  vessels  is  chiefly 
responsible  for  the  degeneration  and  necrosis  of  the  parenchyma  of  tumors. 

Rupture  from  degeneration  or  trauma  gives  rise  to  hemorrhage  and  infil- 
tration with  blood.  Strangulation  of  pedunculated  ovarian  cystomas  or 
uterine  myomas,  cutaneous  sarcomas,  and  even  breast  cancer  may  lead  to 
complete  hemorrhagic  infarction,  necrosis,  and  sloughing. 

Hyaline  degeneration  of  vessel  walls  yields  a  characteristic  structure  in 
certain  sarcomas,  as  in  the  ovary. 

The  vessels  of  invaded  tissues  are  passively  compressed  or  react  with 
periarteritis  and  round-cell  infiltration  or  the  walls  are  invaded  by  tumor- 
cells  by  way  of  the  vasa  vasorum,  and  the  perivascular  lymphatics  form  a 
channel  directing  the  course  of  invading  cells.  Arterial  trunks  long  resist 
the  attack  of  most  tumors,  but  fall  a  ready  prey  to  squamous  epithelioma 
whose  cells  penetrate  the  adventitia,  split  up  the  muscularis,  occlude  the 
lumen,  and  thus  cause  necrosis  of  the  invaded  tissues.  In  such  vessels  the 
tumor-cells  may  largely  disappear  with  fibrous  organization.  In  the  veins 
tumor-cells  readily  penetrate  to  the  intima,  producing  nodular  swellings, 
endophlebitis  carcinomatosa,  and  eventually  rupturing  into  the  vein. 

It  has  often  been  noted  that  very  vascular  tumors  may  long  fail  to  develop 
metastases,  yet  the  invasion  of  tissue  veins  is  the  chief  source  of  metastatic 
growths  in  sarcoma  and  with  many  carcinomas.  An  intravascular  position 
characterizes  the  growth  of  certain  tumors  throughout  most  of  their  history. 
Chorioma  of  the  uterus  and  testis  is  remarkable  for  its  limitation  to  pelvic, 
vaginal,  abdominal,  and  pulmonary  veins.  According  to  Marchand  and 
Risel  other  rare  tumors  growing  in  or  invading  the  blood-vessels  may  imitate 
the  hydatidiform  appearance  of  chorioma.  Hypernephroma  often  passes 
up  the  renal  vein,  and  distends  the  vena  cava  and  the  hepatic  veins  before 
generalizing.  An  adenocarcinoma  of  the  liver  regularly  appears  as  a  circum- 
scribed growth  distending  the  large  branches  of  the  portal  vein  in  this  organ. 


DEFINITION.     CLASSIFICATION.    GENERAL  PATHOLOGY  59 

Course  and  Rate  of  Growth. — Many  variations  are  observed  in  the  course 
and  rate  of  growth  of  tumors. 

1.  Rapid  and  progressive  multiplication  of  tumor-cells  without  notable 
intermission  or  hindrance  is  characteristic  of  most  highly  malignant  neo- 
plasms. 

Lymphosarcoma  in  adult  or  young  subjects  may  run  its  course  in  a  few 
weeks  with  extensive  metastases  in  many  organs.  Cancer  of  the  liver  in 
elderly  subjects  may  terminate  with  steadily  progressive  symptoms  in  three 
months.  Some  melanotic  tumors  after  becoming  established  run  a  very 
rapid  course.  Children  are  especially  susceptible  to  such  forms  of  fulminant 
blastomatosis. 

Pregnancy  usually  accelerates  tumor  growth.  I  have  observed  cancer 
of  the  breast  arising  after  gestation  prove  fatal,  with  wide-spread  metastases, 
before  term.  With  experimental  tumors  pregnancy  sometimes  accelerates, 
but  at  other  times  retards  growth  (Moreau,  Loeb). 

2.  Intermittent  periods  of  relative  or  complete  quiescence  occur  in  the 
course  of  many  malignant  tumors.     It  is  probable  that  such  quiescence  is 
often  more  apparent  than  genuine.    The  progress  of  the  edges  of  carcinomas 
and  the  involvement  of  lymph-nodes  often  appear  to  be  sudden  and  the 
growth  reaches  certain  dimensions  in  a  few  weeks  after  which  progress  is 
much  slower.    Exhaustion  of  growth  capacities  may  partly  account  for  such 
cases,  but  usually  it  is  referable  to  pressure  on  a  distended  capsule  or  hindrance 
to  the  increased  blood-supply.     The  onset  of  edema,  hemorrhage,  retention 
of  secretions,  inflammatory  complications,  or  central  necrosis,  fibrosis,  con- 
traction, and  evacuation  of  fluids,  simulate  changes  in  the  rate  of  growth. 
Or  a  primary  tumor  may  be  at  a  standstill  while  internal  metastases  are 
active. 

The  general  nutrition  of  the  body  has  considerable  influence  on  the  rate 
and  extent  of  growth  of  many  tumors.  This  influence  is  most  clearly  seen 
when  the  tumor  is  encapsulated  and  secondary  complications  are  absent. 
Any  factor  which  influences  the  nutrition  of  the  body  as  a  whole  is  apt  to 
affect  the  size  of  a  tumor.  Infectious  diseases,  starvation  diet,  alimentary 
obstruction,  etc.,  by  reducing  the  general  nutrition  often  reduce  the  size  of 
tumors,  and  may  thus  give  a  false  impression  of  a  favorable  therapeutic 
influence.  On  the  other  hand,  some  lipomas  have  been  observed  to  grow  to 
a  bulky  size  in  emaciating  patients. 

Transplantable  tumors  of  lower  animals  have  been  found  to  follow  the 
normal  laws  of  growth  in  many  particulars. 

Yet  apart  from  these  conditions  there  appears  to  be  a  frequent  tendency 
in  certain  tumors  to  grow  steadily  to  a  certain  bulk  and  then  to  remain  sta- 
tionary until  trauma  or  other  external  factors  initiate  a  new  period  of  growth. 
A  definite  form  of  intermittent  growth  is  observed  in  cancer  of  the  stomach 
and  epithelioma  of  mucous  membranes  which  remain  localized  ulcers  for  a 
time,  but  suddenly  extend  more  rapidly  upon  the  invasion  of  liver  or  lymph- 
nodes.  Malignant  change  in  a  benign  tumor  is  marked  by  sudden  accel- 
eration of  growth,  as  when  myosarcoma  develops  on  a  uterine  myoma. 

3.  A  natural  limit  exists  to  the  course  of  some  tumors,  and  the  rule  of 
endless  increase  is  by  no  means  invariable.  Myomas  of  uterus  may  cease 
to  grow  at  the  climacteric.  Warts  and  lipomas  may  be  self-limiting.  The 
relative  bulk  is  in  part  an  indication  of  the  general  momentum  of  growth  of 
tumors.  Thus  squamous  epithelioma  does  not  as  a  rule  produce  a  bulky 
growth,  and  seldom  yields  bulky  metastases.  Epithelioma  of  skin  or  even 
of  esophagus  may  produce  ulcers  which  after  steadily  growing  to  certain 
dimensions  long  remain  practically  quiescent,  and  on  section  one  finds  a 


60  NEOPLASTIC  DISEASES 

firm  basis  of  connective  tissue  beneath  the  ulcer  and  few  or  no  mitoses  in 
the  tumor-cells.  Martland  has  reported  a  mixed  tumor  of  a  salivary  gland 
of  20  years'  duration  and  long  stationary.  The  same  numerous  and  com- 
plex factors  which  interrupt  growth  may  succeed  in  establishing  a  perma- 
nent limit.  It  is  also  beginning  to  appear  that  a  local  or  general  immunity 
may  be  slowly  established  and  effectually  prevent  growth. 

4.  Spontaneous  cure  is  observed  with  certain  tumors  under  peculiar  condi- 
tions. 

There  is  a  considerable  series  of  polypoid  tumors  of  skin  and  mucous 
membranes  where  nutrition  is  cut  off  by  constriction  of  the  pedicle  and  wiiich 
are  either  completely  extruded  or  regress  without  detachment.  Fibromas 
and  chondromas  may  accidentally  compress  their  nutrient  vessels  with  regres- 
sion or  sloughing. 

Within  the  tumor  hyaline  degeneration  of  vessels  and  mucous  degenera- 
tion of  stroma  and  parenchyma  usually  retard  growth  and  may  completely 
exhaust  the  capacity  for  growth.  Calcification  of  parenchyma  and  capsule 
may  incarcerate  the  tumor. 

Inflammation  about  the  borders  and  in  the  body  of  the  tumor  seems  to 
cause  the  occasional  extrusion  of  certain  sarcoid  growths  of  the  skin  (Ran- 
dolph, Watson).  Accidental  infection  by  erysipelas  has  been  followed  by 
spontaneous  regression  of  sarcomas. 

For  somewhat  uncertain  reasons  benign  tumors  have  been  known  to 
regress,  as  exostoses  (Nasse,  Starch)  and  papilloma  of  the  bladder  (Nitze). 
A  local  or  general  immunity  seems  to  be  the  only  explanation  of  an  increasing 
list  of  spontaneous  cures  of  highly  malignant  tumors. 

Most  of  these  cures  are  only  partial.  Among  them  are  sarcomas,  squa- 
mous  epitheliomas,  and  glandular  carcinomas  (Czerny). 

Tripier  records  a  case  of  multiple  round-  and  spindle-cell  sarcomas  of 
wide  distribution  with  pulmonary  hemorrhages  which  disappeared  after  the 
condition  seemed  hopeless.  The  exact  nature  of  this  case  is  uncertain. 
Kaposi  has  recorded  the  disappearance  of  lymphosarcoma  of  the  upper  jaw 
while  internal  metastases  were  in  progress,  and  Reichel,  of  a  spindle-cell 
sarcoma  of  forehead. 

Some  of  the  cures  have  followed  persistent  recurrence  after  operation 
(Shepherd,  Watson).  In  dermatological  literature  there  is  a  considerable 
list  of  reported  spontaneous  cures  of  cutaneous  sarcomas.  While  the  true 
nature  of  many  of  these  processes  is  uncertain,  I  do  not  believe  that  they 
can  properly  be  rejected,  as  Williams  would,  from  the  field  of  neoplasms. 

Spontaneous  recovery  from  chorioma  belongs  in  a  special  category  owing 
to  the  peculiar  relations  of  this  tumor.  In  15  cases  this  process  has  been 
known  to  regress  after  the  occurrence  of  pulmonary  or  vaginal  metastases, 
in  3  of  which  neither  uterus  nor  vaginal  nodules  were  removed.  In  7  other 
cases  recovery  followed  partial  removal  (Ewing). 

Recovery  after  partial  removal  of  ovarian  adenocarcinoma  is  not  infre- 
quent. Rotter  has  described  a  case  of  complete  cure  of  an  original  malignant 
adenoma  of  the  rectum,  although  after  3  years  a  metastasis  of  the  iliac  bone 
was  found  at  autopsy.  Here  a  complex  form  of  local  tissue  immunity  seems 
to  have  existed. 

With  cancer  of  the  breast  there  is  a  group  of  cases  in  which  the  disease 
becomes  locally  extensive  and  internal  metastases  form,  the  patient  becom- 
ing greatly  debilitated,  but  at  this  stage  the  picture  changes  and  very  marked 
improvement  sets  in  attended  with  regression  or  even  disappearance  of  many 
tumors.  Although  these  patients  usually  die  of  the  disease,  they  may  enjoy 
good  health  for  many  years.  General  debility  cannot  account  for  such  a 


DEFINITION.     CLASSIFICATION.    GENERAL  PATHOLOGY  61 

course,  and  there  seems  to  be  no  other  explanation  than  the  development 
of  a  relative  general  immunity.  In  MacKay's  case  improvement  was  coinci- 
dent with  absorption  of  a  pleural  exudate,  and  I  have  followed  several  very 
resistant  cases  which  were  marked  by  continuous  ascites,  sometimes  chyli- 
form  (Hodenpyl). 

Somewhat  similar  are  those  cases  in  which  primary  tumors  disappear 
and  the  patient  long  enjoys  fair  health,  during  the  very  slow  progress  of 
internal  metastases  (Bryant,  Gould,  Broca,  Hutchinson). 


FIG.    9. — Almost  complete  replacement  of  liver  by  metastatic  fibrosing  carcinoma  of 
breast.     The  external  tumors  in  this  patient  had  notably  regressed. 

The  self-limiting  tendencies  of  certain  epitheliomas  seem  to  have  resulted 
in  spontaneous  cure  in  cases  reported  by  Sanger.  Many  interesting  cases 
of  this  general  type  are  collected  by  Williams. 

The  morphology  of  spontaneous  regression  presents  special  characters 
with  each  type  of  tumor,  among  which  are  the  calcification  and  giant-cell 
formation  in  epithelioma  (Petersen),  giant-cell  degeneration  in  chorioma 
(Teacher)  (Ewing),  extreme  hyalinosis  in  cancer  of  the  liver,  and  simple 
atrophy  of  parenchyma  in  the  large  cell  tumor  of  the  testis. 


CHAPTER   III 
MALIGNANCY  AND  ITS  EFFECT  ON  THE  ORGANISM 

The  Significance  of  Malignancy. — The  distinctions  between  benign  and 
malignant  tumors  involve  questions  of  great  interest  from  both  the  theoret- 
ical and  the  practical  sides.  If  malignancy  were  a  purely  clinical  conception 
it  would  be  impossible  to  draw  any  rigid  distinctions  between  benign  and 
malignant  tumors,  since  nearly  all  tumors  may  occasionally  prove  fatal.  Yet 
the  tendency  is  to  restrict  the  term  to  tumors  which  exhibit  certain  features 
which  are  essentially  deleterious  to  the  host.  The  most  important  of  these 
features  are  infiltrative  growth,  local  destructive  properties,  recurrence  after 
removal,  formation  of  metastases,  local  interference  with  function  and  general 
toxic  action  of  absorbed  tumor  products.  These  elements  involve  both 
anatomical  and  clinical  effects. 

Infiltrative  growth  is  the  most  important  of  the  anatomical  factors  in 
malignancy  This  property  facilitates  local  and  general  extension,  renders 
removal  difficult,  is  responsible  for  many  recurrences,  and  is  a  constant  pre- 
liminary to  the  local  destruction  of  tissue.  The  controlling  influence  of  encap- 
sulation is  seen  in  the  harmless  course  of  many  very  cellular  tumors  which 
may  readily  be  enucleated  while  circumscribed,  but  which  on  rupture  of  the 
capsule  take  on  infiltrative  and  malignant  properties.  It  is  also  demonstrated 
in  transplantable  tumors  which  upon  incision  of  the  capsule  may  be  trans- 
formed from  regressing  into  malignant  infiltrative  growths  (Loeb). 

During  experimental  increase  of  growth  Bashford  and  others  have  shown 
that  originally  circumscribed  mouse  tumors  take  on  infiltrative  qualities. 
Yet  Borst  notes  that  early  fibroma  of  the  kidney  showing  infiltrative  growth 
later  becomes  encapsulated  and  the  same  observation  applies  to  myomas. 

Rapidity  of  growth  is  usually  associated  with  infiltrative  qualities  and 
deleterious  effects  and  if  carefully  separated  from  simple  increase  in  size 
from  other  causes  is  a  nearly  constant  sign  of  a  dangerous  tumor.  Local 
destruction  of  tissue  is  a  variable  feature  prominent  only  in  certain  types  of 
tumors,  appearing  early  in  squamous  epithelioma,  and  constituting  the  sole 
malignant  quality  of  rodent  ulcer.  In  benign  tumors  destruction  of  tissue 
is  a  secondary  effect  of  pressure.  Hemorrhage  from  destruction  of  vessels 
may  be  the  chief  instrument  in  the  cachexia  which  marks  the  course  of  many 
ulcerating  tumors  as  in  the  stomach  and  uterus.  Pain  from  involvement 
of  nerves  is  often  the  first  and  even  the  last  clinical  problem  in  the  course 
of  a  lethal  neoplasm. 

Formation  of  metastases  may  be  held  to  constitute  any  tumor  malignant. 
Being  usually  the  result  of  infiltrative  growth,  invasion  of  vessels,  and  cel- 
lular character,  and  signifying  dissemination  and  collapse  of  defensive  powers, 
it  is  the  most  impressive  external  sign  of  malignancy.  It  is,  however,  by  no 
means  constant  in  lethal  tumor  processes,  as  in  glioma,  rodent  ulcer,  etc., 
and  certain  tumors  otherwise  benign  may  occasionally  yield  distant  secondary 
growths,  as  chondroma  and  myoma. 

Local  interference  with  function  is  the  chief  dangerous  feature  of  many 
gliomas,  epitheliomas  of  larynx,  esophagus,  cardia,  and  cancer  of  the  pylorus 
and  rectum,  and  many  benign  tumors  become  serious  chiefly  from  effects 
of  pressure. 

62 


MALIGNANCY  AND  ITS  EFFECT  ON  THE  ORGANISM  63 

The  general  intoxication  resulting  from  tumor  growth  is  a  complex  subject 
which  has  long  been  recognized  as  one  of  the  most  obscure  and  important 
problems  in  the  natural  history  of  malignant  tumors.  Hemorrhage,  mechan- 
ical interference  with  nutrition,  pain,  the  psychical  condition,  abnormal 
secretions,  destruction  of  important  tissues,  the  toxic  action  of  products 
absorbed  from  degenerating  and  ulcerating  areas,  and  bacterial  infection 
combine  to  produce  the  cachexia  of  tumors  and  require  consideration  in  a 
separate  chapter.  When  the  clinical  signs  of  malignancy  declare  themselves 
the  conditions  exciting  them  often  belong  to  the  past  history  of  the  disease 
and  are  often  irremediable. 

Diagnosis  of  Malignancy. — The  prediction  of  the  course  that  a  given 
tumor  will  take  is  based  upon  two  sources  of  information,  anatomical  and 
microscopical  diagnosis  and  accumulated  experience  regarding  the  usual 
behavior  of  tumors  of  known  histological  structure.  Fortunately  a  parallel 
exists  to  a  very  marked  degree  between  the  histological  structure  and  the 
usual  clinical  course. 

The  main  subdivisions  of  tumors  into  benign  and  malignant  is  accom- 
plished at  once  and,  as  a  rule,  only  by  microscopical  structure.  Under  some 
circumstances  the  microscopical  structure  may  stand  alone  and  override 
all  other  considerations.  Far  more  usual  is  it  to  find  the  interpretation  of 
structure  to  be  greatly  influenced  by  clinical  information  regarding  the  exact 
location  of  the  tumor,  its  attachments,  the  presence  of  a  capsule,  and  the 
age  and  condition  of  the  patient. 

Pathologists  and  surgeons  alike  commonly  ignore  these  essential  condi- 
tions of  accurate  diagnosis,  a  delinquency  which  is  responsible  for  the  wide 
and  firm  differences  of  opinion  regarding  the  relation  of  microscopical  struc- 
ture and  prognosis.  It  must  also  be  urged  that  tumor  diagnosis  is  commonly 
assigned  to  the  relatively  inexperienced,  whereas  the  correct  interpretation 
of  structure  in  the  light  of  clinical  data  requires  a  very  wide  experience  not 
only  with  the  general  tendencies  of  specific  structures,  but  with'the  observed 
clinical  courses  of  different  tumors. 

A  somewhat  general  estimate  of  the  malignancy  of  tumors  may  be  based 
on  the  distinctions  between  adult  and  embryonal  or  anaplastic  growth.  It 
has  long  been  recognized  that  the  greater  the  variation  in  type  between  a 
tumor  and  its  originating  tissue,  the  more  malignant  the  tumor,  and  Hanse- 
mann  has  effectively  emphasized  this  principle,  pointing  out  that  the  morpho- 
logical evidences  of  anaplasia  have  a  physiological  significance  indicating  the 
degree  to  which  the  process  is  freed  from  growth  restraints  and  the  control 
of  the  organization.  Yet  here  is  encountered  the  difficulty  of  distinguishing 
between  original  embryonal  qualities  and  signs  of  acquired  anaplasia.  One 
group  of  tumors  arises  from  embryonal  cells  which  have  lagged  behind  in 
development  and  such  tumors  bear  an  embryonal  stamp.  The  histological 
signs  of  this  embryonal  character  are  often  difficult  to  distinguish  from  the 
signs  of  anaplasia,  and  if  they  are  wrongly  interpreted  an  erroneous  impression 
may  be  drawn  of  the  malignancy  of  the  tumor.  The  great  theoretical  value 
of  the  distinction  between  embryonal  and  anaplastic  cells  is  not,  however, 
equalled  in  practical  importance,  since  both  types  of  tumors,  especially  the 
latter,  are  usually  quite  malignant.  The  histological  signs  of  anaplasia  are 
a  cellular  character,  marked  variations  in  size  in  either  direction  from  the 
originating  cells,  increase  of  chromatic  nuclear  substance,  abundance  and 
abnormality  of  mitoses,  and  loss  of  polarity  and  diffuse  infiltrative  growth 
of  cells.  In  many  instances  lack  of  reaction  of  the  tissues  against  the  infil- 
tration of  tumor-cells  is  a  significant  feature.  Equally  important  are  the 
general  signs  of  exalted  nutrition  and  vitality  of  the  cells.  Upon  these  fea- 


64  NEOPLASTIC  DISEASES 

tures  one  may  safely  base  the  estimate  of  growth  capacity  and  potential 
malignancy  of  tumors. 

The  clinical  course  does  not  always  accord  with  the  signs  of  growth  ca- 
pacity. Many  factors  besides  the  surgeon's  knife  influence  the  progress  of 
growth.  One  must  distinguish  between  the  potential  malignancy  and  the 
clinical  course  of  tumors.  The  histological  signs  of  malignancy  measure 
the  potential  malignancy  of  a  tumor,  but  the  clinical  course  is  subject  to  wide 
variations  from  the  position  of  the  tumor,  hemorrhage,  trauma,  changes 
in  rate  of  growth,  bacterial  infection,  etc.,  any  one  of  which  influences  may 
greatly  alter  the  course.  With  these  important  limitations  it  may  be  asserted 
that  there  is  a  close  parallel  between  histological  structure  and  the  malig- 
nancy of  a  tumor. 

In  practice  the  most  frequent  source  of  discrepancy  between  histological 
signs  of  malignancy  and  clinical  course  arises  from  the  confusion  of  embry- 
onal with  anaplastic  qualities.  Some  of  the  most  malignant  looking  tumors, 
as  the  congenital  sarcoma  of  the  kidney,  teratoma  testis,  sarcoma  of  skin, 
adenoma  of  thyroid,  gastro-intestinal  tract  and  other  organs,  and  large  cell 
epithelioma  of  the  skin,  long  remain  localized  and  spare  the  lymph-nodes. 
These  tumors  are  of  embryonal  origin,  and  the  growth  capacities  of  their 
abundant  atypical  undiff  erentiated  cells  are  much  below  those  of  other  tumors 
whose  cells  show  true  anaplasia  and  increasing  loss  of  growth  restraints. 
Recurrent  adult  and  highly  malignant  squamous  epithelioma  yields  cells 
with  little  trace  of  pavement  character,  which  closely  resemble  those  of  a 
benign  embryonal  epithelioma.  Here  and  in  many  other  fields  it  is  neces- 
sary to  know  the  history  and  to  divine  the  origin  of  the  tumor  in  order  to 
construct  the  prognosis. 

Different  standards  apply  to  different  tissues  in  estimating  the  significance 
of  cell  growth.  The  thyroid,  liver,  uterine  mucosa,  and  lymph-nodes  re- 
spond readily  to  various  stimuli,  and  the  gross  and  microscopical  criteria 
applicable  to  those  organs  cannot  be  employed  for  the  breast,  kidney,  or 
stomach. 

The  nature  and  origin  of  many  round-cell  growths  are  obscure  and  difficult 
to  recognize,  while  their  natural  history  is  imperfectly  known,  so  that  in  this 
group  there  are  many  apparent  discrepancies  between  structure  and  prog- 
nosis. Finally,  there  is  a  natural  limit  to  the  onward  growth  of  many  malignant 
tumors  and  it  should  occasion  no  surprise  if  in  advanced  stages  certain  malig- 
nant tumors  should  advance  more  slowly,  become  stationary  or  even  regress. 
Further  knowledge  may  possibly  show  that  under  some  conditions  the  presence 
of  tumor  tissue  is  a  safeguard  rather  than  a  menace  to  the  organism. 

The  transformation  of  a  benign  into  a  malignant  tumor  occurs  in  rare 
instances.  To  be  separated  from  this  category  are  those  cases  in  which  one 
element  of  teratoma  gains  the  upper  hand  and  eventually  outstrips  the  rela- 
tively benign  portions.  Apparently  this  event  may  occur  at  any  stage  of 
the  growth  of  teratomas.  In  a  case  which  I  have  reported  a  teratoma  of 
the  testicle  containing  adult  thyroid,  epidermoid  cysts  and  diffuse  carcinoma, 
the  malignant  process  was  delayed  for  years.  In  an  ovarian  dermoid  which 
had  broken  into  the  colon,  I  have  seen  epithelioma  developing  from  the  irri- 
tated epithelial  surface.  In  another  group  of  cases  a  pigmented  mole  or 
adrenal  rest  in  the  kidney  after  growing  slowly  for  years  may  suddenly,  per- 
haps after  trauma,  take  on  malignant  qualities.  Here  the  neoplastic  nature 
of  the  originating  cell  group  may  be  doubted. 

When  an  encapsulated  nearly  stationary  but  potentially  malignant  tumor 
breaks  through  its  capsule  and  grows  rapidly  there  is  no  ground  for  assum- 
ing a  change  in  the  quality  of  the  tumor.  Different  portions  of  many  tumors 


MALIGNANCY  AND  ITS  EFFECT  ON  THE  ORGANISM  65 

differ  widely  in  structure,  and  many  apparent  changes  in  type  of  tumors 
rest  on  the  mistaken  conclusions  of  a  biopsy. 

The  impression  that  the  tissue  of  a  well-established  benign  tumor  may 
after  a  long  period  take  on  diffuse  malignant  characters  is  based  chiefly  upon 
observations  of  uterine  myomas.  About  3  per  cent,  of  such  tumors  are  said 
to  become  sarcomatous,  but  the  exact  significance  of  this  change  has  always 
been  subject  to  doubt  and  discussion.  In  the  great  majority  of  such  cases 
the  impression  that  a  malignant  change  has  occurred  is  based  on  the  discovery 
of  a  myosarcoma  by  operation  on  a  tumor  of  which  the  previous  history  has 
been  imperfectly  traced.  In  a  smaller  proportion  a  very  slowly  growing 
fibroid  has  been  known  to  exist  for  years  when  it  suddenly  begins  to  grow 
rapidly  and  on  removal  one  portion  of  the  tumor  is  found  sarcomatous.  This 
portion  is  often  connected  with  an  ulcerated  surface  of  the  endometrium, 
an  observation  which  justifies  the  conclusion  that  the  ulceration  and  the 
sarcomatous  change  are  in  some  way  related.  In  other  cases  the  myoma 
has  been  cystic  or  angiomatous.  Sarcomatous  change  of  this  sort  has  occurred 
in  several  authentic  cases  (Piquand).  The  true  interpretation  of  this  change 
remains  uncertain.  It  may  be  that  the  sarcoma  results  from  a  new  tumor 
process  arising  in  the  stroma;  or  a  sarcomatous  process  becomes  established 
in  the  stroma  of  the  endometrium  subsequently  invading  the  myoma  (W. 
Williams) ;  or  the  more  rapid  growth  and  the  cell  changes  represent  the  natural 
course  of  the  original  tumor  which  has  not  thereby  acquired  any  new  powers 
of  growth  (Borst).  The  enumeration  of  these  possibilities  suffices  to  reveal 
some  of  the  complications  of  this  subject. 

Carcinoma  has  been  known  to  develop  from  the  epithelial  elements  present 
in  many  uterine  fibroids,  as  in  cases  recorded  by  Klob,  Roily,  and  others, 
More  often  uterine  fibroids  are  invaded  by  malignant  tumors  of  adjacent 
or  distant  organs,  as  by  cancer  of  the  endometrium,  lung  (Schafer),  or  breast 
(Bender). 

In  the  breast,  cancer  and  sarcoma  have  been  found  in  connection  with 
nbro-adenoma,  and  it  appears  that  the  malignant  tumor  has  arisen  from  the 
tissues  of  the  benign.  In  the  case  of  ovarian  cystomas  there  is  no  evidence 
to  show  that  varying  grades  of  malignancy  exhibited  by  these  usually  benign 
tumors  constitute  a  definite  change  in  type. 

While  therefore  the  transformation  of  certain  benign  tumors  into  malig- 
nant forms  has  been  shown  to  exist,  this  event  is  among  the  rare  occurrences 
in  the  natural  history  of  tumors.  In  the  fields  where  it  is  supposed  to  be  most 
frequent  R.  Williams  has  shown  that  benign  tumors  are  much  less  liable 
to  change  of  type  than  are  the  norm'al  tissues  to  develop  cancer.  This  con- 
clusion accords  with  the  rule  that  a  tumor  process  becomes  established  at 
a  certain  momentum  which  it  tends  to  maintain  throughout  its  entire  course. 

EFFECTS  ON  THE  BODY 

The  emaciation  accompanying  tumor  growth  has  long  been  recognized  as 
one  of  the  most  significant  and  obscure  of  its  many  features.  It  may  be  said 
to  be  a  constant  effect  of  both  very  malignant  and  relatively  benign  tumors. 
It  occurs  early  or  late,  with  or  without  anemia,  though  probably  always  with 
diminution  in  the  total  volume  of  blood,  sometimes  with  preservation  of  the 
fat  deposits,  and  is  preceded  by  distinct  muscular  weakness.  It  affects 
chiefly  the  muscular  system  but  also  all  cellular  organs  and  tissues.  Inani- 
tion is  undoubtedly  the  chief  factor  in  the  loss  of  weight.  Mental  depression 
leading  to  distaste  of  food,  the  lowering  of  digestive  capacity,  and  mechanical 
obstruction  to  the  alimentary  passages,  reduce  the  amount  of  food  absorbed. 
5 


66  NEOPLASTIC  DISEASES 

In  6  cases  of  uterine  cancer  v.  Noorden  calculated  the  voluntary  ingesta  at 
300  to  1200  calories.  The  importance  of  starvation  is  strikingly  emphasized 
by  the  rapid  increase  in  weight  following  relief  of  esophageal  and  pyloric 
stenosis. 

Abnormal  loss  of  proteins  figures  in  many  cases,  by  hemorrhage,  exudation, 
albuminuria,  and  diarrhea.  A  febrile  destruction  of  proteins  occurs  very 
often  and  is  a  somewhat  neglected  factor  especially  in  low  forms  of  infection, 
and  the  difficulty  of  securing  bacteria-free  tumor  tissue  suggests  that  bacterial 
poisons  may  often  be  at  work  when  not  suspected.  The  influence  of  actively 
regenerating  tissues  upon  the  general  organism  has  been  generally  over- 
looked in  discussions  of  the  tissue  atrophy  of  cancer.  The  exalted  capacity 
of  tumor-cells  to  absorb  nutriment  may  long  be  successfully  met  by  physio- 
logical processes,  but  there  is  a  point,  as  mentioned  by  Cramer,  when  the 
general  body  tissues  begin  to  yield  their  food  supply  to  the  tumor.  That 
this  process  may  actually  lead  to  atrophy  of  normal  tissues  has  been  shown 
experimentally  by  Stockard  who  observed  marked  diminution  of  the  remain- 
ing arms  of  Medusa  during  the  normal  regeneration  of  amputated  arms. 
The  restored  individuals  were  sometimes  only  half  as  large  as  the  original. 

The  conception  of  a  toxic  destruction  of  protein  tissues  emanated  from 
the  observations  of  F.  Miiller,  1889,  upon  7  febrile  cancer  patients.  In  2 
of  these,  pancreatic  and  mammary,  a  toxic  destruction  was  not  apparent, 
but  in  4  gastric  cases  the  nitrogen  loss  was  excessive,  and  in  a  case  of  cancer 
of  penis  with  metastases,  an  intake  of  21  gm.  N.,  3064  calories,  failed 
to  balance  the  loss.  These  observations  support  the  general  belief  that  the 
products  of  degenerating  necrosing  and  infected  tumors  cause  toxic  destruc- 
tion of  tissues  in  cancer  as  in  other  diseases. 

Yet  the  belief  in  a  specific  toxic  destruction  of  protein  tissues  in  cancer 
has  never  been  fully  accepted.  It  is  worth  noting  that  Wilks  in  1868  from 
the  study  of  2000  autopsies  at  Guy's  hospital  concluded  that  cancer  as  such 
does  not  cause  cachexia.  This  conclusion  has  steadily  gained  support. 

Many  observers  have  failed  to  detect  the  toxic  nitrogen  loss  described  by 
Miiller  and  verified  by  Klemperer.  Many  cases  with  entirely  normal  protein 
metabolism  have  been  observed  by  Widal,  Setti,  Braunstein,  Clowes,  and 
Lewin,  and  even  a  nitrogen  retention  has  been  found  in  cases  studied  by 
Schopp  and  Moraczewski.  It  is  possible  that  a  correct  interpretation  of 
these  cases  must  consider  such  factors  as  masking  of  a  nitrogen  loss  by  inade- 
quate excretion  by  the  kidneys,  or  by  the  sparing  action  of  carbohydrate  diet. 
Schmidt  points  out  many  resemblances  between  the  supposed  toxic  destruc- 
tion of  cancer  and  that  of  fever,  as  the  sparing  of  fat,  and  the  high  oxygen 
consumption,  which  is  yet  not  in  proportion  to  the  protein  catabolism.  Yet 
these  objections  merely  emphasize  the  difficulty  of  securing  a  suitable  subject 
for  investigation,  among  which  gastric,  hepatic,  intestinal,  and  ulcerating  or 
infected  cases  must  not  be  included.  In  a  case  of  mammary  cancer  which 
seemed  to  meet  all  obvious  requirements  Benedict  and  Gorslin  at  New  York 
Hospital  readily  maintained  nitrogen  equilibrium  and  found  no  abnormality 
in  the  partition  except  marked  increase  of  creatin  over  a  terminal  period  of 
10  days.  Our  present  knowledge  derived  from  careful  clinical  study,  from 
observation  at  autopsy,  and  finally  from  chemical  investigation,  seems  to 
warrant  the  conclusion  that  a  peculiar  toxin  secreted  by  cancer-cells  and 
leading  to  cachexia  does  not  exist. 

This  conclusion  does  not  seem  to  need  revision  in  the  light  of  various 
chemical  analyses  of  cancer  tissue  (Petry,  Wolf,  Beebe,  Schaffer),  since  no 
new  and  abnormal  toxic  substances  have  been  shown  to  exist  in  tumor  tissue, 
although  quantitative  variations  in  their  split  products  may  occur. 


MALIGNANCY  AND  ITS  EFFECT  ON  THE  ORGANISM  67 

Tumor  Ferments. — It  is  everywhere  agreed  that  cellular  tumors  are  very 
prone  to  degenerate  and  that  their  products  may  cause  intoxication.  This 
subject  appears  in  a  new  phase  in  the  study  of  tumor  ferments.  Petry  em- 
phasized the  well-known  rapid  autolysis  of  tumor  tissue  which  he  referred 
to  autolytic  ferments.  Buxton  found  quantitative  but  no -qualitative  differ- 
ences between  tumor  and  normal  tissue  ferments. 

A  heterolytic  action  of  tumor  ferments  has  been  actively  claimed  by  Neu- 
berg,  Jacoby,  and  Blumenthal  and  Wolff,  but  I  think  on  insufficient  grounds. 
None  of  these  authors  has  considered  the  influence  of  bacterial  or  leukocytic 
ferments,  factors  which  seem  to  me  to  influence  their  results  and  to  explain 
their  inconstancy,  and  warn  against  the  hasty  acceptance  of  the  compre- 
hensive deductions  drawn  from  them.  Kepinow  has  pointed  out  the  obvious 
defects  of  this  work  and  with  Miiller  has  shown  that  when  free  from  leuko- 
cytes and  bacteria  cancer  tissues  do  not  accelerate  autolysis  in  other  organs. 
Petry  also  was  unable  to  find  evidence  of  specific  ferment  activities  in  the 
aseptic  blood  of  cancer.  Abderhalden  and  his  associates  have  endeavored  to 
show  that  the  splitting  of  optically  active  polypeptids  in  the  presence  of  tumor 
juice  follows  a  different  course  than  with  extracts  of  normal  tissue,  but  their 
results  were  inconstant. 

The  study  of  experimental  tumors  in  lower  animals  has  given  additional 
support  to  the  belief  in  the  innocency  of  well-nourished  tumor  tissues.  Espe- 
cially in  mice  it  is  observed  that  tumors  nearly  as  large  as  the  animal  itself 
may  be  well  borne  until  the  moment  when  ulceration,  infection,  or  necrosis 
occur. 

The  Blood  in  Cancer. — Changes  in  the  blood  are  of  interest  to  the  student 
of  tumors  chiefly  in  their  relation  to  cachexia  and  to  the  problems  of  immunity. 

Benign  tumors  exert  little  or  no  influence  upon  the  blood,  and  the  very 
slight  change  of  the  early  stages  of  malignant  tumors  may  be  cited  in  support 
of  the  view  that  in  the  beginning  cancer  is  a  local  disease.  Likewise  in  the 
established  stages  of  many  malignant  tumors  the  blood  remains  practically 
normal  in  quality,  and  even  in  advanced  stages  there  are  many  records  show- 
ing normal  cells  and  hemoglobin.  Cabot  collected  19  cases  of  gastric  cancer 
with  over  5,000,000  red  cells.  Laache  noted  the  same  immunity  of  the 
blood  against  the  effects  of  a  bleeding  uterine  carcinoma  and  concluded  that 
there  is  an  individual  insusceptibility  to  the  effects  of  malignant  tumors. 
In  some  gastric  cancers  there  may  be  a  concentration  of  the  blood,  probably 
from  diminished  fluid  ingesta  which  maintains  the  quality.  Leichtenstern, 
Patrigeon,  and  the  writer  have  observed  cases  of  gastric  cancer  with  increase 
of  Hb.  to  100  per  cent.,  shortly  before  death.  Even  when  marked  emacia- 
tion occurs  the  blood  may  fail  to  deteriorate  in  quality,  so  that  Hampeln, 
Neubert,  and  others  speak  of  a  marantic  as  opposed  to  the  usual  anemic  type 
of  malignant  disease. 

Yet  the  great  majority  of  malignant  tumors  are  associated  throughout 
most  of  their  course  with  progressive  deterioration  in  the  quality  and  quan- 
tity of  the  blood.  Usually  this  anemia  takes  the  form  of  a  secondary  chlo- 
rotic  process,  with  loss  of  Hb.  exceeding  the  reduction  of  cells,  low  Hb.  index, 
and  slight  leukocytosis.  In  a  notable  group  of  cancers  of  the  stomach  the 
anemia  dominates  the  clinical  picture,  and  takes  a  secondary  pernicious  form. 
The  sources  of  the  anemia  of  malignant  tumors  are  numerous  and  complex 
and  being  variously  combined  must  be  estimated  separately  for  each  case. 

Hemorrhage  is  the  most  obvious  source  of  deterioration  of  the  blood, 
but  occasional  escape  from  its  natural  effects  has  been  recorded  as  above. 
It  is  quite  as  capable  of  causing  emaciation  as  anemia.  Interference  with 
ingestion  of  food  leads  to  anemia  and  emaciation  in  cancer  of  esophagus  and 


68  NEOPLASTIC  DISEASES 

stomach.  The  absorption  of  hemolytic  agents  from  ulcerating  and  infected 
surfaces  and  from  necrosing  areas  of  closed  tumors  is  a  chief  factor  in  pro- 
ducing anemia.  Maragliano,  Kullman,  Bard,  Polk,  and  many  others  have 
demonstrated  the  presence  of  hemolytic  properties  in  the  blood  of  cancer. 
Elsberg  found  that  normal  red  cells  injected  beneath  the  skin  of  cancerous 
subjects  were  soon  hemolyzed,  yielding  a  characteristic  discoloration  of  the 
skin,  and  he  proposed  this  method  as  a  diagnostic  test  for  carcinoma.  In 
extracts  of  degenerating  and  necrosing  tumors  Weil  demonstrated  thermola- 
bile  and  thermostabile  hemolysins  not  differing  from  those  obtained  from 
necrosing  normal  organs.  Clinical  effects  of  the  action  of  such  hemolysins 
were  observed  by  Bard  who  pointed  out  that  in  cancerous  pleuritic  exudates 
the  red  cells  are  often  hemolyzed,  while  in  other  bloody  pleural  fluids  the 
red  cells  are  intact.  The  presence  of  these  circulating  hemolysins  may  render 
transfusion  of  cancer  patients  with  normal  blood  a  dangerous  procedure. 
Against  their  own  serum  the  red  cells  are  resistant  and  since  the  specific 
gravity  of  the  blood  is  usually  lew  the  red  cells  are  resistant  to  hypotonic 
solutions.  Since  hemolytic  agents  and  variations  in  the  resistance  of  red 
cells  are  commonly  present  in  other  diseases  these  properties  have  not  been 
found  reliable  in  the  diagnosis  of  cancer. 

The  specific  gravity  of  the  blood  in  most  cases  does  not  differ  from  that  of 
other  forms  of  secondary  anemia,  but  in  well-established  cachexia  the  gravity 
has  often  been  found  remarkably  low.  Dieballa,  Peiper,  and  Moraczewski 
found  lower  specific  gravity,  1012  to  1032,  in  cancer  of  stomach,  than  in 
pernicious  anemia  of  equal  grade.  The  albumins  of  both  plasma  and  serum 
are  distinctly  low  in  such  cases  (Grawitz).  In  a  case  of  gastric  cancer  Wendel- 
stadt  and  Bleibtreu  found  0.79  gm.  instead  of  the  normal  2  to  2.25  gm.  in 
100  gm,  blood-serum. 

Rieder  believed  that  the  lymphocytosis  of  cancer  resulted  from  accelerated 
flow  of  lymph  and  Grawitz  attributed  the  dilution  of  the  blood  to  the  same 
factor,  finding  that  watery  extracts  of  cancer  tissue  when  injected  into  rabbits 
produced  a  marked  increase  of  lymph  flow. 

Leukocytosis  was  early  recognized  as  a  very  frequent  condition  in  cancer, 
having  been  described  postmortem  by  Andral  in  1823,  and  in  the  circulating 
blood  by  Lucke  and  Virchow  about  1867.  The  leukocytes  were  long  regarded 
as  derivatives  of  the  tumor.  Virchow  referred  their  presence  to  increased 
flow  of  lymph. 

Although  some  disturbance  of  the  leukocytes  is  very  frequently  observed, 
the  uncomplicated  tumor  process  seems  to  have  no  capacity  to  attract  leuko- 
cytes to  the  circulation.  This  conclusion  accords  with  the  fact  that  tumors 
excite  no  uniform  local  reaction.  The  cause  of  leukocytosis  must  therefore 
be  sought  in  some  other  factor  than  the  presence  of  growing  tumor  tissue. 

Ulceration  or  other  inflammatory  complications  are  the  most  definite 
causes  of  leukocytosis  in  cancer,  and  the  resulting  hemorrhage  adds  to  the 
increase  of  white  cells  seen  in  bleeding  and  necrosing  tumors.  Bacterial 
infection,  local  and  general,  may  intensify  the  effects  of  absorption  of  tissue 
toxins  and  loss  of  blood. 

Degeneration  and  necrosis  of  tissue  and  foci  of  cells  must  account  for 
the  leukocytosis  of  many  large  cellular  and  rapidly  growing  tumors.  The 
inflamed  lymph-nodes  in  the  vicinity  of  malignant  tumors  indicate  absorption 
or  irritants,  but  these  nodes  seem  to  furnish  few  new  cells  to  the  blood  since 
the  leukocytosis  is  usually  polynuclear. 

As  a  reaction  of  immunity  may  be  considered  the  lymphocytosis  asso- 
ciated with  certain  tumors  about  whose  edges  round-cells  gather  in  masses, 
but  there  seems  to  be  no  ground  in  the  human  subject  for  assuming  the  same 


MALIGNANCY  AND  ITS  EFFECT  ON  THE  ORGANISM  69 

interpretation  of  polynuclear  leukocytosis.  With  the  onset  of  cachexia  the 
way  is  open  for  the  action  of  many  causes  of  leukocytosis  which  are  as  numer- 
ous as  the  elements  in  the  cachexia  itself. 

With  these  theoretical  principles  the  results  of  leukocyte  counting  in 
tumor  patients  offer  only  a  partial  parallel.  The  temptation  is  often  strong 
to  assume  some  specific  chemotactic  influence  residing  in  the  tumor  process 
to  account  for  pronounced  leukocytosis  observed  in  certain  cases.  Hayem 
observed  marked  leukocytosis  with  scirrhus  of  the  breast  which  subsided 
after  operation  only  to  return  with  recurrence  of  the  growth.  In  many  rapidly 
growing  but  apparently  uncomplicated  tumors,  especially  in  children,  pro- 
nounced leukocytosis  has  been  observed  without  satisfactory  explanation. 
In  the  extensive  series  of  blood  reports  of  Alexander,  Price- Jones,  Cabot, 
and  others,  it  is  not  always  possible  to  refer  the  leukocytosis  to  definite  factors 
apart  from  the  tumor  process.  In  fulminant  carcinosis  of  breast  and  other 
organs  the  disease  may  be  actively  febrile  and  associated  with  marked  poly- 
nuclear  or  mixed  leukocytosis.  Renal  carcinoma  is  very  frequently  marked 
by  intermittent  fever  and  leukocytosis.  Satisfactory  explanation  of  these 
peculiarities  is  wanting. 

Certain  specific  events  in  the  course  of  malignant  tumors  may  be  marked 
by  definite  changes  in  the  leukocytes.  Severe  cachexia  with  anemia  is  usually 
attended  with  the  presence  of  myelocytes,  and  myelocytes  with  nucleated 
red  cells  are  often  seen  with  marrow  metastases.  Kurpjuweit  collected  13 
cases  in  which  considerable  numbers  of  myelocytes  were  associated  with 
bone  metastases.  Eosinophilia  is  regarded  by  Neusser  as  diagnostic  of  bone- 
sarcoma.  In  general,  sarcoma  affects  the  blood  and  leukocytes  earlier  and 
more  than  carcinoma,  and  in  many  cases  of  sarcoma  the  increase  has  reached 
the  higher  limits  of  inflammatory  leukocytosis  (Martin,  Matthewson,  Alex- 
ander). In  certain  cases  of  systemic  lymphosarcoma,  myeloma,  and  in  leukemic 
chloroma  it  is  probable  that  numbers  of  tumor-cells  reach  the  blood  and 
may  be  found  in  stained  specimens.  In  2  cases  of  localized  saTcoma  Loeper 
and  Loeste  claim  to  have  found  specific  tumor-cells  in  the  centrifuged  sedi- 
ment of  the  blood.  The  many  details  of  differential  diagnosis  by  the  blood 
may  be  left  to  the  special  treatises  upon  this  subject. 

The  total  quantity  of  blood  in  cases  of  malignant  tumor  varies  greatly,  but, 
as  Louis  showed  in  1846,  it  is  usually  much  diminished.  The  distinction 
between  the  anemic  and  the  marantic  cases  is  here  quite  pronounced,  the 
vessels  in  the  former  type  showing  at  autopsy  a  considerable  volume  of  watery 
blood,  while  the  others  may  give  a  much  reduced  quantity  of  concentrated 
blood  of  fair  quality.  The  cases  with  arterial  hypotension  observed  by  Jane- 
way  must  usually  fall  in  the  former  class. 

The  regeneration  of  the  blood  in  cancer  has  been  found  by  Bierfreund  to 
require  much  longer  than  in  other  surgical  conditions,  and  in  progressive 
cases  the  Hb.  seldom  reaches  the  ration  existing  before  operation.  Yet  it  vs 
impossible  to  establish  any  general  rule  in  this  matter.  In  a  woman  who  in 
four  years  underwent  six  operations  for  recurrent  adamantinoma  of  the  superior 
maxilla,  I  found  the  highest  Hb.  (85  per  cent.)  and  good  general  health,  al- 
though the  tumor  had  again  recurred. 

The  resistance  of  the  red  cells  to  various  destructive  agents  has  been  found 
about  normal  in  early  stages  of  cancer,  but  in  advanced  cases  it  is  much  in- 
creased, probably  as  a  result  of  reaction  to  hemolytic  factors  (Schmidlech- 
ner).  So  marked  may  the  increased  resistance  become  that  Conte  regarded 
this  property  as  of  diagnostic  significance. 

Alkalescence  of  Blood. — Determinations  of  the  alkalescence  of  the  blood 
have  yielded  results  which  differ  with  the  method  employed  and  the  particular 


70  NEOPLASTIC  DISEASES 

factors  brought  into  consideration.  Klemperer  found  a  reduced  amount 'of 
€02  in  the  blood  of  advanced  cancer.  Peiper,  titrating  the  whole  blood,  found 
very  low  grades  of  alkalescence  in  advanced  cachexia,  and  Rumpf,  Limbeck, 
and  others,  dealing  with  the  whole  blood,  obtained  uniform  diminution  of 
alkali  in  advanced  cases.  It  is  clear  that  the  chief  factor  in  these  results 
was  anemia,  although,  as  claimed  by  v.  Noorden,  liberation  of  acids  from 
destruction  of  proteins  and  acidosis  may  occasionally  be  present  (Herter). 
Yet  H.  Strauss,  titrating  laked  blood,  found  marked  variations,  some  cases 
showing  normal  and  some  increased  alkalescence. 

Methods  dealing  with  the  serum  yield  directly  opposite  results.  In  1906 
Moore  and  Wilson  found  that  the  serum  alkalescence  to  dimethylamido- 
azobenzol  showed  a  striking  increase  in  cancer  as  compared  with  healthy 
subjects  and  other  hospital  patients,  while  the  basic  capacity  of  the  inorganic 
salts  after  removal  of  proteins  by  incineration  showed  a  small  but  distinct 
increase.  Gamble,  Royle  and  Watson  secured  similar  results  by  the  same 
methods  in  both  carcinoma  and  sarcoma,  but  in  very  advanced  cachexia 
the  alkalinity  was  barely  above  normal.  Neither  extirpation  nor  #-ray  treat- 
ment produced  any  change.  Sturroch  improved  the  di-methyl  technic  and 
found  an  average  alkalinity  of  the  serum  of  0.190  N.  and  often  more  than 
0.200  N.  in  cancer,  while  non-malignant  cases  gave  an  average  of  0.173  N. 

Hyperglycemia  with  a  percentage  of  glucose  reaching  0.33  was  regularly 
found  in  the  blood  of  cancer  by  Freund  and  again  in  many  cases  by  Trinkler. 
Yet  Matrai  could  not  find  that  the  anemia  of  cancer  varied  in  this  respect 
from  other  forms.  Lewis  and  Benedict  found  quite  variable  relations  be- 
tween sugar  content  of  the  blood  and  the  progress  of  malignant  tumors,  but 
usually  an  increase  in  the  later  stages. 

A  retention  of  chlorin  and  phosphorus,  especially  the  former,  was  ob- 
served by  Moraczewski  to  be  earlier  and  more  pronounced  in  the  anemia  of 
cancer  than  in  other  forms. 

Theis  and  Stone  found  the  non-protein  nitrogen  arid  urea  nitrogen  gener- 
ally low  in  the  blood  of  cancer  patients,  especially  in  malignant  cases.  In  2 
cases  of  melanoma  the  uric  acid  was  increased.  Blood-sugar  was  somewhat 
above  normal  in  26  per  cent.,  and  below  normal  in  13  per  cent.,  of  their  cases. 

Influence  of  Cancer  on  Digestion. — Gastric  Digestion. — The  absence  of 
free  HC1  in  the  gastric  contents  of  cancer  of  the  stomach,  discovered  by  Van 
der  Velden  in  1879,  and  thoroughly  investigated  by  many  later  writers,  stands 
as  a  prime  factor  in  the  anemia  and  malnutrition  of  this  disease.  In  all  but 
10  to  13  per  cent,  of  such  cases  free  hydrochloric  acid  is  missing  (Richter). 
When  cancer  is  grafted  on  simple  ulcer  the  early  stages  of  the  process  may 
be  marked  by  the  excess  of  free  HC1  belonging  to  the  former  condition,  but 
as  a  rule  this  excess  declines  and  eventually  disappears,  sometimes  suddenly 
as  the  disease  progresses  (Rosenheim,  Schneider).  In  most  cases  the  loss 
occurs  early  in  the  disease  (Riegel). 

Several  factors  appear  to  be  combined  in  determining  the  loss  of  free  HC1. 
In  most  cases  of  gastric  cancer  one  finds  a  general  chronic  catarrhal  inflamma- 
tion, in  some  cases  there  is  atrophy  of  the  mucosa,  and  in  one  group  a  diffuse 
infiltration  of  mucosa  and  muscularis  is  observed.  There  is  every  reason 
to  attribute  to  these  anatomical  lesions  a  loss  of  functional  capacity  partly 
accounting  for  the  loss  of  HC1.  Yet  the  failure  of  free  acid  occurs  in  many 
early  cases,  and  is  relieved^  after  excision  of  the  cancer  (Rosenheim).  In 
other  cancers  not  involving  'the  stomach  a  similar  deficiency  of  HC1  occurs, 
so  that  it  seems  necessary  to  assume  that  malignant  disease  exerts  some  gen- 
eral influence  which  affects  gastric  secretion,  even  in  the  absence  of  severe 
anemia  and  cachexia. 


MALIGNANCY  AND  ITS  EFFECT  ON  THE  ORGANISM  71 

Reissner  showed  that  in  gastric  cancer  the  total  chlorids  secreted  are 
not  below  normal,  that  decrease  of  free  acid  is  nearly  always  associated  with 
increase  of  fixed  chlorids,  and  that  the  acid  is  promptly  combined  in  the 
stomach  with  alkalis  of  the  blood  and  serum  exuded  from  the  tumor.  Since 
an  increased  supply  of  NaCl  from  the  tumor  juices  can  probably  be  elimi- 
nated, it  would  appear  that  the  loss  of  free  acid  in  early  cases  results  from 
its  neutralization  by  alkalis  and  not  from  any  functional  deficiency  of  an 
apparently  normal  mucosa.  This  explanation  can  hardly  apply  to  late  and 
cachectic  cases  and  to  other  forms  of  cancer  in  which  the  total  chlorides  are 
diminished.  That  the  tumor  yields  such  free  alkalis  is  further  indicated  by 
Stahelin's  observation  that  free  HC1  introduced  into  the  cancerous  stomach  is 
actively  neutralized;  by  the  neutralization  of  HC1  by  cancer  tissue  in  artificial 
digestive  mixtures  (Rosenberger) ;  and  by  the  increased  quantity  of  protein 
found  in  the  stomach  juice  after  previous  washing  (Salomon). 

Moore  and  Palmer,  from  the  study  of  a  series  of  cases  of  carcinoma,  sarcoma, 
and  non-malignant  tumors,  found  in  nearly  all  a  diminution  of  HC1,  which 
they  attribute  to  reduction  of  hydrogen  ions  of  the  blood.  In  many  of  these 
cases  it  is  evident  that  they  have  to  deal  with  the  effects  of  cancerous  cachexia, 
but  in  others  which  were  not  cachectic  Parker  suggests  that  the  general  un- 
hygienic hospital  surroundings  were  at  fault.  Copeman  and  Hake  with 
Cramer  secured  the  interesting  result  from  observations  on  500  mice  that 
the  implantation  of  cancer  in  these  animals  is  followed  by  decided  increase 
in  the  physiologically  active  HC1. 

There  are,  therefore,  a  specific  influence  of  tumor  juices  neutralizing 
secreted  HC1  of  the  gastric  juice,  a  diminished  functional  capacity  of  an 
organ  damaged  by  an  extensive  tumor,  and  an  effect  of  cachexia  in  reducing 
the  hydrogen  ions  of  the  blood  and  impairing  the  secretion  of  acid,  all  to  be 
considered  in  the  relation  of  cancer  to  the  acid  of  the  gastric  juice. 

The  gastric  ferments  persist  long  after  the  disappearance  of  free  HC1 
(Oppler).  According  to  Glassner  both  rennet  and  pepsin  are  diminished  with 
tumors  of  the  fundus  in  which  there  is  considerable  destruction  of  the  mucosa, 
whereas  pepsin  alone  is  diminished  with  cancers  of  the  pylorus  in  which  region 
it  is  principally  secreted.  Emerson  found  that  one  hour  after  a  test  break- 
fast 16.9  per  cent,  of  the  proteins  in  the  normal  stomach  has  been  hydro- 
lyzed  to  the  stage  in  which  they  are  not  precipitable  by  phosphotungstic  acid, 
while  in  cancer  of  the  stomach  27.6  per  cent,  reached  this  stage.  In  a  diges- 
tion mixture  containing  a  piece  of  fresh  cancer  tissue  he  found  proteolytic 
digestion  to  proceed  further  than  in  mixtures  of  pepsin — HC1.  These  experi- 
ments indicate  that  cancer  tissue  contains  a  ferment  similar  to  that  found 
in  other  autolyzing  tissues.  Whether  this  ferment  is  specific  of  cancer  tissue; 
to  what  extent  the  advanced  proteolysis  observed  in  cancerous  stomachs 
is  the  effect  of  this  ferment;  and  the  part  played  by  leukocytes  and  bacteria, 
are  matters  yet  to  be  elucidated.  Rosenberg  has  verified  these  results  and 
the  method  has  been  found  of  value  in  the  diagnosis  of  gastric  cancer. 

Neubauer  and  H.  Fischer  have  found  in  the  stomach  washings  of  gastric 
cancer  and  in  the  expressed  juice  of  carcinoma  and  sarcoma  a  ferment  which 
splits  glycyl-tryptophan  and  this  test  has  been  extensively  employed  in  diag- 
nosis with  satisfactory  results.  Lately  it  appears  to  have  been  shown  that 
this  ferment  is  ptyalin  from  saliva.  Fischer  points  out  that  amino-acids 
appearing  in  the  abnormal  digestion  of  cancer  of  stomach  unite  with  free 
HC1  through  the  amino-group,  while  the  total  acidity  may  remain  normal 
on  account  of  the  acid  reaction  of  the  free  carboxyl  group. 

Disturbance  of  motility  of  the  stomach  dominates  the  clinical  signs  in 
cancer  of  the  pylorus,  leading  in  many  cases  to  dilatation  of  the  stomach  and 


72  NEOPLASTIC  DISEASES 

stagnation  with  abnormal  fermentations  of  the  contents.  Of  the  influence 
of  cancer  on  absorption  by  the  stomach  little  is  definitely  known.  With 
diffuse  infiltration  of  the  wall  and  contraction  of  the  cavity,  evacuation  of 
the  organ  may  be  accelerated  and  absorption  must  be  greatly  reduced. 

As  a  result  of  diminished  digestive  capacity,  disturbance  of  motility, 
and  retarded  absorption,  abnormal  fermentative  processes  become  estab- 
lished and  various  bacterial  species  find  a  favorable  soil.  The  products  of 
fermentation  include  lactic,  butyric,  and  .acetic  acids,  alcohol,  and  protein 
decomposition  products.  Boas  at  one  time  claimed  that  the  presence  of 
lactic  acid  in  the  gastric  contents  was  specific  of  carcinoma  and  appeared  at 
an  early  stage  when  stagnation  and  loss  of  free  HC1  did  not  exist,  but  it  has 
since  been  shown  that  the  presence  of  lactic  acid  is  dependent  upon  impaired 
motility  and  deficiency  of  HC1  (Strauss,  Wagner,  Seelig).  Since  these  con- 
ditions are  present  very  early  in  cancer  and  since,  as  Sick  has  shown,  forma- 
tion of  lactic  acid  is  favored  by  decomposition  products  of  cancer  tissue, 
the  test  for  lactic  acid  is  of  considerable  diagnostic  value. 

Intestinal  digestion  suffers  in  many  ways  from  malignant  tumors  of  the 
gastro-intestinal  tract  and  its  accessory  glands.  With  gastric  cancer  the 
discharge  of  abnormal  digestive  putrefactive  and  bacterial  products  into  the 
intestine  tends  to  incite  disorder  throughout  the  entire  course  of  digestion, 
and  Wasbutski,  Kast,  and  others  have  shown  that  intestinal  decomposition 
occurs  especially  in  cases  with  loss  of  free  HC1  and  active  fermentation  in 
the  stomach.  Rarely  there  is  severe  diarrhea  in  the  terminal  stages  of  such 
cases.  The  main  effects  of  tumors  of  the  intestinal  tract  are  the  result  of 
stenosis  and  ulceration,  and  either  of  these  conditions  in  pronounced  form 
has  a  prompt  influence  on  general  nutrition.  Detailed  studies  in  this  field 
are  meager.  Excessive  indicanuria  tells  of  absorption  of  putrefactive  products 
in  stenosis,  and  formation  of  fistulous  tracts  may  complicate  and  terminate 
the  course  without  much  influence  on  the  extent  of  this  absorption. 

Blood  in  the  stools  offers  a  means  of  diagnosis  in  ulcerating  tumors,  and 
constitutes  a  serious  source  of  anemia.  Acholic  stools  result  from  cancerous 
stenosis  of  the  common  duct,  and  impaired  digestion  of  fats  follows  destruc- 
tion of  the  pancreas  and  occlusion  of  its  duct. 

Tumors  of  the  liver,  bile  passages,  pancreas,  cecum,  and  rectum  produce 
various  important  clinical  types  of  disease  the  full  discussion  of  which  may 
be  left  to  works  on  special  pathology.  Here  it  may  only  be  said  that  all  of 
these  conditions  tend  to  produce  cachexia  through  the  combination  of  very 
numerous  factors  which  must  be  analyzed  for  each  case  and  the  variety  of 
which  reveals  the  very  complex  nature  of  tumor  cachexia. 

Changes  in  the  Urine. — Specific  alterations  in  the  urine  of  cancer  have  not 
been  demonstrated,  but  its  composition  varies  greatly  according  to  general 
rules.  Specific  substances  appear  in  the  urine  with  melanoma  and  myeloma. 
The  entire  subject  invites  further  study  by  improved  methods. 

The  total  nitrogen  varies  with  the  diet  throughout  the  main  course  of  the 
disease,  while  at  the  termination  may  be  observed  the  increased  nitrogen 
output  which  Muller  interpreted  as  a  sign  of  toxic  destruction  of  proteins, 
or  the  diminished  excretion  of  starvation.  The  distribution  of  the  urinary 
nitrogen  fails  to  show  any  specific  characters.  The  percentage  of  urea  is 
influenced  mainly  by  starvation,  falling  to  a  very  low  figure  in  extreme  cases. 

Uric  acid  may  be  increased  without  relation  to  leukocytosis  (Cario). 
The  course  of  this  substance  in  cases  of  various  cellular  tumors  has  not  been 
determined.  Brandenburg  and  Blumenthal  found  the  nitrogen  of  alloxur 
bodies  relatively  high  in  most  of  their  cases,  while  Setti  failed  to  find  any 
uniform  increase. 


MALIGNANCY  AND  ITS  EFFECT  ON  THE  ORGANISM  73 

Ammonia  nitrogen  has  not  been  found  to  show  any  variations  other  than 
those  dependent  on  digestion  and  nutrition.  Herter  found  high  ammonia 
in  the  coma  of  gastric  cancer. 

Creatinin  excretion  has  been  found  low  in  cachectic  cases  by  Benedict 
and  Gorslin,  an  observation  which  accords  with  Shaffer's  view  that  the 
creatinin  coefficient  is  a  measure  of  muscular  efficiency.  Creatin  appears 
in  moderate  amounts  in  cachexia. 

Rest  nitrogen,  chiefly  amino-acids,  is  higher  than  in  some  other  abnormal 
states  and  increases  with  the  progress  of  the  disease  (Setti).  Salkowski  has 
drawn  attention  to  an  increase  in  the  colloidal  nitrogen  precipitable  by  alco- 
hol, in  cancer.  This  fraction  corresponds  partly  to  the  amino-acids  (Wolf). 
Later  Salkowski  estimated  the  nitrogen  precipitable  by  lead  acetate  after 
removal  of  phosphates  by  alkaline  barium  chlorid,  finding  that  this  nitrogen 
fraction  is  greatly  increased  in  cancer.  The  nitrogen  estimated  by  Salkowski 
probably  includes  the  oxyproteic  acids  and  polypeptids. 

An  increase  in  unoxidized  sulphur  has  also  been  observed  by  M.  Weiss 
and  others,  and  Salomon  and  Saxl  have  demonstrated  such  a  notable  and 
uniform  increase  in  oxidizable  neutral  sulphur  as  to  indicate  its  value  in 
diagnosis.  Lehman  points  out  that  the  results  of  this  test  depend  largely 
on  the  diet  without  the  control  of  which  the  examination  is  useless.  From 
observations  in  this  field  Saxl  concludes  that  various  analytic  methods  demon- 
strate the  occurrence  in  notably  increased  amounts  of  protein  derivatives, 
chiefly  oxyproteic  acids,  which  escape  the  normal  transformation  into  urea. 
In  general  he  finds  a  somewhat  specific  disturbance  of  metabolism  in  cancer 
marked  by  a  nearly  constant  excess  in  total  metabolism,  relative  reduction 
in  urea  formation,  increased  ammonia  excretion  and  increase  of  protein  deriv- 
atives which  fail  of  oxidation  into  urea.  In  no  other  disease  except  certain 
special  intoxications  is  the  internal  oxidation  of  protein  so  much  disturbed 
as  in  cancer.  Saxl  goes  on  to  show  that  the  disturbance  of  oxidation  is  prob- 
ably due  to  accumulation  in  the  system  of  rhodan,  an  oxidation  product  of 
hydrocyanic  acid,  since  this  substance  is  increased  in  the  urine  in  cancer  and 
when  administered  to  man  reproduces  the  typical  metabolic  disturbance  of 
cancer.  The  basis  of  this  theory  remains  to  be  verified. 

The  urinary  chlorids  show  no  specific  relation  to  cancer.  Although 
Beneke  supposed  that  the  cancerous  constitution  was  marked  by  deficiency 
of  alkaline  chlorids,  observation  shows  that  these  urinary  principles  depend, 
as  in  other  diseases,  chiefly  on  the  diet,  the  presence  of  disintegrating  protein 
tissues,  and  the  activity  of  the  kidneys.  In  severe  inanition  the  chlorides  / 
fall  very  low  (Miiller,  Braunstein),  but  an  increased  excretion  has  often  been 
observed  (Schopp).  Chlorid  retention  may  occur  with  cardiac  or  renal 
insufficiency  and  may  be  associated  with  anemia  and  edema  (Laudenheimer). 
Chlorin  loss  may  result  from  active  destruction  of  tumor  or  other  tissues. 
Marked  disproportion  between  urinary  nitrogen  and  chlorine  in  favor  of  the 
latter  occurs  in  states  of  inanition  with  little  protein  intake  and  much  destruc- 
tion of  tissue,  as  in  cancerous  stenosis  of  esophagus.  Schopp  concluded  that 
NaCl  might  be  retained  in  the  building  up  of  tumor-tissue  in  cancer  of  the 
liver,  but  Laudenheimer  found  the  same  proportion  of  NaCl  in  liver  tumor 
and  normal  liver  tissue.  Royle  finds  retention  of  both  Na  and  Cl  in  cancer, 
that  of  Na  being  greater  than  Cl.  He  concludes  that  extra  Na  combines  with 
phosphoric  acid  and  that  the  retention  of  chlorine  seems  to  counterbalance 
the  alkaline  phosphates  of  the  blood  and  maintain  the  proper  relation  of 
salts  in  the  plasma.  In  10  cases  of  carcinoma  Braunstein  found  no  changes 
in  the  urine  which  could  be  regarded  as  specific.  In  3  cases  the  excretion 
of  Na  and  Cl  was  practically  normal  and  the  loss  of  P  ran  parallel  with  that 


74  NEOPLASTIC  DISEASES 

of  N.  Phosphoric  acid  excretion  is  increased  in  most  cases  both  absolutely 
and  in  proportion  to  the  nitrogen  with  which  in  general  it  runs  parallel.  The 
P  :  N  ratio  runs  i  :  4  or  i  :  5  :  6  instead  of  the  normal  i  :  7  (Braunstein). 
Its  excess  suggests  a  source  in  tissues  rich  in  P,  as  the  bones,  glandular  organs, 
or  the  tumor  tissue  itself.  Sulphuric  acid  excretion  is  parallel  with  that  of 
nitrogen,  but  Cario  observed  somewhat  increased  proportions  in  2  cases  of 
cancer  of  esophagus.  The  partition  of  the  sulphur  has  not  been  determined, 
but  high  percentages  of  ethereal  sulphates  may  be  expected,  with  ulcerating 
tumors  and  intestinal  disturbance. 

Urobilin. — Considerable  urobilin  was  frequently  observed  and  regarded 
as  somewhat  characteristic  of  cancer,  especially  of  cachectic  and  hepatic  cases, 
by  F.  Miiller  and  Gerhardt.  Yet  Hoppe-Seyler  had  previously  found  little 
urobilin  in  several  cases,  and  Blumenthal,  who  observed  an  excess  in  gastro- 
intestinal and  ulcerating  cases,  often  found  it  absent  in  others.  Braunstein 
from  the  study  of  22  cases  concludes  that  urobilin  is  missing  in  cancer  so 
long  as  fever  and  complications  are  absent,  but  appears  with  metastases 
especially  in  the  liver;  with  necrosis  and  decomposition  of  the  tumor,  and 
with  complicating  pneumonia.  In  cancer  of  the  liver  when  the  bile-ducts 
are  closed  he  found  that  bilirubin  replaced  the  urobilin. 

Products  of  putrefaction  of  proteins  are  found  in  increased  quantities 
in  the  urine  of  advanced  cancer,  but  the  exact  source  of  these  substances  has 
not  been  fully  determined.  Indican,  phenol,  aromatic  oxyacids,  and  ethereal 
sulphates  have  been  estimated  by  several  observers  who  attribute  their 
presence  to  intestinal  putrefaction,  to  decomposition  of  secretions,  and  to 
destruction  of  tumor-tissue.  That  intestinal  putrefaction  is  not  the  sole 
source  is  indicated  by  the  considerable  quantities  of  such  substances  observed 
with  decomposing  tumors  of  breast  and  uterus  (Brieger,  Haberlin,  Hennige). 
Lewin  finds  excess  of  aromatic  acids  in  patients  with  N  loss,  but  not  with 
those  showing  N  retention,  and  concludes  that  these  substances  are  derived 
from  the  toxic  destruction  of  tumor  and  tissue  proteins  and  not  wholly  from 
intestinal  putrefaction.  Yet  it  still  remains  uncertain  whether  aromatic 
oxyacids,  indol  and  phenol,  may  arise  in  the  course  of  nitrogenous  metabolism, 
and  it  is  clear  that  patients  laying  on  nitrogen  are  not  likely  to  be  suffering 
from  excessive  intestinal  disturbance. 

Acidosis  of  Cancer. — The  acetone  bodies  in  cancer  follow  the  same  rules 
as  in  other  conditions.  Their  presence  in  the  urine  bears  no  relation  to  the 
growth  of  cancer  as  such,  and  these  substances  are  absent  in  the  early  stages 
of  the  disease  and  when  the  patient  is  well  fed  (Waldvogel).  With  the  advent 
of  protein  loss  and  cachexia  acetone  and  diacetic  acid  commonly  appear 
in  the  urine  and  beta-oxybutyric  acid  is  added  in  severe  inanition.  Hirsch- 
feld  relieved  the  acidosis  by  giving  sugar. 

In  cases  chiefly  of  esophageal,  gastric,  and  hepatic  cancer  v.  Jaksch,  Riess 
and  Senator  described  a  form  of  cancer  coma  in  which  the  dyspnea,  acidosis, 
and  diminished  alkalescence  of  the  blood  were  present  as  in  diabetes.  In 
2  such  cases  Klemperer  observed  a  daily  N  loss  of  5  to  9  gm.  which  he 
interpreted  as  signifying  toxic  destruction  of  tissues.  The  coma  he  referred 
not  to  the  acidosis  but  to  the  general  toxic  process,  v.  Jaksch  also  stated  that 
these  patients  were  not  always  suffering  from  starvation,  but  that  the  appear- 
ance of  acetone  bodies  ushered  in  a  severe  type  of  general  cachexia.  It  is  not 
entirely  clear  that  cancer  coma  is  purely  an  acid  intoxication,  and  it  seems 
probable  that  the  rapid  burning  of  tissue  fats  and  proteins  of  which  acidosis 
is  only  one  result  may  be  responsible  for  some  of  the  sudden  terminations  of 
malignant  tumors. 

Von  Noorden's  observation  of  considerable  quantities  of  lactic  acid  in  the 


MALIGNANCY  AND  ITS  EFFECT  ON  THE  ORGANISM  75 

urine  of  2  cases  suggests  that  the  acidosis  of  cancer  may  involve  hepatic 
disturbance  as  well  as  pure  acidemia. 

Demineralization  occurs  in  cancer  cachexia  as  in  other  conditions  and  is 
associated  with  nitrogen  loss,  with  which  it  maintains  a  parallel.  Of  1 1  cases, 
Lewin  observed  loss  of  mineral  salts,  1.36  to  8.9  gm.,  and  of  nitrogen,  in 
7,  and  slight  retention  of  both  in  4.  One  important  source  of  these 
mineral  salts  is  probably  the  bones,  which  become  increasingly  fragile  in 
many  wasting  diseases.  The  shafts  become  thinner,  the  cancellous  spaces 
and  Haversian  canals  larger,  and  Campbell  has  shown  that  the  breaking  strain 
is  greatly  reduced.  In  some  cases  of  cancer  the  calcium  depots  become  greatly 
disturbed  and  extensive  deposits  of  calcium  salts  are  found  frequently  in  the 
tumor,  occasionally  in  the  lung. 

Albuminuria  occurs  in  most  cases  of  cancerous  cachexia,  but  is  absent  in 
the  early  stages  of  the  disease.  According  to  Miiller  it  occurs  in  35  to  72  per 
cent,  of  all  cases  of  carcinoma.  In  cancer  of  the  intestinal  tract  albumoses 
are  very  often  present  (Ury,  Lilienthal),  either  by  direct  absorption  of  diges- 
tive products  through  the  ulcerated  surface  (Maixner)  or  from  the  disinte- 
gration of  tumor  tissues  (Pacanowski).  In  many  cases  of  myeloma  a  peculiar 
protein,  Bence- Jones  body,  appears  in  the  urine. 


CHAPTER  IV 
METASTASIS 

The  formation  of  secondary  tumors  is  a  cardinal  property  of  malignant 
tumor  growth.  The  appearance  of  a  secondary  tumor  at  some  distance  from 
the  primary  growth  may  represent  one  of  several  events.  It  may  mean  a 
multiple  origin,  and  a  new  tumor;  or  a  continuous  extension  from  the  primary 
growth;  or  a  true  metastatic  growth  arising  from  tumor-cell  emboli.  Only 
a  critical  estimate  of  the  known  tendencies  of  particular  tumors  can  deter- 
mine which  of  these  events  has  occurred.  Melanoma  and  multiple  fibroma 
both  produce  very  numerous  tumors  of  the  skin,  the  one  from  cell  emboli, 
the  other  by  multiple  growth  of  new  tumors. 

Multiple  origin  of  new  tumors  is  observed  with  a  considerable  list  of  neo- 
plasms, already  considered,  including  fibroma  molluscum,  myeloma,  epithe- 
lioma  of  skin,  sarcoid  growths  of  skin,  adenoma  and  adenocarcinoma  of  mucous 
membranes,  chondroma  of  spine,  myoma,  lipoma,  etc. 

Lymphatic  Permeation. — By  continuous  extension  of  primary  infiltrating 
tumors  through  the  lymphatics,  apparently  discrete  tumors  often  appear 
at  points  widely  distant  from  the  original  growth.  In  multiple  carcinoma 
of  the  skin  continuous  chains  of  cells  may  extend  through  convenient  lym- 
phatics until  the  cells  reach  a  locality  favorable  for  growth  and  there  mul- 
tiply, producing  discrete  tumors  connected  with  the  primary  growth  only 
by  a  thin  strand  of  cells.  It  is  conceivable  that  accidental  breaks  may  occur 
in  this  chain  of  cells  completely  separating  the  secondary  from  the  primary 
growth.  There  are  many  tumors  in  which  this  process  leads  to  formation 
of  secondary  growths.  At  what  remarkable  distances  secondary  tumors  may 
arise  by  this  method  has  only  recently  been  demonstrated. 

In  cancer  of  the  breast  Handley  has  shown  that  there  may  be  continuous 
extension  of  tumor-cells  through  the  lymphatics  of  the  deep  pectoral  fascia 
to  the  axillary  and  supraclavicular  nodes;  thence  to  overlying  skin  and  to 
humerus;  through  the  deep  lymphatics  to  the  ribs,  pleura,  lung,  and  spine; 
across  the  chest  wall  to  the  opposite  breast;  downward  through  the  abdom- 
inal wall  to  the  epigastric  region,  and  thence  by  the  falciform  ligaments  to  the 
liver;  and  further  to  the  inguinal  region  with  involvement  of  lymph-nodes, 
skin,  and  femur.  Extension  through  superficial  lymphatics  is  much  less  wide. 
Invasion  of  the  humerus  occurs  at  the  deltoid  insertion  and  of  femur  at  the 
trochanter,  where  these  bones  are  closest  to  the  skin,  through  the  deep 
lymphatics  of  which  the  bone  invasion  follows.  The  leg  and  arm  bones  escape 
infection,  which  is  inconsistent  with  a  free  embolic  origin  through  the  blood- 
vessels. Passing  through  the  deep  lymphatics  of  chest  or  abdominal  wall 
the  cells  enter  the  pleura  and  peritoneum  and  become  implanted  on  the  serous 
surfaces  and  produce  superficial  infiltrations  of  the  lung,  liver,  intestines, 
and  ovary.  Or  the  viscera  may  be  invaded  through  their  main  lymphatic 
vessels  giving  central  tumors.  The  liver  is  involved  through  the  lymphatics 
of  the  falciform  and  round  ligaments,  or  by  transperitoneal  implantation, 
or  by  way  of  portal  nodes;  the  lung  by  transpleural  implantation  or  through 
bronchial  nodes  and  hilus.  Abdominal  invasion  by  the  epigastric  route  is 
earlier  and  more  frequent  than  the  thoracic,  occurring  without  thoracic  lesions 
in  12  per  cent,  of  all  cases.  The  diaphragm  is  invaded  by  the  epigastric  peri- 

76 


METASTASIS  77 

toneal  route,  and  through  the  descending  lymphatics  of  its  crura  the  retro- 
peritoneal  nodes  and  kidneys  are  attacked.  This  process  of  lymphatic  permea- 
tion Handley  believes  is  the  master  process  of  general  dissemination  in  cancer. 
Lymphatic  embolism  he  would  reduce  to  a  very  secondary  factor.  Handley 
bases  his  conclusions  on  the  study  of  long  slices  of  thoracic  and  abdominal 
parietes  in  advanced  cases  of  mammary  cancer.  In  such  material  he  finds 
the  lymphatics  continuously  filled  by  tumor-cells.  The  only  breaks  occur 
as  the  result  of  perilymphatic  fibrosis,  an  inflammatory  reaction  excited  by 
the  tumor  process  and  resulting  in  complete  atrophy  of  tumor-cell  cords 
at  many  points. 

While  recognizing  the  value  of  Handley's  studies  it  must  be  considered 
that  the  condition  at  autopsy  may  not  clearly  indicate  the  manner  in  which 
the  lymphatics  have  become  filled.  It  is  conceivable  that  cell  emboli  lodging 
at  different  points  in  a  lymphatic  chain  may  grow  in  both  directions  and 
after  a  time  fill  the  lymphatic  completely.  Many  observers  believe  that 
lymphatic  embolism  is  commonly  associated  with  continuous  permeation 
in  most  mammary  and  in  many  other  cancers.  However,  the  result  of  these 
processes  is  practically  the  same,  ending,  in  prolonged  cases,  in  very  wide- 
spread and  nearly  continuous  invasion  of  lymphatics. 

The  theory  of  continuous  permeation  is  of  fundamental  importance  in 
surgical  procedure.  To  what  extent  this  process  prevails  in  different  forms 
of  cancer  can  be  determined  only  by  careful  study  in  each  case.  Such  studies 
are  not  yet  available  and  are  essential  before  this  theory  can  safely  be  adopted. 
In  epithelioma  of  esophagus  Borrmann  has  found  that  the  metastatic  tumors 
in  the  stomach  wall,  which  have  long  been  regarded  as  implantations  through 
the  esophagus,  are  connected  with  the  primary  tumor  by  an  unbroken  chain 
of  cancerous  lymphatics.  Bloodgood  believes  that  successful  extirpation  of 
cancer  of  the  tongue  and  infected  lymph-nodes  may  be  accomplished  only 
by  removal  of  all  lymphatics  joining  ulcer  and  lymph-nodes. 

Yet  the  majority  of  observers  fail  to  find  in  early  cases  such  uniform  and 
continuous  connection  between  primary  cancers  and  infected  regional  lymph- 
nodes  and  are  agreed  that  such  infection  is  usually  by  means  of  cell  emboli. 

1  have  repeatedly  failed  to  find  any  trace  of  invaded  lymphatics  connecting 
carcinomas  in  the  breast  with  infected  axillary  nodes,  and  have  been  equally 
unsuccessful  with  cancer  of  tongue  and  penis.    Metastases  from  lingual  cancer 
often  appear  first  in  rather  distant  nodes,  sometimes  on  the  opposite  side 
of  the  neck.    The  metastases  from  melanoma  of  foot  and  other  regions  are 
usually  incompatible  with  the  theory  of  continuous  permeation.    In  general 
it  appears  probable  that  the  rapidly  growing  epidermoid  and  glandular  carci- 
nomas disseminate  chiefly  by  lymphatic  embolism,  while  slowly  growing 
and  recurrent  tumors,  especially  in  the  skin,  often  extend  by  continuous  per- 
meation.   This  belief  is  strengthened  by  such  observations  as  those  of  Gussen- 
bauer  who  found  cancer-cells  in  the  cervical  lymph-nodes  in  29  of  32  cases, 
and  of  Kuster,  who  found  the  axillary  nodes  free  from  cancer-cells  in  only 

2  of   117  operative  cases  of  breast  cancer.     Since  definite  growing  tumors 
of  the  lymph-nodes  are  much  less  common  it  is  clear  that  embolic  cancer- 
cells  are  frequently  present  in  lymph-nodes  and  that  they  are  probably  de- 
stroyed there  under  some  circumstances.    Yet  it  is  extremely  rare  to  find 
in  lymph-nodes  any  appearance  suggesting  the  destruction  of  small  groups 
of  embolic  tumor-cells.    On  the  other  hand,  evidences  of  retardation  of  growth 
by  fibrosis  and  encapsulation  are  relatively  common. 

The  frequency  of  lymph-node  metastases  varies  with  different  tumors, 
with  different  varieties  of  the  same  tumor,  and  with  different  positions  of  the 
tumor  in  the  same  organ,  and  must  be  separately  considered  for  each  case. 


78  N  EOF  LA  STIC  DISEASES 

Cancer  of  breast  probably  stands  high  on  the  list,  very  few  fully  malig- 
nant cases  of  this  disease  failing  to  involve  the  nodes  if  allowed  to  remain 
more  than  a  few  months.  Williams  found  the  nodes  involved  in  86  (73  per 
cent.)  of  118  cases  at  first  examination,  and  in  40  (90  per  cent.)  of  44  autop- 
sies. The  variety  of  the  cancer  is  here  of  paramount  importance,  and  is  a 
factor  often  underestimated. 

Epithelioma  of  the  tongue  or  tonsil  very  early  and  nearly  constantly 
invades  the  lymph-nodes,  but  here  again  the  type  of  the  tumor  is  the  deter- 
mining factor.  Williams  recorded  86  (83  per  cent.)  of  104  lingual  cases  in- 
fected at  time  of  first  examination,  and  56  of  57  cases  coming  to  autopsy. 
Epithelioma  of  the  lower  lip  invades  the  lymph-nodes  more  slowly,  but  event- 
ually in  almost  all  cases.  In  186  cases  of  cancer  of  stomach  examined  at 
autopsy  by  Moore,  Cuneo,  and  Colwell,  lymph-nodes  were  involved  in  149. 

The  lymph-nodes  escape  in  many  cases  of  uterine  cancer,  especially  with 
tumors  of  the  fundus.  Epithelioma  of  the  skin  is  slow  in  reaching  the  lymph- 
nodes,  and  rodent  ulcer  and  adenoid  cystic  epithelioma  are  remarkable  for 
the  long  or  permanent  immunity  of  adjacent  lymph-nodes.  Of  34  malignant 
tumors  of  the  testis  Butlin  found  the  lymph-nodes  free  in  only  3,  but  in  a 
series  of  19  cases  I  found  several  which  had  not  attacked  the  inguinal  nodes. 
The  tumor  usually  first  affects  the  epigastric  nodes. 

The  value  of  available  statistics,  however,  is  very  limited,  since  most 
authors  fail  to  distinguish  between  the  different  types  of  cancer,  although  it 
is  well  known  that  some  are  very  prone  to  invade  the  lymphatics  while  others 
long  remain  circumscribed.  It  is  little  help  to  know  that  75  per  cent,  of  the 
cancers  of  the  breast  involve  the  lymph-nodes  within  a  year  of  their  onset, 
when  the  surgeon  might  learn  that  his  case  is  an  adenocarcinoma  which  long 
spares  the  nodes. 

For  the  same  reasons  available  statistics  regarding  the  period  at  which 
lymph-node  invasion  occurs  appear  to  be  of  uncertain  value.  Thus  Fink 
observed  it  in  breast  cancer  as  early  as  the  sixth  and  always  after  the  thir- 
teenth months,  yet  I  have  examined  a  mucoid  breast  cancer  of  10  years' 
duration,  service  of  Dr.  Hartley  at  Roosevelt  Hospital,  without  invasion  of 
the  nodes.  Similar  variations  are  observed  with  many  other  tumors,  while 
it  should  be  noted  that  some  cancers  show  general  dissemination  without 
palpable  enlargement  of  regional  nodes. 

Changes  in  lymph-nodes  draining  malignant  tumors  show  that  the  im- 
plantation of  metastases  is  preceded  by  a  period  of  preparation  of  the  soil. 
For  weeks  or  months  before  actual  tumor  invasion  the  regional  lymph-nodes 
may  be  moderately  swollen.  During  this  period  many  new  lymph-nodes  may 
develop  in  the  course  of  the  vessels.  On  section  the  swollen  nodes  show  diffuse 
hyperplasia  with  catarrhal  exfoliation  of  sinus  endothelium,  or  multiplica- 
tion of  follicles.  It  is  not  uncommon  also  to  find  the  nodes  atrophic  and 
fibrous,  or  extensively  invaded  by  fat  tissue,  conditions  which  reduce  their 
effectiveness  as  filters.  Owing  to  a  variety  of  causes  old  changes  of  this  latter 
class  may  permit  the  passage  of  cancer-cells  through  or  around  a  given  group 
only  to  lodge  in  a  more  central  area.  The  former  class  of  recent  alterations 
must  be  referred  to  the  absorption  of  toxic  products  from  the  tumor,  auto- 
lytic  and  bacterial.  There  are  no  specific  histological  features  of  the  pre- 
cancerous  condition  of  the  lymph-nodes,  but  there  are  reasons  to  believe 
that  regressing  tumor-cells  may  be  found  in  the  sinuses  before  definite  im- 
plantation has  occurred.  As  previously  noted,  Kuster  found  that  in  only 
2  of  117  cases  were  the  axillary  nodes  removed  with  breast  cancer  free 
from  invasion.  Yet  the  proportion  of  lymph-node  recurrences  when  the  nodes 
are  not  removed  is  very  much  less.  Nevertheless  it  is  extremely  rare  to  find 


METASTASIS  79 

any  metastatic  focus  in  a  lymph-node  which  does  not  appear  to  be  safely 
implanted  and  capable  of  growth. 

The  earliest  nodules  appear  in  the  sinuses,  from  which  they  invade  and 
compress  the  pulp  with  complete  atrophy  of  lymphoid  tissue.  From  this 
point  the  cells  may  invade  the  capsule  and  the  peripheral  lymphatics, 
blood-vessels,  fats,  or  fibrous  tissue. 

When  the  metastatic  period  is  established  lymph-node  invasion  may  fol- 
low rapidly.  In  a  case  of  cancer  of  breast  a  swollen  axillary  node  examined 
in  March  showed  only  inflammatory  hyperplasia  with  no  demonstrable  tumor 
in  the  breast,  but  in  June  the  entire  breast  was  infiltrated  by  a  flat  diffuse 
growth  and  some  axillary  nodes  were  completely  replaced  by  cancer.  Since 
many  tumor  metastases  long  remain  confined  to  the  regional  lymph-nodes 
and  fail  to  make  any  headway  through  the  blood-stream  it  may  be  assumed 
that  there  is  a  regional  and  a  general  immunity  against  implantation.  Yet 
in  not  a  few  cases  cancer  skips  the  regional  nodes  and  yields  distant  met- 
astases. According  to  Gross  this  occurred  in  i  out  of  7  cases  of  breast  cancer. 
With  some  rapidly  growing  tumors  both  local  and  general  susceptibility  to 
metastasis  exists  at  a  very  early  period,  and  in  most  cases  one  must  conclude 
that  the  growth  capacities  of  the  cells  are  of  chief  importance  in  determining 
the  fate  of  cell  emboli. 

Invasion  of  the  Thoracic  Duct. — In  not  a  few  cases  of  advanced  cancer 
the  thoracic  duct  is  invaded,  an  event  which  commonly  leads  to  wide-spread 
dissemination  by  lymph  and  blood-stream. 

One  of  the  striking  results  of  invasion  of  the  thoracic  duct  is  the  appear- 
ance of  enlarged  nodes  in  the  supraclavicular  region.  Troisier  in  1886  first 
emphasized  the  diagnostic  importance  of  this  symptom  in  cases  of  abdominal 
and  especially  of  gastric  and  uterine  cancer,  and  similar  cases  have  since  been 
reported  by  many  observers  (Lit.  in  Williams,  p.  425). 

It  has  also  been  observed  with  cancer  of  pancreas  (Raw),  testis  (Poncet), 
prostate  (Hurlemont),  adrenal  (Troisier).  Nevertheless  it  is  a  late  and,  with 
improving  diagnosis,  a  rare  symptom  of  diminishing  importance,  and  must 
be  distinguished  from  other  affections  of  the  nodes,  and  according  to  Williams, 
from  Verneuil's  "pseudolipome  sus-claviculare."  According  to  Rousseau,  in 
37  cases  presenting  Troisier's  symptom,  the  left  nodes  were  involved  in  29, 
the  right  in  4,  both  sides  in  4. 

Inguinal  lymph-node  invasion  is  also  associated  with  and  occurs  without 
involvement  of  the  thoracic  duct,  with  abdominal  cancers,  especially  of  the 
uterine  fundus,  prostate  (Viannay),  bladder,  rectum,  chorion,  and  occasionally 
with  many  other  primary  tumors.  Among  other  symptoms  resulting  from 
occlusion  of  the  thoracic  duct  are  chylous  ascites  (Leydbecker) ,  chylothorax, 
and  lymph  varices  which  may  lead  to  cysts  of  considerable  size.  The  results 
of  invasion  of  the  blood-stream  from  the  duct  with  multiple  tumors  of  the 
lung  are  frequently  observed. 

Winkler  has  given  a  full  description  of  27  cases  (12  original)  of  cancer  and 
i  of  round-cell  sarcoma  of  the  thoracic  duct.  The  invasion  followed  most 
frequently  cancer  of  the  stomach,  then  of  uterus,  while  other  cases  arose 
from  the  gall-bladder,  testis,  colon,  and  kidney.  In  all  these  cases  the  abdom- 
inal nodes  were  enlarged  and  adherent  to  the  duct,  offering  abundant  oppor- 
tunity for  the  invasion  by  this  means.  The  duct  presented  one  of  three  con- 
ditions: (i)  Free  masses  of  tumor-cells  lying  in  a  coagulum,  with  thrombo- 
sis or  occlusion.  (2)  Papillary  masses  of  tumor  growth  adherent  to  the  wall 
and  organized  from  it,  usually  at  the  valves,  with  numerous  varices  often 
resembling  a  string  of  pearls.  (3)  Complete  thrombosis  by  tumor  masses 
invading  the  wall  and  mingled  with  fibrin. 


80  NEOPLASTIC  DISEASES 

Invasion  of  Serous  Cavities. — The  large  serous  cavities  are  penetrated 
by  many  pathways  and  in  the  course  of  a  considerable  number  of  tumors 
chiefly  those  of  the  contained  organs.  The  most  frequent  source  of  free 
peritoneal  growths  is  the  ovarian  adenocarcinoma  which  at  any  period  may 
rupture  its  covering  and  be  disseminated  through  the  cavity.  Its  cells  readily 
become  implanted  on  the  peritoneum,  producing  many  miliary  or  large  solid 
papillary  or  cystic  tumors  with  a  tendency  to  ascites.  One  of  the  most  re- 
markable forms  of  peritoneal  cancer  arises  from  small  adenocarcinomas  of 
colon  or  appendix,  which  early  perforate  the  peritoneum,  spread  rapidly 
throughout  the  greater  sac  and,  retaining  the  large  alveolar  structure,  produce 
enormous  quantities  of  mucus  greatly  distending  the  abdomen.  In  very  large 
tumors  of  this  sort,  several  liters  of  gelatinous  material  may  be  evacuated 
and  it  may  be  extremely  difficult  to  discover  any  trace  of  living  tumor-cells. 
I  have  seen  gelatinous  cancer  of  the  rectum,  following  an  extraperitoneal  route, 
fill  the  pelvis  inclosing  rectum  and  bladder,  pass  up  the  abdominal  parietes  in 
front  and  retroperitoneal  tissues  behind,  separating  liver  from  diaphragm, 
inclosing  the  entire  abdominal  cavity  in  a  rigid  shell  3  to  5  cm.  in  thickness, 
and  eventually  invading  the  mesentery  and  subserous  intestinal  lymphatics, 
but  without  any  trace  of  intraperitoneal  growth.  This  condition  may  be 
designated  as  abdominal  cancer  en  cuirasse. 

Peritoneal  invasion  is  a  very  common  late  complication  of  breast  cancer, 
and  occurs,  as  Handley  has  shown,  often  by  way  of  the  epigastric  lymphatics. 
From  the  subperitoneal  lymphatics  and  along  the  falciform  and  round  liga- 
ments of  the  liver  he  has  found  cancer  nodules  opening  into  the  peritoneum. 
Loose  cells  often  become  implanted  first  in  Douglas'  sac  or  on  the  ovary. 
More  frequently  there  is  a  wide-spread  permeation  of  the  subperitoneal 
lymphatics,  which  may  become  nearly  universal.  It  is  associated  writh  active 
growth  of  hard  fibrous  tissue,  producing  nodules  and  adhesions.  Eventually 
the  entire  peritoneum  becomes  thickened,  leathery  and  opaque,  and  the 
omentum  shrinks  to  a  firm  globular  infiltrated  mass.  Such  patients  show 
marked  resistance  to  cachexia  and  may  suffer  for  months  or  years  from  in- 
creasing ascites  which  gradually  drains  their  strength  or  suddenly  terminates 
life  by  asphyxia. 

The  peritoneum  seems  to  have  very  little  capacity  to  destroy  cancer- 
cells,  so  that  the  invasion  once  accomplished  is  usually  progressive.  Gravity 
and  the  muscular  contraction  of  stomach,  intestine,  diaphragm,  and  parietes 
assure  a  general  dissemination  of  cells.  These  movements  also  may  cause  the 
separation  of  tumor  masses  which  have  been  found  free  in  the  peritoneal  and 
pleural  cavities,  while  the  aspirated  fluid  nearly  always  contains  exfoliated 
cancer-cells. 

Intrapleural  and  intrapericardial  cancerous  invasion  occurs  chiefly  by 
direct  invasion  from  cancer  of  breast,  bronchi,  and  lung,  with  results  very 
similar  to  those  produced  by  breast  cancer  in  the  peritoneum. 

Penetration  of  the  cerebrospinal  membranes  occurs  in  rare  cases  of  carci- 
noma, chiefly  of  the  breast,  and  may  lead  to  a  universal  cerebrospinal  carci- 
nomatosis  resembling  meningitis.  In  a  breast  case  observed  at  New  York 
Hospital,  service  of  Dr.  Conner,  isolated  cells,  small  groups  of  cells  and  thin 
plates  were  found  from  the  vertex  to  the  cauda  equina,  infiltrating  the  pia, 
and  penetrating  many  sulci,  with  little  cellular  or  serous  exudate. 

Lymphatic  Invasion  by  Sarcoma. — It  is  a  somewhat  important  dis- 
tinction that  lymphatic  invasion  by  carcinoma  is  frequent,  by  sarcoma  rare. 
Not  a  few  epithelial  tumors  violate  this  rule  and  travel  through  the  blood- 
vessels, but  sarcomas  that  tend  to  invade  lymphatics  are  much  less  numerous. 
The  lymphosarcomas  are  the  only  sarcomas  that  frequently  travel  by  the 


METASTASIS  81 

lymphatics,  and  the  origin  of  these  tumors  within  the  lymph-nodes  fully 
accounts  for  this  tendency.  The  blood-vessels  also  serve  as  channels  for  the 
dissemination  of  lymphosarcoma,  so  that  certain  forms  of  this  tumor  yield 
the  most  abundant  and  widely  disseminated  metastases  seen  with  any  type  of 
neoplasm. 

Most  statistical  reports  of  lymph-node  invasion  in  sarcoma  are  of  doubtful 
value  owing  to  the  uncertainty  connected  with  the  diagnosis  of  sarcoma. 
Most  of  the  sarcomas  reported  of  the  testis  and  thyroid  are  probably  epithe- 
lial tumors,  and  commonly  invade  the  lymph-nodes.  Melanoma  declares  its 
specific  nature  by  frequently  (41.7  per  cent.  Williams)  affecting  lymph-nodes. 
Of  the  bone-sarcomas  the  spindle-cell  and  giant-cell  types  rarely,  the  round- 
cell  or  lymphoid-cell  types  frequently  involve  the  adjacent  nodes  (Gross). 
The  frank  spindle-cell  sarcomas  of  the  parietes  and  its  contained  structures, 
and  those  of  the  internal  organs  affect  lymph-nodes  in  5  to  15  per  cent,  of 
cases.  As  a  rule  the  blood-vessels  as  well  as  the  lymphatics  may  be  the  route 
of  entry. 

The  comparative  immunity  of  lymphatics  against  invasion  of  sarcoma 
is  probably  to  be  explained  chiefly  by  the  greater  local  fixation  of  sarcoma- 
cells  as  compared  with  the  mobile  and  sometimes  ameboid  cancer-cell.  It  is 
in  accordance  with  this  view  that  the  lymphosarcomas  behave  much  like 
carcinomas.  At  the  same  time  sarcomas  are  usually  more  vascular  than 
carcinomas  so  that  cells  rapidly  break  into  the  blood-vessels  whose  walls  are 
thin  or  deficient.  The  growth  of  most  sarcomas  is  more  expansive  than  with 
carcinomas  and  more  often  encapsulated,  so  that  lymphatic  channels  are 
closed  and  only  the  nutrient  blood-vessels  remain  pervious.  I  do  not  think 
that  the  original  relations  between  lymphatics  and  epithelium  or  connective- 
tissue  cells  have  an  influence  on  the  character  of  tumor  metastases,  since  at 
the  period  when  dissemination  begins  these  relations  are  greatly  altered. 

Dissemination  by  Blood-vessels. — The  blood-vessels  are  the  chief  chan- 
nel of  the  extension  of  sarcomas,  they  are  frequently  invaded  by  carcinomas, 
and  several  epithelial  tumors  show  a  remarkable  capacity  to  flourish  in  and 
travel  through  the  veins.  The  abundance  of  thin-walled  blood-vessels,  the 
presence  of  naked  sinuses,  and  the  tendency  toward  necrosis  and  hemorrhage 
rather  than  fibrosis,  may  largely  explain  the  predominance  of  blood-vessel 
invasion  by  sarcoma  as  compared  to  carcinoma.  In  many  cases,  as  in  fascial 
myxosarcoma,  the  tumor-cells  appear  to  be  mechanically  forced  into  the  veins 
by  the  presence  of  rapidly  growing  and  swollen  tumor  tissue. 

The  entry  into  the  veins  is  accomplished  through  the  defective  vessels 
within  the  tumor,  or  by  invasion  and  rupture  of  adjoining  vessels,  or  by  infil- 
tration along  the  vasa  vasorum  and  intima,  with  gradual  erosion  of  the  wall. 
Carcinoma  often  penetrates  the  wall  via  the  perivascular  lymphatics. 

The  result  of  such  invasion  is  at  first  a  thrombosis  complete  or  partial, 
at  the  point  of  entry.  The  tumor-cells  may  then  be  destroyed  by  organiza- 
tion and  fibrosis  of  the  thrombus  with  subsequent  canalization  (Schmidt), 
or  the  cells  continue  to  grow  within  the  vein,  they  become  attached  to  the 
wall,  produce  flat  or  polypoid  outgrowths,  many  cells  or  cell  masses  become 
detached  from  the  wall  or  from  the  original  tumor  and  are  carried  to  the 
first  zone  of  capillary  vessels,  usually  the  lungs,  where  they  lodge  as  emboli. 
Here  again  they  are  exposed  to  destructive  agencies  and  may  perish,  but 
more  often  develop  secondary  tumors. 

If  the  detached  masses  are  large  they  regularly  lodge  in  the  lungs,  or 

become  arrested  in  the  right  heart.    Direct  transport  of  emboli  or  continuous 

growth  in  the  veins  is  by  far  the  most  important  mode  of  dissemination  in 

blood-vessels,   and   several  well  known   tumors  offer   striking  illustrations. 

6 


82  NEOPLASTIC  DISEASES 

Chorioma  originates  in  the  uterine  sinuses  and  maintains  throughout  its 
intravascular  and  hemorrhagic  tendencies,  producing  retrograde  vaginal  and 
renal  metastases,  honeycombing  the  uterine  wall,  and  yielding  forward  metas- 
tases  in  the  lungs.  Portions  of  the  stroma  of  villi  as  well  as  tumor-cells  have 
been  found  in  the  pulmonary  emboli  of  chorioma.  Hypernephroma  regularly 
perforates  the  renal  vein  and  may  extend  in  a  solid  column  of  tumor-tissue 
into  the  heart.  Adenoma  of  the  liver  is  commonly  found  distending  the 
portal  veins.  The  intravascular  hydatid  growths  of  teratoma  testis  are 
among  the  oldest  observed  forms  of  intravenous  extension.  When  a  sarcoma 
or  carcinoma  ruptures  into  a  pulmonary  vein  wide-spread  dissemination  re- 
sults and  very  numerous  tumors  appear  rapidly  in  different  tissues  and  organs. 

The  form  assumed  by  tumors  growing  within  vessels  is  sometimes  influ- 
enced by  the  existing  mechanical  and  nutritional  conditions.  Freedom  from 
pressure  allows  the  cells  to  reveal  their  natural  tendencies,  and  the  intra- 
vascular tumor  may  be  more  "typical"  than  the  original.  Or  a  more  rapid 
and  diffuse  growth  is  assumed.  In  the  axillary  vein  the  cells  of  breast  cancer 
may  become  larger  and  more  anaplastic,  and  I  have  seen  evidence  of  multi- 
plication of  loose  cells  in  this  situation  and  in  the  thoracic  duct.  The  organ- 
ization of  a  tumor  thrombus  with  fibrosis  and  reopening  of  the  lumen  occurs 
rarely.  The  advancing  mass  of  hypernephroma  in  the  renal  vein  is  usually 
very  edematous  and  the  cells  hydropic.  Fuhrmann  and  Risel  believe  that 
some  tumors,  especially  myxoma,  tend  to  assume  an  hydatidiform  growth 
when  invading  blood-vessels,  and  they  would  attribute  the  chorion-like  form 
of  certain  testicular  teratomas  to  the  influence  of  the  intravascular  position 
and  not  to  any  intrinsic  chorionic  character. 

Are  vagrant  tumor-cells,  destroyed  in  the  blood  or  lymph  stream  or  their 
associated  organs,  and  if  so  by  what  mechanism?  To  this  fundamental 
question  only  a  very  incomplete  answer  can  be  given. 

The  scope  of  the  conditions  to  which  the  question  applies  is  very  wide, 
including  many  different  forms  of  tumors  and  cells,  involving  the  natural 
life  span  of  the  cells  and  the  facility  with  which  they  may  reach  the  circula- 
tion. It  must  be  assumed  at  once  that  in  many  systemic  sarcomas  and  other 
rapidly  growing  neoplasms,  cells  are  constantly  reaching  the  circulation  and 
perishing  there  at  least  by  natural  autolytic  processes.  It  is  a  very  prevalent 
belief,  however,  that  cells  of  most  carcinomas  from  an  early  period  of  their 
growth  frequently  reach  the  blood  and  lymph  and  are  actively  dissolved  by 
antagonistic  substances  in  the  blood.  Many  general  considerations  favor  this 
view.  The  active  infiltration  of  capillaries  and  lymphatics  by  rather  loose 
tumor-cells  suggests  an  easy  and  frequent  passage  into  the  moving  current. 
The  list  of  observed  emboli  even  of  normal  cells  is  quite  large.  The  experi- 
mental cultivation  of  tumor-cells  by  Burrows  shows  that  they  are  regularly 
capable  of  growth  in  the  isolated  state,  and  in  many  human  tumors,  as  in 
thyroid  adenoma,  it  has  been  shown  that  blood-clot  may  be  penetrated  by 
loose  tumor-cells  much  as  in  an  artificial  culture.  In  several  well-known 
tumors  cited  elsewhere,  as  chorioma,  hepatic  carcinoma,  and  mammary  car- 
cinoma, tumor  masses  and  loose  tumor-cells  are  observed  within  the  vessel 
lumen. 

The  belief  that  such  loose  tumor-cells  are  destroyed  in  the  blood-  or 
lymph-stream  is  based  on  rather  scanty  evidence.  Usually  wide  dissemina- 
tion is  observed  to  follow  the  invasion  of  blood-vessels.  M.  Schmidt,  however, 
has  shown  that  tumor-cell  emboli  are  much  more  frequent  in  the  lungs  than 
are  secondary  tumors  of  these  organs.  In  28  cases  he  found  emboli  in  the 
pulmonary  arterioles  in  all,  but  definite  metastases  in  only  13.  From  the 
study  of  the  lungs  in  these  cases  Schmidt  concludes  that  in  carcinoma  of  the 


METASTASIS  83 

abdominal  organs  there  is  frequently  and  repeatedly  a  discharge  of  cancer- 
cells  which  lodge  in  the  small  arteries  of  the  lungs.  Only  a  small  portion  of  these 
cell  emboli  produce  metastatic  tumors  or  grow  into  the  perivascular  lymphatics. 
Most  of  them  are  inclosed  in  fibrin,  organized,  encapsulated,  and  in  spite  of 
retained  vitality,  rendered  harmless.  Some  of  them  grow  through  their  cap- 
sule into  the  capillaries  and  small  veins  whence  they  may  form  the  source  of 
late  general  metastases.  All  of  these  processes  may  occur  without  macroscop- 
ical  changes  in  the  lungs.  The  chief  source  of  these  emboli  he  believes  to  be 
through  the  pervious  thoracic  duct.  The  endophlebitis  carcinomatosa  which 
Goldmann  finds  to  be  nearly  constant  in  generalized  carcinoma,  he  regards 
as  a  sequel  of  pulmonary  emboli.  In  chorio-adenoma  it  has  been  shown  that 
pulmonary  emboli  occur  in  cases  which  recover  after  hysterectomy,  but  the 
mechanism  of  destruction  of  the  embolic  cells,  if  they  exist,  has  not  been  fol- 
lowed. In  many  hepatomas  the  growth  is  from  the  first  into  the  veins,  but 
pulmonary  or  other  metastases  are  almost  unknown  with  this  tumor. 

In  the  lymph-nodes  while  it  has  been  shown  that  microscopic  invasion 
is  more  frequent  than  growing  metastases,  actual  observation  of  late  regress- 
ing cell  emboli  in  the  nodes  is  not  satisfactorily  reported.  The  lymph-nodes 
seem  to  retain  and  retard  the  growth  rather  than  destroy  the  cells. 

Experimental  research  has  suggested  the  existence  of  a  premetastatic 
period  during  which  the  organism  is  incapable  of  developing  metastatic 
tumors.  Gay  found  that  he  could  not  successfully  reinoculate  tumor-bearing 
animals  until  a  certain  period  had  elapsed  after  the  first  implantation.  Yet 
these  results  are  not  uniform.  Tyzzer  by  manipulating  his  grafted  tumors 
was  able  to  cause  numerous  metastases,  apparently  without  regard  to  the 
period  of  growth. 

Serological  studies  have  in  general  failed  to  demonstrate  in  the  blood 
serum  of  natural  or  immune  animals  any  substances  capable  of  destroying 
tumor-cells.  The  most  direct  evidence  favoring  the  existence  of  cytolytic 
powers  of  the  blood  is  contributed  by  Freund  and  Caminer.  THese  observers 
claim  to  have  shown  that  normal  blood  dissolves  cancer-cells  in  vitro,  while 
the  blood  of  cancer  patients  has  lost  this  property.  With  many  others  I  have 
been  unable  to  verify  these  observations,  and  believe  that  Freund  was  dealing 
with  erratic  autolytic  and  bacterial  effects  and  not  with  true  cytolytic  agents. 
In  any  case  Freund's  studies  would  not  encourage  the  view  that  tumor-cells 
are  destroyed  in  the  circulating  blood  of  cancer  patients. 

Retrograde  transport  was  first  emphasized  by  v.  Recklinghausen  as  an 
important  process  in  the  dissemination  of  tumors  through  both  blood-  and 
lymph-vessels.  The  basis  of  his  conclusions  had  been  laid  in  many  previous 
observations  on  the  fate  of  insoluble  particles  injected  into  the  veins.  Retro- 
grade transport  occurs  chiefly  in  those  organs  in  which  there  is  a  normal 
venous  pulse,  lungs,  liver,  kidneys,  heart,  and  brain,  and  in  which  violent 
expiration  or  increase  of  intrathoracic  pressure  from  any  cause  may  trans- 
form the  weak  forward  into  a  backward  current.  When  the  main  lymphatic 
or  vein  is  occluded  the  flow  is  entirely  disordered  and  backward  transport 
is  facilitated.  Occlusion  of  the  trunk  vessel  is  probably  essential  for  back- 
ward metastasis  in  lymphatics,  but  not  in  veins.  In  either  case  the  backward 
progress  is  probably  slow  and  intermittent,  although  wide  distances  seem  at 
times  to  be  traversed  (Arnold,  Ernst).  In  the  organs  retrograde  metas- 
tases arise  from  tumors  originating  in  these  organs  and  from  distant  tumors. 
Thus  a  large  tumor  thrombus  lying  in  an  arched  vein  of  the  kidney  in  primary 
sarcoma  of  tibia  could  originate  only  by  backward  passage  through  the  renal 
vein  of  an  embolus  traveling  from  below.  Emboli  in  a  cerebral  sinus  with 
cancer  of  breast  (Arnold),  in  an  hepatic  vein  from  intestinal  or  thyroid  cancer 


84  NEOPLASTIC  DISEASES 

(Heller,  Bonome),  and  in  cerebral,  cardiac,  pulmonary,  and  hepatic  veins  with 
hypernephroma  (Ernst),  are  not  infrequent'  examples.  Backward  passage 
through  obstructed  lymphatics  may  be  assumed  in  cases  of  advanced  cancer 
of  bronchial  nodes  with  subpleural  lymphatic  invasion,  but  without  involve- 
ment of  pulmonary  parenchyma.  Cases  of  gastric  cancer  with  involvement 
of  portal,  lumbar,  and  inguinal  nodes  v.  Recklinghausen  referred  to  retrograde 
passage  of  obstructed  lymphatics.  Metastases  in  supraclavicular  nodes  from 
tumors  of  abdomen  and  testis,  with  invasion  and  occlusion  of  thoracic  duct, 
have  been  explained  by  several  observers  as  retrograde  lymphatic  growth 
(Troisier,  Poncet,  Most).  A  cancer  of  gall-bladder  with  retrograde  metas- 
tases  in  renal  lymphatics,  the  veins  being  free,  has  been  described  by  Vogel. 
With  cancer  of  pancreas  is  sometimes  found  continuous  lymphatic  invasion 
down  the  aorta  to  the  pelvic  nodes  and  discrete  nodules  along  the  mesentery. 
In  many  of  these  cases  it  may  be  difficult  to  eliminate  backward  permeation, 
as  Handley  has  shown,  and  some  writers,  especially  Ribbert,  doubt  or  deny 
the  occurrence  of  retrograde  lymphatic  embolism.  Yet  there  seems  to  be  good 
reason  for  holding  that  such  embolism  frequently  occurs  especially  when  a 
lymphatic  trunk  is  occluded. 

That  tissue-  and  tumor-cells  pass  through  the  pulmonary  capillaries  has 
frequently  been  demonstrated,  and  in  certain  tumors,  especially  the  lympho- 
sarcomas,  general  metastases  develop  in  this  way.  Passing  the  lungs  the 
embolic  cells  tend  to  lodge  in  organs  with  feeble  circulation,  as  liver,  bone- 
marrow,  and  subcutaneous  tissue.  Or  being  arrested  in  the  lung  the  embolic 
cells  may  grow  through  the  vessels  and  break  into  the  pulmonary  veins  (sec- 
ondary embolism).  Zahn  speaks  even  of  a  tertiary  embolism,  metastatic  tumors 
of  the  liver  producing  pulmonary  emboli  which  grow  through  the  lung. 

Abnormal  communications  between  the  cardiac  chambers  may  permit 
the  passage  of  larger  emboli  into  the  aorta.  In  a  case  of  sarcoma  of  the  se- 
minal vesicles  and  in  one  of  thyroid  cancer,  metastases  were  found  in  the  kid- 
neys, but  not  in  the  lungs,  from  which  Zahn  concluded  that  emboli  had  passed 
through  a  patent  foramen  ovale,  a  process  which  he  termed  paradoxic  em- 
bolism. Finally  the  blood-vessels  are  reached  by  way  of  the  thoracic  duct. 

Thus  invasion  of  the  blood-stream  may  occur  by:  (i)  Direct  invasion  of 
vessels  in  primary  or  secondary  tumors,  (2)  secondary  embolism,  (3)  tertiary 
embolism,  (4)  retrograde  transport,  (5)  paradoxic  embolism,  (6)  passage  of 
single  cells  through  pulmonary  venules,  (7)  through  the  thoracic  duct. 

Metastasis  of  a  benign  tumor  was  first  claimed  by  Cohnheim  for  thyroid 
adenoma,  and  similar  observations  have  since  been  reported  by  many  writers. 
The  great  vascularity  of  this  gland,  the  immediate  contact  of  epithelium  with 
capillary  endothelium,  and  the  extreme  hyperplasia  which  may  follow  func- 
tional stimuli,  offer  unusual  conditions  in  the  thyroid  favoring  the  dislodg- 
ment  of  adenomatous  alveoli  and  even  of  simple  hyperplastic  cells.  The 
occurrence  of  such  metastases  has  been  accepted  by  the  majority  of  observers 
(Borst),  but  Williams  and  many  others  believe  that  in  all  such  cases  a  small 
malignant  tumor  exists  in  the  thyroid  which  gives  origin  to  the  metastases. 
The  question  is  further  complicated  by  the  great  difficulty  of  estimating  from 
their  morphology  the  growth  capacities  of  thyroid  cells.  It  is  a  fact,  however, 
that  thyroid  cells  have  unusual  powers  of  proliferation  and  growth,  and  it 
would  seem  necessary  to  admit  that  under  rare  conditions  thyroid  adenoma 
and  hyperplastic  thyroid  cells  may  give  rise  to  distant  benign  tumors.  Defi- 
nite proof  of  such  an  event  requires  minute  search  of  the  main  and  any  acces- 
sory thyroids,  which  has  been  lacking  in  my  own  and  many  other  reports. 

Similarly  for  the  benign  hydatid  mole  and  even  for  the  normal  placenta 
there  is  a  very  suggestive  group  of  facts  which  has  led  Marchand  and  others 


METASTASIS  85 

to  believe  in  the  occurrence  of  malignant  metastases  of  normal  chorionic 
epithelium. 

Pure  chondroma  not  infrequently  enters  veins  and  its  ameboid  cells  pro- 
duce distant  metastases.  In  the  notable  case  of  Ernst's  a  chondroma  of  the 
vertebral  column  advanced  through  the  lumbar,  adrenal,  spermatic,  azygos, 
and  cava  inferior  veins  into  heart  and  lungs.  Discontinuous  metastases  usually 
in  the  lungs  have  often  been  observed  from  chondroma  of  pelvis,  scapula, 
fibula,  etc.  (Lit.  Ernst).  The  metaplasia  of  undifferentiated  tumor-cells  de- 
rived from  teratomas  or  sarcomas  must  account  for  some  chondromatous 
metastases  from  tumors  of  testis  and  probably  from  other  organs. 

Metastases  have  been  observed  with  leiomyoma  of  the  uterus  (Klebs, 
Langerhans,  Beetson,  Schlagenhauf  er) ;  of  the  stomach  (Hansemann,  Moser, 
Borrmann) ;  and  jejunum  (Ribbert).  In  some  cases  the  structure  of  the  tumor 
has  not  varied  from  the  usual  benign  myoma,  but  in  others  the  cells  were 
larger  and  nuclei  large  and  oval.  Some  were  cystic  and  vascular.  Birch- 
Hirschfeld  speaks  of  the  invasion  of  uterine  lymph-vessels  by  myoma.  Wil- 
liams denies  that  the  simple  uterine  myoma  ever  produces  metastases. 

Contact  Infection. — Contact  of  a  cancerous  surface  with  an  opposed, 
abraded  or  inflamed  mucous  surface  is  a  rare  source  of  transfer  of  tumors. 
The  best  known  example  is  the  infectious  lymphosarcoma  of  dogs  which  is 
commonly  transferred  by  coitus.  This  and  other  tumors  of  lower  animals 
may  sometimes  be  transferred  by  rubbing  a  granulating  surface  with  a  portion 
of  tumor. 

The  cases  of  cancer  a  deux  in  man  have  figured  prominently  at  times,  but 
in  none  has  the  actual  transfer  by  coitus  been  proved.  Demarquay  collected 
134  cases  of  cancer  of  penis  in  only  i  of  which  transfer  by  coitus  appeared 
possible.  Of  27  such  cases  collected  by  Gueillott  none  seems  to  me  beyond 
question.  Yet  the  genuineness  of  some  of  these  cases  cannot  be  denied. 

Transfer  of  epithelioma  of  lower  lip  to  upper  is  difficult  to- establish,  but 
seems  to  have  occurred  in  a  few  cases  (v.  Bergmann).  In  a  case  reported  by 
Hartmann  and  Lecene  a  cylindrical  cell  cancer  of  the  cervix  seems  to  have 
become  implanted  on  the  squamous  epithelial  surface  of  the  vagina. 

Implantation  of  epithelioma  of  esophagus  in  the  stomach  has  been  widely 
accepted  as  a  fact  (Borst),  but  Borrmann  has  found  continuous  permeation 
of  the  lymphatics  connecting  such  tumors.  Similar  evidence  has  not  been 
adduced  against  implantation  of  renal  tumor  fragments  in  the  ureter  (Butlin). 
Likewise,  the  contact  transfer  of  carcinoma  has  been  reported  from  one  point 
to  another  in  the  urinary  bladder,'  vagina,  vulva  (Thorn,  Walter),  cheek 
(Lucke),  thighs  (Williams),  stomach  (Klebs),  vocal  cords  (Semon),  and  from 
hand  to  conjunctiva  (Kaufmann).  In  most  of  these  cases  it  is  difficult  to 
eliminate  lymphatic  extension  and  primary  multiple  tumors,  so  that  the  doc- 
trine of  contact  infection  has  always  excited  a  legitimate  skepticism.  Bucher, 
Kaufmann,  and  others  have  fully  stated  the  many  grounds  for  this  skepticism 
and  it  is  obvious  that  the  evidence  must  be  very  complete  before  any  case  can 
be  accepted.  The  transferred  tumor  should  be  of  different  structure  from  that 
arising  in  the  implanted  surface  and  the  lymphatics  should  be  free  from 
invasion. 

"Genius  loci,"  or  the  particular  susceptibility  of  a  tissue  to  develop 
secondary  tumors,  is  an  interesting  phase  of  the  study  of  metastases.  Familiar 
examples  are  the  predominance  of  pulmonary  metastases  in  chorioma,  which 
is  simply  explained  by  the  intravascular  position  of  this  tumor;  the  bone- 
marrow  metastases  of  hypernephroma  and  cancer  of  prostate,  and  the  multiple 
cutaneous  tumors  secondary  to  lymphosarcoma  testis.  The  mechanism  of 
the  circulation  will  doubtless  explain  most  of  these  peculiarities,  for  there 


86  NEOPLASTIC  DISEASES 

is  as  yet  no  evidence  that  any  one  parenchymatous  organ  is  more  adapted 
than  others  to  the  growth  of  embolic  tumor-cells.  The  spleen,  however, 
seems  to  escape  with  peculiar  frequency. 

Virchow  observed  that  organs  frequently  originating  cancers  are  rarely 
the  seat  of  metastatic  cancer.  Yet  Zahn  collected  16  metastatic  cancers  of 
the  stomach,  and  26  invasions  of  the  ovary  in  366  cases  of  mammary  cancer. 

The  preservation  of  structural  type  in  metastatic  tumors  is  often  remark- 
able, yet,  as  a  rule,  there  is  increased  anaplasia  and  more  rapid  growth  in 
metastatic  tumors  and  especially  in  recurrences  after  operation. 

Adenocarcinoma  of  the  alimentary  tract  invades  the  lymph-nodes  and 
the  peritoneum,  and  produces  distant  metastases  while  rigidly  maintaining 
its  large  alveolar  type.  Adenocarcinoma  of  the  stomach  has  been  recognized 
in  a  metastasis  over  the  scapula.  The  metastases  of  benign  tumors  are  always 
typical  in  structure.  The  bone  metastases  of  hypernephroma  are  usually 
recognizable.  Metastatic  melanoma  is  usually  but  not  always  pigmented. 
On  the  other  hand,  the  general  metastases  of  chorioma  tend  to  be  overgrown 
by  Langhans  cells  with  loss  of  syncytium.  Squamous  epithelioma  may  yield 
spindle-cell  tumors  in  the  liver. 

In  general,  there  is  a  gradual  loss  of  structure  in  metastatic  tumors.  The 
liver  metastases  of  mammary  cancer,  hypernephroma,  and  chorioma  may 
be  indistinguishable.  The  more  anaplastic  the  original  tumor,  the  less  is  the 
room  for  change  in  its  metastases.  Mixed  tumors  tend  therefore  to  become 
simple,  and  certain  elements  may  be  eliminated  in  metastases  and  recurrences. 
This  rule  is  best  illustrated  in  the  great  variety  of  simple  metastatic  growths 
arising  from  teratoma  testis.  A  peculiar  form  of  elimination  of  epithelium 
is  seen  in  the  regional  metastases  of  mixed  tumors  of  the  parotid  which  are 
often  purely  myxomatous  or  chondromatous. 

Tridermal  metastases  which  rarely  arise  from  teratoma  of  testis  or  ovary 
indicate  either  that  all  three  tissues  are  contained  in  the  cell  embolus,  or  that 
undifferentiated  cells  unfold  their  potencies  after  lodging  in  distant  organs. 

The  osteoplastic  carcinoma  of  the  prostate  offers  a  remarkable  change  of 
type  and  tendency  in  its  pulmonary  metastases.  Here  osteosarcoma  appears 
to  accompany  the  carcinomatous  elements.  A  satisfactory  explanation  of 
this  process  cannot  be  given,  but  Schmorl  supposes  that  the  original  bone 
metastases  incite  osteosarcomatous  growth  from  wThich  embolic  cells  yield 
osteoid  tumors  in  the  lung. 

It  is  characteristic  of  certain  cases  of  several  tumors  that  a  very  small 
original  focus  gives  rise  to  very  bulky  secondary  growths.  This  course  is 
followed  by  some  cancers  of  the  breast  with  large  tumors  in  the  axilla,  by 
melanoma  of  the  skin  or  cancer  of  gall-bladder  invading  the  liver,  by  mucoid 
cancer  of  colon  involving  the  peritoneum.  On  the  other  hand,  squamous 
epithelioma  rarely  produces  bulky  metastases. 

Recurrence. — After  apparently  complete  removal  of  malignant  and  of 
some  otherwise  benign  tumors  the  growth  may  recur.  The  recurrence  is 
usually  in  the  operation  wound  or  its  immediate  neighborhood  (local  recur- 
rence),  or  in  adjacent  lymph-nodes  (regional  recurrence),  or  it  may  appear 
in  distant  organs  from  metastatic  emboli.  Sarcoma  often  recurs  at  a  distance 
from  the  original  growth,  while  local  and  lymphatic  recurrence  is  the  rule 
with  carcinoma. 

Recurrence  by  implantation  from  abdominal  tumors  in  the  laparotomy 
wound  or  in  the  peritoneum  is  a  well-recognized  hazard  of  operations.  The 
return  of  many  malignant  tumors  is  prompt  and  local,  but  many  years  may 
elapse  between  the  removal  of  choroidal  melanoma  and  its  reappearance  in 
widely  distant  regions. 


METASTASIS  87 

The  very  wide  variations  in  the  periods  of  recurrences  are  the  result  of 
many  complex  factors  so  that  statistical  reports  in  this  field  are  of  limited 
significance.  Yet  Williams  has  gathered  a  very  interesting  collection  of 
such  records.  Among  the  most  striking  of  these  reports  are  the  long  inter- 
vals sometimes  elapsing  between  operation  and  recurrence,  in  cancer  of  breast, 
30  years  (Heurteaux,  Verneuil);  rectum,  21  years  (English);  of  tongue,  18 
years  (Guinard);  choroidal  sarcoma,  14  years  (Fischer  and  Box);  uterine 
cancer,  15  years  (Pomard).  The  records  of  repeated  recurrence  are  also  of 
interest  as  encouraging  the  surgeon.  Thus  Gross  performed  22  operations 
in  54  recurrent  tumors  in  a  case  of  sarcoma  of  the  breast  during  four  years, 
the  patient  finally  recovering. 

Recurrent  tumors  may  reproduce  exactly  the  structure  of  the  original  or 
follow  the  rules  already  stated  for  metastatic  growths.  Local  recurrences 
usually  show  increasing  malignancy  and  anaplasia,  and  at  times  the  recurring 
tumor  shows  an  astonishing  variation  from  the  original  type.  Clinical  observa- 
tion is  here  supported  by  the  results  obtained  with  transplantable  tumors 
which  by  repeated  passage  may  be  considerably  heightened  in  activity. 
Squamous  epithelioma  is  comparatively  stable  in  type,  as  is  also  adenoma 
destruens.  Most  alveolar  carcinomas  tend  to  lose  the  alveolar  form  and 
recur  diffusely.  Myxoma  of  the  skin  recurs  repeatedly  with  the  same  struc- 
ture, while  melanoma  may  retain  or  lose  its  pigment.  Recurring  mixed 
tumors  tend  rapidly  to  become  simple.  One  sees  pure  chondroma  in  the 
returns  of  parotid  tumors.  In  the  second  to  fourth  recurrences  of  a  complex 
tridermal  teratoma  testis  I  found  pure  angiosarcoma.  In  a  case  of  adaman- 
tinoma  originating  as  squamous  epithelioma,  L'Esperance,  in  this  laboratory, 
has  recorded  progressive  changes  through  plexiform  epithelioma,  glandular 
carcinoma,  diffuse  small  spindle-cell  structures,  alveolar  round-cell  sarcoma, 
and  finally  in  the  sixth  operation,  diffuse  round-cell  "sarcoma." 

There  appear  to  be  no  indications  that  a  recurrent  tumor  may  be  less 
anaplastic  than  the  original,  but  Apolant  claims  to  have  reduced  an  alveolar 
carcinoma  to  an  adenoma  by  transplantations  in  immunized  mice. 

Recurrent  tumors  in  the  great  majority  of  cases  arise  from  cells  or  portions 
of  the  tumor  which  have  escaped  removal.  Microscopic  section  of  the  edges 
of  specimens  removed  at  operation  often  reveals  that  the  knife  has  passed 
through  strands  of  tumor  tissue  or  vessels  containing  tumor-cells.  There 
can  be  little  doubt  that  the  rough  manipulation  of  cellular  tumors  in  the 
preparation  of  the  patient  and  in  the  excision  of  the  growth  widens  the  field 
of  infection  by  forcing  cells  through  vessels  and  tissue  spaces.  Or,  viable 
cells  are  scattered  through  the  wound  by  piece-meal  removal  from  inacces- 
sible regions.  The  practice  of  removing  a  portion  of  the  tumor  for  diagnosis 
may  add  to  the  dangers  of  local  dissemination.  With  myxoma,  a  tumor 
which  is  characterized  by  persistent  local  recurrence,  the  semifluid  tissue 
may  very  readily  be  forced  into  the  surrounding  fat  tissue. 

Arising  from  remnants  of  the  original  growth  recurrence  is  usually  prompt, 
multiple,  in  the  line  of  incision  or  near  by,  and  of  the  same  type  as  the  original 
growth  or  more  malignant.  Yet  there  are  many  records  of  cases  in  which 
recurrence  in  the  line  of  incision  has  been  delayed  for  years.  Such  cases 
require  the  conclusion  that  displaced  cells  may  long  remain  dormant.  The 
many  instances  in  which  partial  removal  of  malignant  tumors  has  been  fol- 
lowed by  regression  of  the  remnant,  as  in  ovarian  carcinoma  and  in  chorioma, 
indicate  that  the  mechanical  disturbance  of  nutrition,  or  removal  of  local 
sources  of  growth  stimulus,  or  the  general  relief  of  the  organism  from  toxic 
products,  turn  the  balance  in  favor  of  the  patient,  and  lead  to  absorption 
of  tumor-cells.  Thus  tumors  in  rats  sometimes  regress  after  hemorrhagic 


88  NEOPLASTIC  DISEASES 

infiltration  following  crushing  trauma.  The  same  factors  may  be  assumed 
to  retard  the  growth  in  more  malignant  tumors  which  spring  up  at  varying 
periods  after  incomplete  removal. 

As  a  second  source  of  recurrent  tumors  it  has  been  suggested  by  v.  Rind- 
fLeisch,  Beneke,  and  others  that  tumors  exert  a  pervasive  formative  influence 
leaving  the  surrounding  tissues  in  a  state  of  excitation  and  with  a  momentum 
toward  neoplastic  growth,  so  that  after  the  removal  of  the  tumor  the  adjacent 
tissues  give  origin  to  a  new  tumor.  This  somewhat  vague  conception  is  vigor- 
ously rejected  by  Ribbert  and  is  quite  irreconcilable  with  the  theory  of  origin 
from  isolated  cell  groups.  Yet  there  are  several  considerations  which  render 
it  inadvisable  to  discard  such  a  theory  of  recurrences.  This  question  is  closely 
related  to  that  of  the  influence  of  tumor  growth  upon  surrounding  tissues 
and  to  that  of  the  multiple  origin  of  tumors  in  the  same  organ. 

Attention  has  already  been  called  to  the  fact  that  some  tumors  advance 
by  gradual  lateral  extension  over  previously  normal  cells,  so  that  removal 
at  one  stage  of  this  extension  may  leave  other  cells  which  later  reveal  their 
momentum  toward  tumor  growth.  The  local  recurrences  of  some  lingual 
and  laryngeal  cancers  seem  to  accord  with  this  view.  Further,  the  local  pre- 
disposition to  tumor  growth  which  figures  distinctly  in  many  phases  may, 
as  Borst  points  out,  extend  over  a  considerable  area,  in  all  of  which  the  tumor 
growth  does  not  reveal  itself  at  once,  but  develops  in  separate  stages  or  foci. 
Such  conditions  seem  rather  clearly  revealed  in  neurofibromas,  and,  accord- 
ing to  Hauser,  with  various  carcinomas,  especially  those  of  the  gastro-intestinal 
tract. 

Ovarian  cystomas  recur  in  the  opposite  ovary  or  in  fragments  of  the  first 
ovary  or  in  misplaced  ovarian  structures  in  the  neighborhood,  showing  the 
influence  of  local  predisposition  (Velits).  Many  authors  have  pointed  out 
the  great  frequency  of  cancer  after  ovariotomy  and  have  endeavored  to  show, 
without,  I  think,  complete  success,  that  loss  of  the  ovaries  greatly  increases 
the  local  disposition  of  many  tissues  to  cancer  (Wells,  Kratzenstein,  Neuge- 
bauer,  Williams). 

A  third  source  of  recurrence  is  found  in  the  multiple  origin  of  many  tumors. 
The  removal  of  a  small  cancerous  nodule  from  the  breast  with  chronic  mastitis 
may  readily  be  followed  by  the  appearance  of  a  new  tumor  in  an  adjacent 
portion  of  the  gland  or  in  a  supernumerary  gland.  One  seldom  hears  of  recur- 
ring uterine  myomas,  since  these  are  so  clearly  multiple  tumors,  but  multi- 
plicity while  less  obvious  is  perhaps  equally  common  with  epithelioma  and 
sarcoma  of  the  skin  where  the  new  tumor  is  often  regarded  as  a  recurrence. 

New  tumors  following  operation  differ  from  the  true  recurrences  in  not 
appearing  in  the  scar,  developing  usually  after  an  interval,  reproducing  the 
original  growth  without  great  change  in  malignancy,  and  often  being  solitary. 


CHAPTER  V 
CHEMISTRY  OF  TUMORS1;  SEROLOGY 

Constitution  of  Tumor  Proteins. — The  conception  that  tumor  proteins 
must  differ  in  essential  respects  from  those  of  normal  tissues  has  not  been 
demonstrated  by  chemical  methods.  The  nature  of  the  problem  involved 
appears  to  have  presented  itself  in  different  forms  in  the  minds  of  investi- 
gators who  have  attacked  the  problem. 

A  different  distribution  of  normal  proteins  from  that  of  normal  tissues 
has  been  demonstrated  in  tumor  tissue  by  Petry,  Wolff,  and  Beebe,  who  found 
a  higher  content  in  nucleoprotein,  more  uncoagulable  protein,  and  less  globulin 
and  albumin.  It  is  probable  that  these  results  depend  on  the  overgrowth 
of  cell  nuclei,  degenerative  and  autolytic  processes,  and  edema.  Nucleo- 
histon  is  present  only  in  lymph-nodes  among  normal  tissues  and  its  presence 
in  lymphatic  metastases  of  tumors  originally  free  from  this  protein  indicates 
that  metastatic  tumors  receive  chemical  impress  from  the  tissue  in  which 
they  are  growing.  Although  nucleohiston  is  absent  in  primary  carcinoma 
of  breast  and  in  the  testis,  Beebe  found  this  substance  in  lymph-node  metastases 
of  mammary  cancer  and  Bang  in  the  lymphatic  metastases  of  testicular  car- 
cinoma. Nucleohiston  gives  a  precipitate  when  CaCk  is  added  to  a  watery 
solution  of  the  tumor. 

Direct  chemical  analysis  of  the  split  products  of  cancer  proteins  by  Wolff 
yielded  a  high  proportion  (35  per  cent.)  of  glutaminic  acid,  while  Bergell 
and  Dorpinghaus  found  excess  of  alanin,  phenylalanin,  asparagmic  acid,  and 
diamino-acids.  Yet  these  results  conflicted  with  those  of  Petry,  Neuberg, 
and  Beebe. 

Resistance  to  peptic  and  susceptibility  to  tryptic  digestion  was  said  by 
Blumenthal  and  Wolff  to  distinguish  tumor  from  normal  tissues.  Yet  their 
results  were  not  uniform  and  were  probably  determined  by  the  increased 
amount  of  nucleoproteid  in  some  of  the  tumors. 

Excess  of  potassium  and  deficiency  in  calcium  in  rapidly  growing  tumors 
free  from  necrosis,  and  the  opposite  relations  in  slowly  growing  or  old  and 
necrotic  tumors  have  been  demonstrated  by  Beebe  and  by  Clowes. 

Pentose  was  greatly  increased  in  a  fibrocarcinoma  of  the  breast  in  com- 
parison with  the  amount  in  the  normal  breast  in  cases  studied  by  Beebe  and 
Shaffer.  These  authors  also  found  that  the  pentose  content  in  different 
tumors  varied  and  bore  no  relation  to  the  nucleoprotein,  or  to  the  presence 
of  degeneration.  In  hepatic  carcinoma  and  in  hepatic  metastases  of  gastric 
carcinoma  Neuberg  found  70  to  80  per  cent,  more  pentose  than  in  normal 
liver. 

Lactic  acid  appears  in  tumors,  according  to  Fulci,  in  considerable  quan- 
tities. It  is  more  abundant  in  epithelial  than  in  connective- tissue  growths 
and  increases  in  the  more  malignant  actively  growing  tumors.  Its  formation 
is  dependent  on  metabolic  activity  of  the  tumor-cells,  its  source  the  blood 
carbohydrates  and  possibly  the  proteins.  It  appears  to  have  no  relation  to 
cachexia. 

!For  a  fuller  discussion  of  this  subject  with  literature  consult  Wells,  "Chemical 
Pathology." 

89 


90  NEOPLASTIC  DISEASES 

Of  the  total  phosphorus  of  the  normal  liver  B.  Wolter  found  24.68  per 
cent,  as  phosphatid  phosphorus,  in  the  tumor-free  portions  of  a  liver  with 
primary  carcinoma  22.04  per  cent.,  and  in  the  tumor  nodules  16.28  per  cent., 
while  the  protein  phosphorus  in  the  same  materials  ran  20  per  cent.,  25.5 
per  cent.,  and  26.70  per  cent.  In  0.0634  gm.  of  dried  tumor  substance  he 
found  1.40  per  cent,  of  cholesterin. 

Tryptophan  was  markedly  increased  in  an  epidermoid  carcinoma  of  skin, 
and  in  an  hepatic  carcinoma,  over  the  proportions  found  in  normal  skin  and 
liver  in  cases  studied  by  Fasal,  but  this  substance  was  absent  in  a  mammary 
fibrocarcinoma. 

Fats. — The  chemistry  of  tumor  fats  has  been  studied  extensively  in  renal 
and  adrenal  tumors  (q.  v.).  In  general  it  appears  from  Bossart's  work  that 
actively  growing  tumors  free  from  degeneration  contain  little  fat  and  much 
lecithin,  while  with  degeneration  and  necrosis  free  fats  replace  lecithin. 

Purin  bodies  were  found  by  Wells  and  Long  in  about  the  same  form  and 
amount  as  in  normal  tissue  and  less  abundantly  than  the  nuclear  content 
would  suggest.  The  purin  enzymes  were  also  identical  with  those  of  normal 
tissues,  guanase  being  constantly  present  and  adenase  absent. 

The  delicate  methods  of  immunological  studies  indicate  that  there  are 
biological  differences  between  certain  tumor-tissues  which  are  probably  based 
on  chemical  distinctions,  but  the  results  obtained  in  this  field  are  not  decisive. 
Following  Michaelis'  failure  to  produce  specific  immune  bodies  against  mouse 
tumor  cells,  Beebe  working  with  purified  nucleoproteins  of  a  leukemic  spleen 
produced  a  serum  which  agglutinated  the  emulsified  cells  of  this  spleen  and 
those  of  a  lymphosarcoma,  but  acted  feebly  and  only  in  strong  concentration 
on  cells  and  nucleoproteins  of  normal  spleen  and  other  tissues,  as  well  as  of 
cancer  and  spindle-cell  sarcoma. 

Other  data  bearing  on  this  question  are  considered  in  the  discussion  of 
experimental  immunization. 

Tumor  Ferments. — The  study  of  special  ferments  in  tumors  by  Buxton 
and  Shaffer  demonstrated  no  distinct  differences  in  quantity  or  quality  from 
equivalent  normal  tissues.  Weil  using  the  viscosimeter  found  more  proteo- 
lytic  activity  in  certain  cellular  tumors  than  in  certain  normal  tissues,  but 
was  not  prepared  to  say  that  the  difference  did  not  depend  on  leukocytes. 
Abderhalden,  however,  concluded  that  extracts  of  tumor-tissue  and  those  of 
normal  tissue  split  certain  polypeptids  in  a  different  manner.  Extracts  of 
normal  mouse  liver  cleave  certain  polypeptids  slowly,  while  those  of  mouse 
tumor  act  much  more  quickly.  In  comparing  the  extracts  of  mouse  and 
human  tumors  with  those  of  normal  tissues  he  found  differences  in  the  split 
products  of  the  proteins  after  the  action  of  these  ferments.  Comparing  the 
peptolytic  action  of  normal  and  tumor-tissue  from  lower  animals  on  peptone, 
Abderhalden  and  Medigreceanu  found  occasional  but  no  constant  or  striking 
differences. 

Autolysis  is  often  observed  to  proceed  more  rapidly  in  certain  tumor  tissues 
than  in  normal  tissues,  but  it  is  probable  that  all  such  differences  depend  on 
the  more  cellular  character,  and  presence  of  degenerating  tissue,  edema,  leuko- 
cytes, and  bacteria.  It  is  extremely  difficult  to  obtain  normal  tissue  which 
may  safely  be  compared  with  tumor-tissue  in  this  respect. 

The  increased  activity  of  autolysis  is  well  illustrated  in  Yoshimoto's  experi- 
ments in  which  an  hepatic  carcinoma  yielded  7.2  gm.  N  in  the  split  products 
as  compared  to  4.8  gr.  in  equivalent  units  of  normal  liver.  With  a  mammary 
carcinoma  the  difference  was  even  greater.  In  the  tumor  autolysate  purin 
N  was  reduced,  while  that  of  diamino-acids,  peptone,  and  ammonia  was  in- 
creased in  proportion. 


CHEMISTRY  OF  TUMORS;  SEROLOGY  91 

It  is  commonly  believed,  on  the  basis  of  Jacoby's  experiments,  that  auto- 
lytic  ferments  have  a  high  degree  of  specificity  for  the  proteins  of  the  organs 
in  which  the  ferments  are  found.  Blumenthal  and  Wolff  have  reported  that 
when  measured  amounts  of  tumor-tissue  and  of  normal  tissue  are  autolyzed 
separately  in  one  series,  and  conjointly  in  another  the  autolysis  is  always 
greater  in  the  conjoined  series.  They  conclude  that  the  tumor  ferments 
attack  the  normal  tissues  and  exhibit  a  heterolytic  property.  On  this  basis 
rests  the  claim  that  infiltrative  growth  and  cachexia  depend  on  the  heterolytic 
activities  of  the  tumor  ferments.  Baer  and  Ettinger  demonstrated  a  pro- 
teolytic  activity  in  cancerous  ascitic  fluid  which  failed  to  appear  with  ascitic 
fluid  from  other  sources,  but  Kepinow  and  Hess  and  Saxl  were  unable  to 
verify  any  of  these  observations.  The  possible  presence  of  bacteria,  necrosis, 
or  postmortem  decomposition  has  not  apparently  been  considered,  although 
Neuberg  has  subsequently  denied  that  bacteria  or  leukocytes  have  any  influence 
on  the  results. 

Ascitic  fluid  of  carcinomatous  origin  yielded  little  euglobulin  (12.44  per 
cent.),  increased  albumin  (64.92  per  cent.),  and  the  usual  proportion  of  total 
globulin,  35.07  per  cent.  (Joachim,  Wolff).  Similar  proportions  of  proteins 
were  determined  in  edema  fluid  and  expressed  cancer  juice  by  Wolff. 

The  milky  character  of  carcinomatous  ascitic  fluid  is  ascribed  by  Wolff 
to  the  presence  of  cholesterin-acid-ester  combined  with  euglobulin.  In  a 
series  of  cancerous  and  other  ascitic  fluids  Weil  demonstrated  occasional  but 
inconstant  hemolytic  and  hemagglutinative  properties,  abundance  of  comple- 
ment in  two  cancer  cases,  and  some  antitryptic  action,  but  no  constant  dis- 
tinction between  the  cancerous  and  non-cancerous  fluids.  Signs  of  active 
autolysis  in  a  peritoneal  exudate  accompanying  ovarian  carcinoma  are  re- 
ported by  Umber,  who  found  increase  in  non-coagulable  N,  albumose,  leucin, 
and  tyrosin.  Eppinger  reports  similar  findings.  In  a  bloody  cancerous  exu- 
date K.  Wiener  demonstrated  an  ereptic  ferment,  but  any  tryptic  ferment 
present  was  masked  by  the  blood.  In  this  fluid  were  traces  of  histidin  and 
arginin. 

J.  W.  Vaughan  has  observed  a  striking  relation  between  anaphylactic 
sensibility  of  guinea-pigs  inoculated  with  tumor  residue  and  the  lympho- 
cytosis  excited  by  the  inoculation.  Animals  receiving  the  water-soluble 
residue  of  cancer-cells  after  their  extraction  with  alkalized  alcohol,  or  a  vac- 
cine of  tumor-cell  emulsion  after  extraction  with  alcohol,  showed  in  many 
cases  very  high  lymphocytosis,  and  in  such  sensitized  animals  anaphylactic 
death  was  readily  produced.  The  sensitization  was  quite  transitory,  lasting 
only  during  the  4-  to  lo-hour  period  of  lymphocytosis,  and  the  author  interprets 
the  result  as  depending  on  the  action  of  lymphocytic  ferments  on  the  tumor- 
cells. 

Wassermann  Reaction  in  Cancer. — The  results  obtained  with  the  Wasser- 
mann  reaction  in  cancer  patients  have  varied  very  widely.  Caan  secured 
positive  reactions  in  41  per  cent,  of  85  cases;  in  6  of  7  lip  carcinomas;  in  9  per 
cent,  of  breast  tumors;  and  in  17  per  cent,  of  gastro-enteric  tumors.  All  of 
these  cases  were  free  from  clinical  signs  of  lues.  A.  Foerster  secured  36  nega- 
tive reactions  in  37  cases,  and  Noguchi  38  in  39,  while  F.  J.  Fox  reports  5 
positive  reactions  in  210  cases  of  cancer.  Positive  reactions  in  patients  with 
cerebral  tumors  free  from  syphilis  appear  to  be  not  uncommon  (Cohn). 

Complement  Deviation  with  Autogenous  Tumor  Antigen. — In  over  100 
cases  of  carcinoma  and  16  cases  of  sarcoma  the  complement  deviation  test 
of  the  blood-serum  has  been  made,  using  tumor  antigens  of  the  same  or  similar 
tumors.  In  the  majority  of  cases  the  test  has  been  positive,  but  in  a  large 
number  the  results  have  been  negative.  Recently  W.  Barratt,  using  the 


92  NEOPLASTIC  DISEASES 

patient's  own  tumor  as  antigen,  got  negative  results  in  6  cases.  De  Marchis 
often  obtained  negative  results  in  both  early  and  advanced  cases.  A  positive 
result  he  regarded  as  of  considerable  diagnostic  value,  although  it  occasionally 
occurred  in  syphilis  and  other  diseases.  With  an  antigen  prepared  from  human 
carcinoma  v.  Dungern  claims  to  have  obtained  complement  deviation  with 
the  serum  of  both  carcinoma  and  many  other  tumors,  such  as  lymphosarcoma, 
glioma,  and  even  myoma.  These  paradoxical  results  failed  of  verification  in 
the  hands  of  Edzard,  Schenk,  and  Coca. 

It  is  evident  that  the  subject  of  complement  deviation  in  tumors  is  with- 
out substantial  foundation. 

Complement  deviation  by  antigen  of  Micrococcus  neoformans  tested  with 
serum  of  cancer  patients,  in  all  but  7  of  144  cases,  was  secured  by  Yamanouchi 
and  Lytchkowsky.  The  reaction  was  also  positive  in  44  cases  of  lues,  but 
not  in  benign  tumors.  F.  Green  obtained  positive  reactions  in  cancer  with 
the  antigen  of  Micrococcus  neoformans  and  also  with  those  of  staphylococci 
and  streptococci. 

Antitryptic  Power  of  the  Blood. — Blood-serum  has  long  been  known  to 
inhibit  the  action  of  certain  ferments.  Brieger  and  Trebing  first  found  that 
the  serum  of  cancer  patients  inhibits  very  markedly  the  action  of  trypsin. 
Using  various  technical  methods,  these  authors,  followed  by  Bergman  and 
Meyer,  Herzfeld,  Roche,  and  others,  showed  that  in  about  90  per  cent,  of 
cancers  there  was  marked  increase  in  the  antitryptic  power  of  the  blood-serum, 
but  that  considerable  increase  occurred  also  in  many  other  diseases,  especially 
in  those  attended  with  leukocytosis  (Wiens,  Schlecht).  Weil  by  an  exact 
quantitative  method  determined  that  the  "antitrypsin"  is  increased  in  some 
cancer  cases  beyond  that  observed  in  any  other  diseases,  while  in  other  cases 
it  failed  to  fall  as  low  as  the  ratio  observed  in  other  diseases.  All  authors 
agree  that  the  failure  of  any  increase  is  rather  strong  evidence  against  the 
existence  of  established  malignant  disease.  Brieger  regarded  the  phenome- 
non as  a  sign  of  cachexia  and  an  immunity  reaction  against  excessive  amounts 
of  proteolytic  ferments  derived  from  tumor-cells.  Wiens  and  Schlecht  trace 
a  close  relation  with  leukocytosis.  Weil  points  out  that  the  exact  nature  of 
the  inhibiting  substance  is  undetermined  and  that  no  specific  relation  to 
trypsin  need  necessarily  exist,  since  blood-serum  also  inhibits  saponin.  Among 
57  cases  of  cancer  and  3  of  sarcoma  S.  M.  Lewin  found  much  increased  anti- 
tryptic power  in  57.  He  could  not  refer  the  antiferment  action  to  leukocytes, 
but  attributed  it  to  a  reaction  to  proteolytic  ferments  discharged  into  the 
blood  from  degenerating  tumor-tissue. 

Meiostagmin  Reaction. — This  reaction  is  based  upon  a  change  in  the 
surface  tension  of  blood-serum.  When  to  a  dilute  solution  of  an  alcohol- 
ether  extract  of  cancer  tissue  is  added  a  small  portion  of  blood-serum  from  a 
carcinoma  patient,  a  change  in  the  surface  tension  is  produced  which  may 
be  estimated  by  the  reduced  number  of  drops  of  the  fluid  passing  in  a  given 
time  through  a  specially  designed  pipet  or  stalagmometer.  This  physio- 
chemical  alteration  was  employed  by  Ascoli  in  the  study  of  cancer  serum 
and  was  considered  by  him  to  result  from  a  somewhat  specific  interaction 
of  cancer  antigen  and  cancer  antibody  developed  in  the  serum.  The  specific 
character  and  immunological  nature  of  the  reaction  was  soon  set  aside  when 
it  was  discovered  that  extracts  from  many  organs  and  even  synthetic  sub- 
stances, as  linoleic  and  ricinic  acids,  were  equally  effective  as  antigens  (Ascoli, 
Izar).  It  was  also  shown  that  the  sera  of  a  great  variety  of  diseases  and  of 
pregnancy  reacted  in  the  same  manner  with  a  variety  of  antigens,  thus  estab- 
lishing that  the  production  of  the  reacting  factors  was  the  result  of  a  con- 
stitutional process  of  wide-spread  occurrence. 


CHEMISTRY  OF  TUMORS;  SEROLOGY  93 

To  carry  out  the  test  one  may  best  employ  a  solution  of  0.2  gm.  ricinic 
acid  plus  0.5  gm.  of  linoleic  acid  in  10  c.c.  absolute  alcohol.  To  i  c.c.  of  serum 
is  added,  by  dropping  carefully  from  a  pipet,  o.oi  to  0.02  c.c.  of  the  antigen 
solution  and  then  9  c.c.  of  0.85  per  cent.  NaCl  with  thorough  mixing.  As 
a  control  i  c.c.  of  serum  is  added  to  9  c.c.  of  salt  solution.  Both  tubes  are 
kept  i  hour  on  a  water-bath  at  50°  C.  and  after  2  to  6  hours  the  drops  are 
counted  by  the  stalagmometer.  The  count  increases  in  the  sera  receiving 
antigen,  an  increase  of  1.3  or  less  being  regarded  as  negative,  1.7+  positive, 
intermediates  uncertain. 

Various  other  antigens  may  be  employed  according  to  the  choice  of  the 
investigator.  Burmeister  prepared  several  antigens  by  different  methods,  all 
with  practically  identical  results.  The  results  obtained  vary  considerably. 
Ascoli  and  Izar  secured  nearly  constant  figures  with  tumor  sera.  N.  Blu- 
menthal  (1915)  finds  that  78  per  cent,  of  gastro-intestinal  carcinomas  react 
positively,  while  in  other  forms  the  positive  results  are  much  less,  and  in 
cutaneous  and  hepatic  carcinoma  and  sarcomas  very  few.  He  concludes 
that  the  test  is  of  diagnostic  value  only  in  gastro-intestinal  carcinoma,  and 
in  pregnancy,  while  it  is  always  necessary  to  exclude  diabetes,  uremia,  in- 
fectious fever,  tuberculosis,  lues,  chronic  joint  diseases,  and  cirrhosis.  The 
diagnostic  importance  is  therefore  practically  nil. 

Various  hypotheses  have  been  suggested  in  explanation  of  the  reaction. 

1.  The  presence  in  the  serum  of  abnormal  lipoids  resulting  from  fermen- 
tative processes  in  the  cancer-cells.    This  view  is  favored  by  the  heat-resist- 
ance of  the  serum;  by  the  ready  removal  of  the  active  factors  by  extracting 
the  serum  with  alcohol,  ether,  or  chloroform  (Izar,  Michaeli,  Cottoretti);  by 
the  discovery  of  synthetic  antigens,  as  linoleic  acid  (Kohle'r,  Luger) ;  and  by 
the  demonstrated  increase  of  lipoids  in  reacting  sera  (Michaeli,  Cottoretti). 
The  reaction  may  also  depend  on  a  diminution  in  blood  cholesterin  (Izar). 

2.  A  diminution  in  blood  albumins,  and  presence  of  peptone.-  This  condi- 
tion is  observed  in  most  diseases  giving  the  reaction. 

3.  Changes  in  the  alkalescence  of  the  blood.    Heating  the  serum  increases 
the  reaction  and  drives  off  CQz  from  the  bicarbonates. 

The  epiphanin  reaction  of  Weichardt  depends  upon  a  change  in  the  alka- 
lescence of  the  serum.  This  reaction  has  been  found  positive  in  81  per  cent, 
of  a  series  of  cases  studied  by  Jozca  and  Tokioka.  By  this  means  E.  Rosen- 
thai  finds  it  possible  to  demonstrate  antibodies  in  the  blood  of  guinea-pigs 
immunized  by  human  or  mouse  tumor  and  in  the  serum  of  tumor-bearing 
mice. 

Stammler's  Reaction. — Most  tumor  extracts  exhibit  a  slight  or  distinct 
opalescence.  Stammler  observed  that  the  addition  of  cancer  serum  clears 
up  this  opalescence  with  the  formation  of  a  slight  precipitate,  while  most 
normal  sera  fail  to  act  in  this  manner. 

Ransohoff's  Test. — Ransohoff  observed  that  the  injection  of  3  to  5  c.c.  of 
blood-serum  from  cancer  patients  in  guinea-pigs,  which  had  previously  been 
sensitized  by  i  c.c.  of  such  sera,  caused  none  or  very  weak  anaphylactic  reac- 
tion, while  normal  human  serum  produced  the  usual  violent  reaction.  Since 
the  same  immunity  followed  sensitization  by  tumor  extract,  he  concluded 
that  the  immunizing  substance  of  the  serum  was  derived  from  the  tumor. 
In  a  series  of  30  cancer  cases  92  per  cent,  gave  a  positive  reaction,  while  the 
test  was  always  negative  in  other  conditions.  F.  Green  was  unable  to  verify 
these  results. 


CHAPTER  VI 
THEORIES  OF  THE  NATURE  OF  CANCER 

The  Embryonal  Theory. — For  many  years  before  the  appearance  of 
Cohnheim's  work  observations  had  been  accumulating  to  show  that  tumors 
were  in  some  way  related  to  the  embryonal  growth  of  tissue.  Lobstein,  1829, 
likened  the  growth  of  a  tumor  to  that  of  embryonal  tissues  and  conceived 
that  neopiastic  growth  had  lost  the  control  of  the  organism.  Recamier,  1829, 
noted  that  cancer  developed  from  irritated  moles  and  pointed  out  that  super- 
numerary organs,  "tous  les  tissues  extraordinaires  accidentels,"  readily 
degenerated  into  cancer.  Rokitansky  regarded  certain  myxomas,  in  his 
class  of  collonema,  as  derived  from  embryonal  connective  tissue.  Houel, 
1864,  designated  certain  sarcomas  as  embryonal,  because  they  seemed  to 
represent  an  abnormal  growth  of  the  same  elements  which  in  the  embryo 
formed  normal  organs  and  tissues.  In  the  subsequent  decade  there  were 
several  observations  of  tumors  arising  in  connection  with  abnormalities  of 
development,  and  the  embryonal  theory  was  believed  to  apply  to  the  group 
of  complex  teratomas  (Lucke).  A  further  basis  of  the  embryonal  theory 
existed  in  the  belief  maintained  by  Remak,  1854,  that  cancer  arose  from 
misplaced  islands  of  epithelial  cells  in  tissue  not  normally  containing  epithe- 
lium. Paget  in  1853  remarked  that  invisible  defects  in  the  formation  of 
organs  might  render  them  or  portions  of  them  peculiarly  apt  for  the  seats  of 
malignant  disease. 

In  1874  Durante  clearly  stated  the  doctrine  that  all  tumors  arise  from 
embryonal  groups  of  cells.  He  observed  sarcoma  twice  developing  from 
pigmented  moles,  examined  many  nevi,  and  described  the  embryonal  char- 
acter of  the  cells  composing  them.  Hence  he  concluded  that  similar  circum- 
stances must  surround  the  origin  of  all  tumors,  especially  the  malignant 
growths. 

The  modern  embryonal  theory  was  placed  on  a  comprehensive  basis  by 
Cohnheim,  whose  original  views  were  ably  supported  by  his  own  observations, 
and  have  been  steadily  strengthened  by  very  numerous  contributions  from 
many  sources  during  the  past  forty  years.  While  this  is  not  a  theory  of 
universal  application,  yet  that  embryonal  cells  possess  more  than  any  others 
the  essential  factors  of  tumor  growth  is,  perhaps,  the  most  important  single 
fact  in  our  knowledge  of  tumor  genesis. 

Cohnheim  believed  that  tumors  develop  from  masses  of  simple  or  complex 
tissue  misplaced  during  embryonal  development.  Or  they  arise  from  small 
groups  of  superfluous  cells  which  have  retained  their  embryonal  characters, 
but  are  not  necessarily  misplaced.  The  idea  of  the  embryonal  character  of 
the  cells  appeared  to  him  essential.  Most  of  the  embryonal  cells  result  from 
overproduction  after  the  formation  of  the  germ  layers  and  before  the  appear- 
ance of  definite  rudiments  of  the  organs,  and  he  held  that  these  superfluous 
cells  were  either  distributed  throughout  the  viscera  or  were  gathered  at  cer- 
tain points,  as  the  mucocutaneous  junctions.  The  sudden  development  of 
the  cells  he  referred  chiefly  to  changes  in  the  blood-supply. 

The  entire  group  of  mixed  tumors  and  the  simple  heterologous  growths 
were  at  once  included  in  the  scope  of  the  embryonal  theory.  Indeed,  when 
one  explores  the  group  of  teratomas  there  seem  to  be  all  intermediate  forms 

94 


THEORIES  OF  THE  NATURE  OF  CANCER  95 

from  the  complex  sacral  tumors  up  to  parasitic  implantations  containing 
parts  of  organs  or  limbs  and  even  up  to  such  phenomena  as  identical  twins. 
Likewise  when  one  passes  downward  through  the  complex  heterologous 
tu'mors  of  the  parotid  to  the  simple  heterologous  growths  which  arise  from 
small  groups  of  cells  misplaced  or  remaining  embryonal  it  would  seem  that 
tumor  genesis  were  chiefly  a  question  of  the  mechanics  of  development.  The 
present  support  of  Cohnheim's  theory  is  extensive.  Congenital  tumors  of 
many  varieties,  chiefly  mesoblastic,  but  also  epithelial,  exist  at  birth  or  develop 
shortly  after,  and  the  evidence  is  clear  that  embryological  disturbances  are 
concerned  in  their  origin.  Such  tumors  include  fibroma,  myxoma,  lipoma, 
chondroma,  angioma,  glioma,  myoma,  mixed  tumors  of  kidney,  dermoids, 
and  teratomas. 

Congenital  cancers  affect  the  kidneys  (Leibert),  adrenal  (Reiman),  testis 
(Phillip),  vagina,  ovary  (Ahlfeld),  pylorus  (Cullingworth),  pancreas  (Bohn), 
skin  (Braun),  shoulder  (Selberg),  neck  (Kronlein),  pleura  (Muus),  etc. 

The  embryonal  tumors  of  adults  which  yield  a  type  of  tissue  closely  simu- 
lating the  embryonal  counterparts  and  resemble  the  congenital  tumors  of 
the  same  regions  form  a  well-recognized  group  for  which  an  identical  etiology 
seems  highly  probable  (Wilms).  Among  such  tumors  are  myxomas,  rhabdo- 
myoma  of  heart,  amyelinic  neuroma,  tubular  neuro-epithelioma,  and  a  great 
variety  of  very  cellular  malignant  tumors  whose  histogenesis  has  not  been 
fully  traced.  Rudimentary  organs  are  specially  susceptible  to  tumor  growth, 
as  undescended  testes,  Luschka's  gland  (Defosses),  the  paroophoron  (Ricker), 
the  neurenteric  canal  (Kraske). 

Supernumerary  organs  are  frequent  seats  of  tumors.  The  misplaced 
adrenal  rests  have  a  wide  distribution  and  give  origin  to  many  heterotopic 
growths  in  and  about  the  kidney,  along  the  genito-urinary  tract,  in  testis 
and  ovary,  throughout  the  pelvis,  and  elsewhere  (Chiari,  Askanazy, 
Lubarsch).  Supernumerary  breasts  are  occasional  sources  of  mammary 
cancer.  Aberrant  portions  of  thyroid,  thymus,  pancreas,  uterus,  and  ovary 
give  rise  to  many  tumors  in  the  regions  of  these  organs.  Some  authors  assume 
the  presence  of  straggling  sex  cells  all  the  way  from  the  cephalic  to  the  caudal 
extremities  of  the  embryo  to  account  for  complex  teratomas  in  neck,  thorax, 
and  abdomen. 

The  association  of  tumors  with  local  abnormalities  of  development  strongly 
supports  the  embryonal  theory.  Prominent  in  this  category  are  the  melanomas 
arising  from  pigmented  moles  and  pigment  spots  in  sclera  and  choroid;  the 
gliomas  associated  with  spinal  hydromyelia  and  various  abnormalities  of 
cord  and  brain;  sarcoma  in  cystic  kidneys;  adenomyoma  of  uterus;  gliomas, 
dermoids,  and  mixed  tumors,  with  spina  bifida;  adenoma  with  cysts  of  liver. 

Persistent  remnants  of  embryonal  structures  clearly  originate  the  bran- 
chiogenic  cysts,  epitheliomas,  and  chondromas.  The  thyroglossal  duct  gives 
cystic  or  solid  tumors  sometimes  lined  by  ciliated  epithelium  at  base  of  tongue, 
in  floor  of  mouth,  or  deep  in  the  nedc.  Similar  cystic  tumors  with  ciliated 
epithelium  occur  also  in  esophagus,  peritoneum,  and  liver.  Certain  embryonal 
tumors  of  uterus  and  adnexa  and  bladder  are  probably  derived  from  remnants 
of  Wolffian  body  or  Gartner's  duct.  The  pars  postanalis  intestini  yields 
epithelial  tumors  of  the  lumbar  region,  and  the  ompnalomesenteric  duct  and 
urachus  give  rise  to  abdominal  tumorsS 

The  extensive  lists  of  heterologous  tumors  are  most  readily  explained  as 
growths  from  aberrant  cell  groups.  These  include  chondromas  of  tonsil, 
breast,  parotid,  bladder,  uterus,  thyroid;  epithelial  tumors  in  connective 
tissues  and  organs  not  normally  containing  such  cells;  the  mixed  tumors  of 
uterus,  bladder,  breast;  lipoma  of  pia  and  brain,  and  myolipoma  of  sper- 


96  N EOF  LA  STIC  DISEASES 

matic  cord  (Sazarin).  While  the  heterologous  tumors  and  teratomas  of  the 
sex  glands  are  probably  derived  from  sex  cells,  the  origin  of  teratoid  tumors 
in  abdomen,  thorax,  pharynx,  and  other  organs  may  still  be  referred  in  part 
to  aberrant  cell  groups  of  another  type. 

The  predilection  of  tumors  for  mucocutaneous  junctions,  ostia  at  the 
points  of  fusion  of  embryonal  structures,  and  fissures  formed  by  incomplete 
union  of  such  structures,  impressed  Cohnheim  and  all  later  observers  as 
strongly  favoring  the  theory  of  origin  from  superfluous  cells. 

Here  must  be  mentioned  the  frequent  cancers  of  lip,  nares,  anus,  rectum, 
cardia,  pylorus,  portio  vaginalis  uteri,  rete  testis,  and  chose  at  the  tracheal 
and  esophageal  junction  where  squamous  and  ciliated  epithelial  tumors  have 
been  found  transposed  across  normal  boundaries.  Misplacements  at  em- 
bryonal fissures  must  be  connected  with  the  cholesteatomas  and  epidermoids 
of  skin,  breast,  abdominal  and  cranial  cavities,  spinal  canal,  and  middle  ear. 
Many  chondromas  of  the  skeleton,  as  multiple  chondroma  of  spine  and  spinal 
canal,  trachea,  etc.,  are  referred  to  irregularities  in  formation  and  separation 
of  islands  of  cartilage.  The  chordomas  of  spine,  base  of  skull,  and  nares 
reproduce  the  embryonal  chorda  dorsalis.  Dentigerous  cysts,  odontomas, 
and  the  frequent  adamantinoma  of  alveolar  borders  arise  from  superfluous 
or  isolated  remnants  of  the  teeth.  Symmetrical  tumors  sometimes  strongly 
suggest  embryonal  irregularities,  examples  of  which  are  symmetrical  nevi, 
xanthomas  (Rayer,  Ehrmann),  lipomas  (Grosch,  Kottnitz),  angiomas,  -myomas 
(Brigidi,  Marcacci),  sarcoma  of  epiphyses. 

There  are  recorded  many  notable  examples  of  symmetrical  tumors  in 
paired  organs,  as  fibrolipoma  of  kidneys,  adenoma  and  carcinoma  of  kidneys, 
ovaries,  tubes,  breast,  adrenals,  and  lymphosarcoma  of  testis.  Multiple 
systemic  tumors  of  the  nerve-trunks,  neurofibroma,  suggest  an  imperfect 
differentiation  of  endoneurium.  From  this  point  one  is  led  into  the  exten- 
sive field  of  multiple  primary  tumors  of  the  same  or  different  organs.  Studies 
in  this  field  have  usually  led  to  the  conclusion  that  developmental  eccentricities 
were  involved. 

Later  followers  of  Cohnheim's  suggestions,  especially  Ribbert  and  Wilms, 
have  urged  that  in  extra-uterine  life  cell  groups  may  become  isolated  and 
superfluous  by  various  mechanisms,  and  form  the  basis  of  tumors.  The 
history  of  phylogenetic  and  ontogenetic  development  suggests  that  certain 
tumors  signify  spasmodic  reversions  to  the  anatomic  conditions  of  prehis- 
toric man  or  of  other  closely  related  animal  species.  Thus  the  fusion  of 
multiple  renculi,  the  coalescence  of  multiple  uteri  and  breasts,  the  reduction 
in  length  of  stomach,  intestine,  appendix,  and  colon,  loss  of  lymphoid  tissue 
in  the  relatively  narrow  human  cecum,  and  the  elimination  of  hair  and 
sebaceous  follicles  in  the  face,  suggest  a  source  of  superfluous  cells  and  lay  a 
significant  foundation  for  the  atavistic  growth  of  tumors  in  many  organs. 
Such  influences,  however,  probably  form  only  the  feeblest  of  the  predisposing 
causes  of  tumors. 

The  studies  of  R.  Williams,  Lubarsch,  Ribbert,  Borrmann,  Meyer,  and 
many  others  have  shown  that  embryonal  rests  are  far  more  frequent  than 
was  at  first  imagined.  Wiesel,  for  example,  finds  that  adrenal  rests  are  almost 
constantly  present  along  the  spermatic  cord  and  in  the  pelvic  tissues  of  both 
sexes.  It  is  possible  to  argue  with  fair  success,  as  R.  Williams  has  done,  that 
all  known  tumors  of  the  uterus  arise  from  aberrant,  or  superfluous,  or  em- 
bryonal cell  groups.  From  a  study  of  the  various  tumors  of  the  testis  I  have 
been  led  to  the  conclusion  that  practically  all  of  them  are  derived  from  sex 
cells.  For  tumors  of  the  ovary  Ribbert  reached  a  similar  conclusion.  Thus 
the  more  careful  analysis  of  the  origin  of  tumors  has  extended  rather  than 


97 

restricted  the  number  of  tumors  that  are  known  to  arise  from  cells  that  have 
lagged  behind  in  development. 

Limitations  of  Cohnheim's  Theory. — The  pursuit  of  the  embryonal  theory 
has  added  extensively  to  our  knowledge  of  aberrant  cell  groups  and  at  the 
same  time  revealed  many  new  difficulties  in  the  way  of  the  embryonal  theory. 

It  has  been  shown  that  neither  the  isolation  nor  misplacement  nor  abnor- 
mal persistence  of  cell  groups  are  necessarily  followed  by  tumor  growth. 
The  fate  of  tissue  rests  varies:  (i)  they  may  remain  stationary;  (2)  they 
may  pass  through  normal  stages  of  development  and  eventually  atrophy; 
(3)  they  may  experience  only  a  limited  growth;  (4)  cysts  may  form  from 
them,  or  (5)  tumor  growth  may  appear. 

Various  hypotheses  have  been  suggested  to  account  for  neoplastic  growth 
from  rests.  The  period  of  isolation  of  the  cells  is  an  important  factor.  The 
earlier  its  occurrence,  the  less  is  the  differentiation  and  the  greater  the  capacity 
for  growth.  Early  embryonal  rests  when  starting  to  grow  meet  conditions 
which  do  not  favor  normal  development. 

Since  only  certain  rests  produce  tumors  it  may  be  that  the  embryogenic 
disturbance  which  produces  the  rest  stamps  the  cells  with  abnormal  qualities 
(Aschoff).  This  disturbance  may  perhaps  be  associated  with  failure  of  the 
cells  to  experience  their  proper  idioplastic  development  and  thus  leave  them 
in  a  condition  unusually  favorable  to  growth  when  such  potencies  are  in 
excess.  Or  the  relation  to  the  surrounding  tissue  may  influence  the  growth 
of  the  rest.  Separation  from  the  normal  nervous  control  of  the  tissue  is  here 
to  be  considered.  Organized  cell  groups  such  as  those  composed  of  epithelium 
with  supporting  connective  tissue,  according  to  Ribbert.  tend  to  develop  in 
an  orderly  manner,  while  epithelium  alone  tends  to  develop  a  malignant 
tumor.  Considering  the  great  number  of  organized  adrenal  and  thyroid 
rests,  tumors  from  these  sources  are  rare.  The  attempts  to  produce  malignant 
tumors  experimentally  by  transplantation  of  tissues,  adult  and  embryonal, 
have  not  succeeded.  On  the  contrary,  the  very  numerous  studies  in  this  field 
have  served  to  show  that  something  more  than  the  separation  of  cell  groups 
from  their  natural  environment  is  necessary  for  progressive  growth  (cf.  sec- 
tion on  Experimental  Research). 

Thus  it  becomes  evident  that  Cohnheim's  theory,  while  it  explains  the 
structure  and  occurrence  of  many  tumors,  wholly  fails  to  reveal  why  the 
embryonal  cells  begin  to  grow  and  when  growing  produce  malignant  tumors 
instead  of  normal  structures. 

The  limited  growth  of  many  benign  tumors  has  been  approached  by  the 
structures  produced  by  transplanted  tissues,  but  the  complete  emancipation 
of  malignant  neoplasms  from  the  normal  laws  of  growth  remains  the  obscure 
and  essential  element.  In  the  attempt  to  solve  this  difficulty  the  theory  of 
cell  autonomy  has  grown  up. 

Theory  of  Cell  Autonomy. — The  defects  of  Cohnheim's  theory  were 
brought  to  light  by  studies  undertaken  in  its  defense.  They  showed  that 
the  mere  presence  of  embryonal  cells  was  not  sufficient  to  account  for  their 
growth  in  tumors,  and  that  tumors  grow  where  probably  no  embryonal  cells 
exist.  It  is  necessary  to  consider  how  tumors  arise  from  cells  which  are  neither 
originally  misplaced  nor  essentially  embryonal.  In  this  field  the  theory  of 
cell  autonomy  has  developed. 

The  germ  of  the  theory  of  cell  autonomy  appeared  in  the  studies  of  Remak 
and  Thiersch,  who  traced  the  antagonistic  relation  of  epithelium  and  con- 
nective tissue  throughout  embryonal  development.  Epithelium  seemed 
everywhere  to  be  the  dominating  embryonal  tissue  and  to  cease  growing 
when  it  met  sufficient  resistance  from  the  connective  tissues.  Thiersch  found 


98  NEOPLASTIC  DISEASES 

in  the  weakening  of  the  stroma  of  the  involuting  breast  a  relief  of  tension 
capable  of  releasing  the  formative  tendencies  of  gland-cells  with  their  longer 
span  of  vital  activity.  The  decay  of  connective  tissues  he  regarded  as  senile 
atrophy  and  the  growth  of  cells  as  degenerative  proliferation.  The  idea  of 
cell  autonomy  appears  also  in  Cohnheim's  theory,  but  here  it  was  over- 
shadowed by  the  embryonal  element  in  the  originating  cells. 

To  account  for  the  limitless  growth  of  cells,  embryonal  or  adult,  the  theory 
of  cell  autonomy  introduces  the  conception  of  tissue  tension. 

Ribbert  endeavored  to  explain  the  growth  of  tumors  solely  through  the 
removal  of  certain  cells  from  the  influence  of  a  tissue  tension  by  which  their 
growth  is  normally  restrained.  He  abandoned  the  theory  that  the  disturbed 
cells  must  be  embryonal,  claiming  that  the  regenerative  capacities  of  adult 
cells  are  quite  sufficient  to  account  for  all  the  characters  of  malignant  tumors. 

Conception  of  Tissue  Tension. — The  theory  of  tissue  tension  assumes  that 
cells  are  capable  of  growing  indefinitely  unless  restrained  by  a  complex  group 
of  forces.  This  assumption  is  perhaps  not  yet  proved,  but  there  are  many 
facts  in  its  favor.  The  astonishing  regenerative  powers  of  injured  tissues  in 
plants,  lower  animals,  and  of  many  organs  and  tissues  of  vertebrates,  the 
remarkable  rate  of  growth  of  the  vertebrate  embryo,  the  hypertrophy  of 
the  gravid  uterus,  the  indefinite  reparative  capacity  of  injured  or  transplanted 
epidermis,  all  suggest  that  normal  cells,  although  eventually  restrained  by 
organized  forces,  yet  in  proper  environment  are  capable  of  growing  without 
limit.  Ribbert  insists  that  no  unusual  power  of  proliferation  exists  in  cancer- 
cells,  that  these  cells  freed  from  the  restraints  of  tissue  tension  are  merely 
exhibiting  the  powers  of  growth  with  which  they  are  endowed  from  the  ovum. 
Weigert  and  Roux  have  also  asserted  that  the  regenerative  capacities  of  cells 
are  determined  from  the  moment  of  their  derivation  from  the  ovum  and  can 
never  be  increased  by  any  external  stimulus. 

Many  observers  have  not  accepted  the  Weigert-Roux  hypothesis.  Lu- 
barsch  finds  it  incompatible  with  the  extensive  growth  of  metastatic  tumors 
and  claims  that  external  stimuli  may  induce  an  enormous  increase  in  the  re- 
generative capacities  of  cells.  I  believe  it  is  here  necessary  to  distinguish 
between  the  organized  regenerative  properties  of  tissue  cells,  which  are  truly 
determined  in  the  ovum,  and  the  mere  power  of  multiplication  without  organi- 
zation which  is  subject  to  immense  variations  from  the  influence  of  the  environ- 
ment. Tumor-cells  seem  to  have  more  than  their  ancestral  power  of  growth 
as  when  without  pressure  they  erode  bone.  In  any  case  the  facts  of  normal 
and  tumor  growth  seem  to  place  the  doctrine  of  growth  restraints  and  tissue 
tension  in  an  unassailable  position. 

What,  then,  are  the  restraints  to  growth  which  control  the  multiplication 
of  cells  and  maintain  the  tissue  in  a  physiological  condition  while  permitting 
normal  repair?  At  least  four  such  factors  are  known : 

1.  Mechanical  pressure  of  cells  on  each  other. 

2.  The  distribution  of  nutriment. 

3.  The  influence  of  specialized  functions. 

4.  Organization. 

Under  each  of  these  heads  belong  important  contributions  to  the  theory 
of  cell  autonomy. 

i.  The  influence  of  mechanical  pressure  may  be  traced  both  in  the  incep- 
tion and  in  the  course  of  tumor  growth.  In  the  former  case  it  is  somewhat 
difficult  to  visualize  the  action  of  pressure.  Thiersch  thought  that  relief  of 
mechanical  pressure  followed  the  decay  of  the  stroma  about  epithelial  cell 
groups  and  permitted  the  expansion  of  the  cell  mass,  but  this  element  is  in- 
adequate to  explain  the  inception  of  any  tumor.  The  rapid  lateral  growth 


THEORIES  OF  THE  NATURE  OF  CANCER  99 

of  regenerative  epithelium  in  skin-grafts  may  be  referred  in  part  to  the  ab- 
sence of  lateral  pressure.  Loeb  has  made  an  effort  to  analyze  this  element 
experimentally.  Given  a  certain  grade  of  epithelial  overgrowth,  as  in  the 
tense  ducts  of  chronic  mastitis,  trauma  would  relieve  tension  and  facilitate 
expansion  of  the  cell  mass.  Acting  upon  blood-vessels  pressure  is  a  promi- 
nent factor  in  controlling  the  progress  of  tumors.  Fibrous  encapsulation 
causes  some  tumors  to  regress,  and  relief  of  pressure  by  incision  of  capsule 
releases  active  growth.  These  events  are  frequently  seen  in  both  early  and 
late  stages  of  tumor  growth. 

2.  Distribution  of  Nutriment. — Many  clinical  and  experimental  data  have 
established  the  importance  of  blood-supply  both  for  the  physiological  pro- 
liferation of  cells  and  the  inception  and  progress  of  tumor  growth.    The  normal 
development  of  organs  is  regulated  partly  through  the  plan  of  the  arterial 
system,  and  partial  agenesia  follows  arterial  defects.     Cohnheim  believed 
that  cell  rests  begin  to  grow  chiefly  because  of  increased  blood-supply.    The 
minute  study  of  many  early  tumors  indicates  that  increased  vascularity 
precedes  the  hypertrophy  and  multiplication  of  cells.     Yet  relative  anemia 
is  perhaps  equally  common. 

While  the  blood-supply  is  often  increased  the  abnormal  capacity  of  tumor- 
cells  to  absorb  nutriment  is  a  more  obscure  and  significant  feature  of  the 
disturbed  nutrition  of  neoplastic  cells.  Its  explanation  would  throw  much 
light  on  the  nature  of  the  tumor  process.  The  increased  demands  for  func- 
tion determine  increased  vascularity  in  certain  tumors  (thyroid  cancer). 
In  the  case  of  chorioma  an  increased  supply  of  lutein  secretion,  according 
to  Pick  and  others,  is  associated  with  abnormal  growth  of  the  chorion  over1 
whose  normal  growth  this  secretion  presides.  It  is  possible  that  other  hor- 
mones may  by  unusual  activity  favor  the  growth  of  tissues  with  which  they 
are  concerned,  especially  in  the  field  of  multiple  tumors  of  paired  or  func- 
tionally related  organs.  Thus  there  is  extreme  fibrosis  of  the  ovaries  in  many 
cases  of  mammary  cancer.  The  theory  that  a  specific  nutritive  substance, 
not  itself  the  nutrient  molecule,  presides  over  the  growth  of  tumors  has  been 
applied  by  Ehrlich  to  explain  the  results  of  his  zig-zag  transplantation  of 
mouse  tumors,  from  mouse  to  rat  and  back.  While  this  theory  seems  out 
of  accord  with  certain  observations  concerning  these  transplantable  tumors 
and  seems  to  have  little  bearing  upon  the  problem  of  tumor  growth  in  man, 
yet  it  presents  a  new  point  of  view  for  the  study  of  the  origin  of  tumors  in 
general. 

3.  The  Influence  of  Specialized  Functions. — The  energies  of  cells  are  nor- 
mally divided  between  proliferation  and  specialized  function,  between  work 
and  growth.    Normal  function  diverting  the  energies  of  the  cells  must  be  a 
constant  restraint  or  regulator  of  growth.     In  most  organs  certain  groups 
of  cells  are  set  apart  for  growth  and  from  these  are  derived  the  more  specialized 
functionating  cells.     The  germ  center  cells  of  lymph-nodes,  the  cells  at  the 
bases  of  intestinal  villi,  and  the  basal  cells  of  the  epidermis  are  the  ones  that 
respond  to  demands  for  growth,  and  from  them  tumors  arise.    Overresponse 
to  demands  for  growth  and  loss  of  functional  requirements  both  seem  to 
precede  the  development  of  cancer,  as  in  the  adenomas  of  cirrhotic  livers, 
and  in  the  atrophying  breast.    Adami  has  presented  the  general  importance 
of  this  principle  designating  the  tumor  process  as  "the  cumulative  habit  of 
growth,  replacing  the  habit  of  work." 

Thiersch  and  Beneke  have  interpreted  the  tumor  process  as  a  degenera- 
tive overgrowth  of  cells.  That  there  is  overfunction  in  some  degenerating 
cells,  as  in  the  paralytic  hypersecretion  of  glands,  has  been  pointed  out  by 
Oertel  who  urges  that  overgrowth  may  also  characterize  degenerative  proc- 


100  NEOPLASTIC  DISEASES 

esses.  In  protozoa  the  germinative  and  vegetative  functions  reside  in  separate 
nuclear  structures,  the  macro-  and  micronucleus,  and  it  seems  possible  that 
the  overgrowth  of  tumor-cells  may  be  accompanied  by  excess  of  germinative 
nuclear  material.  This  conception  of  idioplastic  variations  in  the  cells  has 
been  pursued  by  Rulf. 

Active  growth  is  usually  associated  with  active  function.  In  thyroid 
cancer  of  fish  there  is  apparently  an  example  of  a  certain  type  of  malignant 
tumor  developing  as  a  result  of  overresponse  to  functional  stimulus.  There 
are  many  examples  of  adenomatoid  hyperplasia  from  excessive  functional 
stimuli  and  it  seems  probable  that  this  element  may  be  concerned  in  the 
inception  of  certain  tumors.  Proliferating  chromatophores  and  mucous 
goblet  cells  exhibit  excessive  function.  Thus  both  overf unction  and  loss  of 
function  seem  to  be  related  to  tumor  growth. 

4.  Organization. — The  limitless  growth  of  tumors  early  suggested  that 
the  cancerous  tissue  had  lost  the  control  of  the  organism.  Recamier  in  1829 
definitely  formulated  this  idea  and  the  conception  has  steadily  enlarged  with 
the  progress  of  biology. 

The  fertilized  ovum  reproduces  its  kind  because  of  very  complex  factors 
which  are  best  interpreted  as  the  influence  of  environment  on  hereditary 
characters.  Yet  after  the  last  analysis  there  is  always  an  unexplained  resid- 
uum about  regeneration  which  justifies  the  teleological  concept.  The  forms 
of  regeneration  among  the  lower  animals  show  many  processes  that  seem  to 
be  purposeful.  The  regeneration  of  limbs  at  the  breaking  joints  of  crusta- 
ceans; the  variable  regeneration  of  one  or  two  heads  in  flat  worms  according 
to  line  of  incision;  the  regeneration  of  the  lens  in  Triton  indifferently  from 
capsule,  iris,  choroid,  or  retina;  the  polarity  of  the  hydroid  Antennularia, 
which  transforms  twigs  into  roots  according  to  its  accidental  needs,  illustrate 
the  extreme  adaptability  of  regeneration  to  the  uses  of  the  organism.  The 
mechanism  by  which  these  results  are  brought  about,  whether  purposeful  or 
not,  is  called  organization.  Some  biologists,  notably  Morgan,  claim  that  this 
influence  can  be  defined  only  in  terms  of  purpose,  and  cannot  be  wholly  re- 
solved into  any  known  physical  forces.  However  that  may  be,  it  is  a  fact 
that  a  tumor  can  be  defined  only  in  terms  of  purpose.  All  the  known  features 
of  a  malignant  neoplasm  are  exhibited  by  the  normal  chorion,  even  the  de- 
structive invasion  and  cachexia,  but  the  process  is  not  a  tumor  because  of 
its  purpose,  which  shows  that  it  is  under  the  control  of  the  organization. 

Embryology  and  cellular  biology  have  thrown  much  light  on  the  nature  of  the" forces 
concerned  in  organization. 

First,  it  has  been  shown  that  at  all  stages  the  organization  has  an  equilibrium  which 
is  maintained  by  the  altruism  of  the  tissues.  The  dividing  embryo  in  some  animals  up 
to  the  sixteen-cell  stage  yields  cells  any  one  of  which  if  separated  from  the  others  is 
capable  of  producing  an  entire  embryo  (Wilson,  Zoja).  Beyond  this  stage  and  usually 
before,  the  cells  become  differentiated,  different  cell  groups  going  to  produce  different 
specific  tissues.  According  to  Weigert  and  Roux  the  differentiation  results  from  an 
unequal  division  among  the  cells  of  the  properties  of  the  ovum  (the  mosaic  theory). 
According  to  others  (Spencer,  Hertwig)  the  differentiation  is  accompanied  not  by  loss 
but  by  suppression  of  certain  properties  of  the  ovum.  Owing  to  the  unequal  distribu- 
tion or  activity  of  qualities  or  potencies,  some  cells  come  to  possess  more  of  one  type 
and  others  come  to  possess  more  of  another,  while  the  sum  total  of  all  the  potencies 
is  necessary  to  maintain  the  equilibrium  of  the  organization.  Hence  the  cells,  tissues, 
and  organs  stand  in  a  relation  of  antagonism  or  correlation  which  maintains  an  equilib- 
rium, any  change  in  one  affecting  more  or  less  all  the  others.  This  interdependence  has 
been  called  by  Hansemann  the  altruism  of  the  cells.  Removal  of  one  kidney  is  followed 
by  compensatory  hypertrophy  of  the  other,  through  the  physical  factors  of  increased 
urea  in  the  blood,  increased  blood-supply  and  nervous  stimulus,  all  acting  harmoni- 
ously under  the  influence  of  the  organization.  There  is  altruistic  hypertrophy  of  bones 
with  tumors  of  the  hypophysis,  and  altruistic  atrophy  of  the  adrenals  in  anencephalic 


THEORIES  OF  THE  NATURE  OF  CANCER  .  ... 

monsters.  A  definite  chemical  substance  conveys  this  altruistic  influence  in  corpus 
luteum  secretion  which  controls  the  growth  of  the  chorion. 

Many  recent  observations  and  experiments  have  emphasized  the  importance  of  the 
current  of  nutrition  in  determining  the  growth  of  no_rmal  and  neoplastic  tissues.  Murphy 
finds  that  the  presence  of  a  small  fragment  of  growing  splenic  tissue  prevents  the  growth 
of  tumor-tissue  implanted  in  the  chicken  egg,  a  result  probably  signifying  that  the 
growing  splenic  tissue  diverts  and  absorbs  the  available  nutriment.  This  principle 
has  received  experimental  confirmation  in  an  interesting  way  by  J.  Loeb  in  observations 
on  plants.  Stockard  shows  how  the  rate  of  regeneration  of  the  amputated  arms  of  the 
starfish  depends  on  the  number  amputated.  There  are  many  clinical  observations 
indicating  that  the  growth  and  even  the  inception  of  tumors  may  depend  chiefly  on 
the  stream  nutrition  to  the  part,  and  also  upon  the  character  of  the  nutrition. 

Second,  the  study  of  cell  division  reveals  a  mechanism  by  which  the  altruism  of  the 
cells  and  the  control  of  the  organization  may  be  disturbed.  As  long  as  the  cells  multiply 


FIG.  10. — J.  Loeb's  experiment  with  leaf  of  Bryophyllum  calicynum,  illustrating 
growth  restraints.  The  leaf,  notched  as  above,  fails  to  develop  shoots  while  attached 
to  stem,  but  does  so  when  severed  from  stem.  The  influence  is  thought  to  depend  on 
the  flow  of  nutriment,  which  ceases  to  pass  from  leaf  when  it  is  severed. 

by  normal  mitosis  and  each  stage  of  differentiation  in  one  group  is  accompanied  by 
equivalent  antagonistic  qualities  in  others,  equilibrium  is  maintained.  But  if  inflam- 
mation or  chemical  or  mechanical  factors  derange  the  mitotic  process  single  chromo- 
somes may  be  destroyed  and  the  resulting  cells  will  not  have  the  proper  antagonists  to 
balance  it.  By  repetition  of  this  process  a  new  type  of  cell  may  arise  which  is  more  and 
more  removed  from  the  normal  and  fails  to  receive  any  restraining  influence  from  the 
organization. 

The  study  of  tumor-cells  shows  that  irregular,  asymmetric  and  multipolar  mitoses 
and  destruction  of  chromosomes  are  frequent  in  malignant  tumors.  Hansemann  applies 
the  term  anaplasia  to  the  condition  of  such  cells,  which  signifies  loss  of  normal  differ- 
entiation, specific  function,  and  organization.  These  physiological  properties  which 
characterize  malignant  tumor-cells  are  usually  but  not  always  associated  with  pro- 
nounced changes  in  morphology.  Anaplastic  cells  are  not  embryonal  cells,  but  a  new 


^02 \  NEOPLASTIC  DISEASES 

type  which  have  lost  their  place  in  the  organization.  More  or  less  anaplastic  cells 
occur  in  inflammation,  but  there  are  many  degrees  of  anaplasia,  and  its  occurrence  in 
inflammation  accords  with  the  fact  that  inflammatory  hyperplasia  may  pass  into 
neoplastic. 

The  abnormal  capacity  for  growth  has  long  suggested  that  tumor-cells 
have  some  relation  to  sex  cells.  In  some  animals  the  entire  series  of  sex  cells 
from  the  fertilized  ovum  up  to  the  new  egg  cell  has  been  traced  as  a  distinct 
series  apart  from  the  somatic  cells.  In  this  series  the  mitotic  nucleus  exhibits 
only  one-half  the  usual  number  of  chromosomes,  and  these  instead  of  assum- 
ing a  V  shape  and  radial  arrangement  are  ring  or  loop  shaped  or  composed  of 
coarse  granules.  This  gametogenous  mitosis  has  also  been  observed  in  the 
growing  edges  of  tumors  (Farmer,  Moore,  Walker)  and  it  may  be  produced 
by  chemical  irritants.  Its  occurrence  does  not  signify  that  tumor-cells  are 
equivalent  to  sex  cells,  and  yet  in  connection  with  the  invasive  properties  and 
striking  altruistic  relations  of  both  classes  it  shows  that  tumor-cells  and  sex 
cells  have  some  interesting  points  of  resemblance.  Spencer,  Hertwig,  and 
others  claim  that  the  sex  potencies  of  somatic  cells  are  not  lost,  but  only  sup- 
pressed. On  this  basis  Williams  has  built  an  elaborate  and  ingenious  argu- 
ment to  show  that  tumor  growth  signifies  the  reawakening  of  the  reproduc- 
tive functions  in  the  somatic  cells.  According  to  this  theory  tumor  growth 
is  a  form  of  agamogenesis  comparable  to  the  budding  of  plants. 

Many  have  supposed  that  tumor-cells  are  fertilized  cells,  through  conju- 
gation with  leukocytes  (Klebs),  by  parthenogenesis  (Waldeyer),  by  conju- 
gation of  endothelium  and  fibroblasts  (Recklinghausen),  by  nuclear  conjuga- 
tion (Auerbach,  Bashford),  or  by  endogenous  cell  infection. 

None  of  these  hypotheses  has  survived  criticism  and  the  theory  of  cell 
autonomy  remains  content  in  the  position  that  tumor-cells  emancipated  from 
growth  restraints  are  merely  exhibiting  their  natural  capacity  for  growth. 

The  theory  of  cell  autonomy  appropriates  all  the  observations  regarding 
the  mechanisms  of  the  isolation  of  cell  groups.  It  also  accepts  the  principle 
that  adult  cells  which  have  not  lagged  behind  in  development  and  are  not 
embryonal  or  superfluous  may  be  isolated  and  freed  from  growth  restraints. 

Ribbert  lays  great  stress  on  the  mechanical  separation  of  epithelial  cells 
by  new  connective  tissue.  In  early  carcinoma  of  stomach,  epithelioma  of  lip, 
and  psoriasis  linguae  he  finds  strands  of  new  connective  tissue  growing  be- 
tween the  epithelium  and  snaring  off  cell  groups.  Or  round-cell  infiltration 
of  inflammatory  origin  beneath  the  epithelium  creates  an  abnormal  environ- 
ment, and  nullifies  the  restraints  to  grow.  Central  enchondromas  and  many 
exostoses  he  refers  to  groups  of  cells  isolated  by  irregular  ossification  as  in 
rickets.  Malignant  tumors  he  thinks  may  develop  from  groups  of  cells  snared 
off  in  the  course  of  benign  tumors  or  from  implantations  during  removal, 
as  of  ovarian  cystomas.  So  carcinoma  develops  from  isolated  cell  groups 
in  cirrhosis  of  liver  or  contracted  kidneys. 

Further,  it  must  be  assumed  that  trauma  isolates  predisposed  cell  groups 
as  in  many  bone-sarcomas.  The  evidence  that  malignant  chorioma  may 
develop  from  emboli  of  normal  chorionic  cells  is  practically  conclusive  (Mar- 
chand,  Pick). 

In  x-ray  carcinoma  there  is  chronic  edema,  round-cell  infiltration,  and 
flbrosis  altering  the  relation  of  the  epithelium  long  before  the  downward 
growth  of  these  cells.  In  chronic  mastitis  multiple  cancer  nodules  appear 
at  minute  points  where  the  fibrosis  is  unusually  dense  and  the  disturbance 
of  normal  relations  most  marked. 

There  is  little  doubt  that  the  minute  study  of  the  conditions  surrounding 
the  early  stages  of  cancer,  as  instituted  by  Ribbert,  forms  a  strong  support  to 


THEORIES  OF  THE  NATURE  OF  CANCER  103 

the  theory  of  cell  autonomy,  while  its  bearing  on  the  early  diagnosis  and  pre- 
vention of  cancer  is  obvious.  Yet  these  observations  fail  to  show  why  the 
isolated  cells  so  often  regress  and  only  rarely  succeed  in  producing  tumors, 
and  it  is  clear  that  the  mechanical  isolation  of  cells  is,  like  the  embryonal 
character,  only  a  predisposing  factor  in  tumor  genesis.  To  cover  this  defect 
various  hypotheses  have  been  maintained. 

i.  The  isolated  cells  have  been  altered  and  their  growth  tendencies  in- 
creased by  previous  irritation.  2.  There  is  a  local  predisposition  to  tumor 
growth.  3.  There  is  a  general  predisposition  to  tumor  growth. 

1.  Billroth's  dictum,  ''Without  previous  chronic  inflammation  cancer  does 
not  exist,"  while  subject  to  exceptions,  is  yet  so  generally  true  as  to  establish 
the  great  significance  of  chronic  irritation  as  a  factor  in  tumor  genesis.    Inter- 
preted according  to  the  principles  of  the  theory  of  cell  autonomy  it  is  clear 
that  successive  generations  of  cells  subjected  to  chronic  irritation  will  suffer 
increasing  loss  of  growth  restraints  with  disturbance  of  their  normal  rate  of 
growth,  the  size  of  their  nuclei  and  cytoplasm,  their  blood-supply,  and  their 
relations  to  neighboring  cells.     All  of  these  changes  are  observable  in  the 
preliminary  stages  of  lingual  and  other  cancers.    In  this  condition  it  seems 
but  a  short  step  to  downward  growth  of  such  cells  when  the  cumulative  proc- 
ess reaches  a  sufficient  stage  or  when  more  abrupt  mechanical  isolation  of 
cells  occurs.     Whether  these  cells  in  their  continued  progress  are  merely 
exhibiting  normal  powers  of  growth  or  have  acquired  new  powers  constitut- 
ing them  an  entirely  new  biological  series  it  is  difficult  to  decide.    Here  it 
must  be  urged  that  the  continued  growth  of  cancer  is  an  entirely  different 
problem  from  its  inception.    Many  new  factors  intervene  to  facilitate  exten- 
sion and  metastases.    It  is  by  no  means  clear  that  malignant  tumor-cells  are 
more  viable  than  normal  cells.    They  are  more  readily  autolyzed  and  in  early 
cases  tumor  emboli  enjoy  less  resistance  to  destructive  forces  than  normal 
cells. 

For  the  inception  of  many  tumor  processes  chronic  irritation  acting  upon 
normal  cells  seems  to  adequately  explain  the  observed  phenomena.  Thus 
the  cumulative  effects  of  chronic  irritation  alter  the  nutrition  and  growth 
activities  of  cells  so  that  when  they  become  isolated  they  are  not  normal  cells, 
but  are  in  a  state  of  disturbed  equilibrium  with  a  tendency  toward  exag- 
gerated growth.  Such  conditions  are  commonly  observed  in  the  precancerous 
lesion. 

2.  A  local  predisposition  to  tumor  growth  must  be  assumed  to  exist  to 
account  for  the  capricious  development  of  many  neoplasms.     The  factors 
which  lead  to  the  inception  of  tumors  in  one  locality  or  individual  often  seem 
incapable  of  bringing  this  result  under  other  circumstances.     Many  of  the 
factors  constituting  this  local  predisposition  form  the  basis  of  Cohnheim's 
theory,  including,  (i)  Isolation  without  misplacement  of  embryonal  cell  groups. 
(2)  Persistence  of  cell  groups  and  organs  which  normally  regress  after  em- 
bryonal life.    (3)  Formation  of  superfluous  cell  groups.    (4)  Gross  abnormalities 
in  development  of  regions,  organs,  and  systems.    (5)  Disturbance  in  the  idio- 
plastic  development  of  cell  groups  without  visible  changes  in  morphology. 

In  addition,  Rindfleisch  assumed  that  imperfect  nervous  control  is  one  of 
the  factors  predisposing  to  exaggerated  growth  of  tissues  and  tumor  forma- 
tion. While  the  effectiveness  of  such  a  factor  may  readily  be  granted,  there 
seem  to  be  no  observations  in  favor  of  its  existence  except  the  absence  of 
intrinsic  nerves  in  tumor-tissue.  Likewise  imperfect  idioplastic  development 
may  be  conceded  as  certainly  favoring  tumor  growth,  but  in  the  absence  of 
definite  criteria  of  such  a  condition  this  factor  remains  largely  in  the  field 
of  speculation  and  as  a  problem  for  future  studies.  A  reasonable  speculation 


104  NEOPLASTIC  DISEASES 

also  is  that  of  Israel,  who  supposes  that  tissue  cells,  like  bacteria,  in  the  course 
of  repeated  or  abnormal  generations  tend  to  vary  and  in  some  tissues  they 
vary  in  the  direction  of  overgrowth.  Yet  as  normal  cells  do  not  vary  in  this 
way  Israel  is  assuming  an  original  local  predisposition  to  overgrowth.  Thus 
the  well-established  elements  in  the  doctrine  of  local  tissue  predisposition 
belong  under  the  embryonal  theory,  while  the  others  still  remain  seductive 
hypotheses. 

3.  A  constitutional  predisposition  toward  tumor  growth  has  long  been  a 
favorite  field  of  discussion.  There  is  a  vast  amount  of  literature  concerning 
the  relation  or  antagonism  between  cancer  and  tuberculosis,  syphilis,  malaria, 
diabetes,  insanity,  arthritism,  obesity,  gall-stones,  dermatoses,  heart  disease, 
mental  disturbance,  etc.  The  many  interesting  observations  in  this  field 
seem  to  have  wholly  failed  to  throw  any  light  on  the  etiology  of  malignant 
tumors,  nor  have  they  established  any  definite  connection  between  cancer 
and  the  diseases  mentioned. 

It  has  long  been  recognized  that  cancer  is  prone  to  develop  in  plethoric 
individuals.  Williams  sums  up  an  elaborate  argument  with  the  conclusion 
that  cancer  occurs  chiefly  in  the  well  nourished,  the  well-to-do,  and  the  well- 
protected  against  infectious  disease,  that  it  is  especially  prevalent  in  peoples 
with  whom  the  consumption  of  meat  is  high,  and  that  it  is  a  tax  on  civiliza- 
tion. Yet  all  of  these  factors  may  exhaust  themselves  in  increased  longevity, 
by  which  more  individuals  of  weaker  type  reach  the  cancer  age,  and  none  of 
them  seems  to  establish  any  definite  predisposition  to  the  disease.  It  is  con- 
ceivable that  overnutrition  should  facilitate  overgrowth,  but  it  is  not  so  clear 
why  overnourished  tissues  should  tend  toward  neoplastic  instead  of  normal 
growth. 

The  immense  variation  in  the  nervous  and  physical  conformation  of  in- 
dividuals suggests  to  Borst  that  there  may  be  equal  divergences  for  or  against 
neoplastic  growth  of  tissue  cells.  The  quality  of  the  body  proteins,  the  general 
organization  of  the  body,  the  relation  of  tissues  and  organs  to  the  vascular 
and  nervous  systems  may  give  rise  to  individual  peculiarities  which  are  of 
importance  in  the  origin  or  failure  of  tumor  growth,  but  there  are  few  facts 
to  support  this  speculation.  At  best  it  can  only  mean  that  the  capacity  for 
tumor  growth  is  far  more  general  than  the  occurrence  of  tumors.  The  existence 
of  multiple  tumors  is  more  properly  referred  to  definite  multiple  disturbances 
of  development  or  to  the  existence  of  several  recognizable  adequate  factors 
than  to  any  general  predisposition. 

The  individual  of  cancerous  type  is  described  by  Benecke  as  revealing 
a  large  heart  and  arteries,  small  lungs  and  pulmonary  arteries,  long  and 
capacious  intestine,  and  well-developed  osseous,  muscular,  and  adipose  tis- 
sues. Yet  these  are  just  the  subjects  most  likely  to  reach  the  cancer  zone, 
where  the  age  factor  becomes  far  more  prominent  than  anything  we  know 
about  predisposition. 

Imperfect  balance  between  the  sexual  and  other  organs,  the  status  of  the 
thyroid  gland,  and  the  chromaffin  system  have  been  suggested  as  forming 
the  basis  of  a  cancerous  predisposition,  but  the  observations  in  these  fields 
are  as  yet  quite  inadequate  to  form  the  ground  of  an  effective  argument. 
Many  of  the  above  considerations  may  be  adduced  in  favor  of  the  hereditary 
theory  of  cancer. 

According  to  Williams  the  growth  of  malignant  tumors  is  favored  by 
an  altered  metabolism  of  the  body  consequent  on  the  decline  of  the  sexual 
functions.  He  refers  to  the  increased  frequency  of  cancer  after  removal  or 
destruction  of  the  ovaries  (Wells,  Kratzenstein),  and  in  cases  of  congenital 
absence  or  defect  of  the  sexual  organs  (Neugebauer).  Stickler  also  found 


THEORIES  OF  THE  NATURE  OF  CANCER  105 

that  50  per  cent,  of  a  series  of  cattle  and  horses  with  malignant  tumors  were 
castrates. 

The  thyroid  gland  exhibits  in  most  adult  cancer  patients  that  tendency 
toward  involution  which  belongs  to  advancing  years,  but  that  this  involution 
is  more  marked  in  cancer  patients  has  not  been  shown;  nor  has  any  relation 
been  established  between  cancer  and  the  various  members  of  the  chromamne 
system.  A  small  proportion  of  adrenal  tumors  is  associated  with  malignant 
tumors  in  other  organs  (Williams,  Adams,  Guthrie).  The  usual  integrity  of 
the  pancreas  does  not  favor  the  theory  of  Beard  that  cancer  depends  on  de- 
fective pancreatic  secretion. 

Thus  although  the  facts  of  tumor  growth  seem  to  demand  the  assumption 
of  a  constitutional  predisposition,  the  basis  of  this  doctrine  is  as  yet  imper- 
fectly laid.  Clinical  observations,  studies  in  histogenesis  and  gross  anatomy, 
and  chemical  researches  fail  to  reveal  why  the  same  factors  succeed  in  one  but 
fail  in  another  subject  to  produce  tumors.  The  most  suggestive  hypotheses 
seem  to  be  those  concerned  with  overnutrition,  the  decline  of  the  sexual  func- 
tions, and  congenital  disturbance  in  the  idioplastic  development  of  the  cells. 
The  constitutional  element  seems  to  be  too  subtle  for  ordinary  methods  of 
study,  and  to  show  itself  most  clearly  in  the  relation  of  heredity  to  tumor 
growth,  where,  however,  with  certain  exceptions,  its  practical  importance 
diminishes  almost  to  the  vanishing  point. 

Heredity. — Nothing  about  cancer  is  more  generally  accepted  than  its 
hereditary  nature,  and  nothing  is  less  satisfactorily  proved.  The  evidence 
favoring  this  doctrine  consists  chiefly  in  records,  some  very  notable,  of  cancer 
families,  and  in  statistical  studies  of  the  incidence  of  the  disease  in  the  rela- 
tives of  numerous  cancer  patients.  Recently  experimental  evidence  has 
been  adduced  in  its  favor. 

Cancer  Families. — In  1837  Warren  reported  a  family  history  in  which  the 
grandfather  had  cancer  of  the  lip,  while  the  son,  his  daughter,  two  sisters, 
and  the  daughter  of  one  of  them  all  died  of  cancer  of  the  breast.  The  most 
famous  cancer  family  is  that  reported  by  Broca,  1866,  of  Madame  Z,  the 
details  of  which  were  furnished  by  a  medical  member  of  the  family.  Of 
26  members,  mother,  children,  and  grandchildren,  reaching  the  age  of  thirty, 

1 6  died  of  cancer  of  breast,  liver,  or  uterus.    Napoleon  I,  his  father,  one 
brother  and  two  sisters,  are  said  to  have  died  of  cancer  of   the  stomach. 
Sibley  observed  cancer  of  the  left  breast  in  a  mother  and  her  5  daughters. 
Korteweg  saw  cancer  of  the  breast,  and  Paget  cancer  of  the  uterus  in  mother, 
daughter,  and  granddaughter. 

Retinal  glioma  occurred  in  10  of  16  children  of  healthy  parents  in  a  fam- 
ily encountered  by  Newton,  and  in  8  children  of  a  family  seen  by  Wilson. 
These,  however,  are  instances  of  congenital,  not  hereditary  origin.  Williams 
has  collected  many  other  references  to  cancer  families. 

Levin  analyzes  the  conditions  under  which  the  clinical  study  of  heredity 
in  cancer  may  be  conducted  and  points  out  that  the  occurrence  of  cancer  in  a 
family  member  may  not  necessarily  mean  an  hereditary  influence.  An  ex- 
tended investigation  of  the  families  of  5  cancer  patients  failed  to  show  any 
unusual  incidence  of  the  disease.  In  fact,  he  seems  to  have  encountered 
unusually  resistant  families  in  which  cancer  was  of  occasional  but  rare  occur- 
rence. Warthin,  on  the  other  hand,  records  several  very  striking  histories 
of  families  in  which  cancer  was  unusually  frequent.  Thus  in  one  family, 

17  of  48  descendants  of  a  cancerous  grandfather  developed  cancer,  chiefly 
of  uterus  or  stomach.    In  another,  8  descendants  of  a  cancerous  great-grand- 
father all  died  of  the  disease.    Warthin  adds  that  these  families  became  extinct, 
but  clearly  not  from  cancer.    These  observations  emphasize  the  occasional 


106  N  EOF  LAS  TIC  DISEASES 

occurrence  of  cancer  families,  and  suggest  that  members  of  such  families 
may  properly  take  definite  precautions  against  the  disease. 

Statistical  studies  began  with  Paget,  who  traced  cancer  or  other  tumors  in 
the  relatives  of  23.6  per  cent,  of  254  cancer  patients,  but  in  only  18.3  per  cent, 
of  147  non-cancerous  tumor  cases.  Baker  found  cancer  in  the  relatives  of 
24.2  per  cent,  of  322  cancer  cases.  Velpeau  thought  that  at  least  one- third 
of  his  cancer  patients  had  a  family  history  of  cancer.  Leichtenstein  collected 
histories  of  1137  cancer  cases  in  which  heredity  appeared  in  17  per  cent. 

The  proportion  of  women  with  cancer  of  breast  in  whose  relatives  there 
was  a  history  of  cancer  has  been  estimated  by  Butlin  at  37  per  cent.,  by  Nunn 
at  29.3  per  cent.,  by  Williams  at  24.2  per  cent.,  and  by  Leaf  at  23  per  cent. 
Yet  Campiche  and  Lazarus-Barlow  place  the  proportion  in  100  recent  records 
of  the  Middlesex  Hospital  at  15.6  per  cent.,  Williams  found  a  history  of  he- 
redity in  cancer  of  uterus  in  19.7  per  cent.,  of  breast  24.2  per  cent.,  of  other 
female  cases  23.9  per  cent.,  and  in  men  suffering  from  cancer  (209  cases)  n 
per  cent. 

On  the  other  hand,  Lebert  placed  the  percentage  of  inheritance  at  8.5  per 
cent.;  Sibley  in  305  cases  at  8.5;  Winniwarter  in  Billroth's  clinic  at  8.8  per 
cent.  Billroth  found  one  parent  affected  in  5.8  per  cent,  of  170  cases.  Till- 
mann  quotes  reports  showing  8.5  per  cent,  and  10  per  cent,  of  hereditary 
cases  of  cancer  of  stomach.  Ziel  collected  200  cases  with  n  per  cent,  heredi- 
tary. H.  Cripps  excluded  distant  relatives,  as  cousins  and  aunts,  and  in  169 
cases  only  6.4  per  cent,  had  a  cancerous  parent.  He  found  that  in  England 
and  Wales  (1861  to  1870)  i  in  29.1  deaths  occurring  after  20  years  of  age  was 
from  cancer.  Comparing  this  ratio  with  that  of  cancerous  parents  of  cancer 
cases  he  concluded  that  cancer  in  one  parent  does  not  increase  the  liability  to 
the  disease.  Recently  Hillier  and  Tritsch  made  an  elaborate  study  of  family 
history  in  3000  cancer  cases  in  the  Middlesex  hospital.  Of  these,  13.1  per 
cent,  had  a  history  of  cancer  in  relatives,  while  of  417  non-cancerous  cases 
14  per  cent,  gave  cancerous  antecedents.  Pearson,  who  interpreted  these 
data,  hesitated  to  accept  the  necessary  conclusion  that  a  family  history  of 
cancer  confers  a  very  slight  immunity  to  the  disease,  yet  unless  the  collection 
of  the  data  was  very  much  biased  it  is  clear  that  statistics  do  not  support  the 
doctrine  of  the  general  hereditary  nature  of  cancer. 

Bashford  points  out  that  in  England  of  those  living  at  35  years  of  age 
i  man  in  u,  and  i  woman  in  8,  die  of  cancer.  This  ratio  signifies  that  a  his- 
tory of  cancer  will  occur  in  i  out  of  every  2  families  of  the  general  population. 
In  the  families  of  669  cancer  patients  he  obtained  a  history  of  cancer  in  311 
or  50  per  cent.  In  Stuttgart,  Weinberg,  examining  the  cancer  records  from 
1872  to  1902,  found  no  evidence  that  heredity  plays  a  dominant  part  in  the 
etiology  of  cancer.  His  data  show  that  the  deaths  from  cancer  in  each  100 
relatives  of  cancer  patients  were,  of  the  patients'  parents,  6.6,  brothers  and 
sisters,  3.9;  of  their  husbands  and  wives'  parents,  5.9;  brothers  and  sisters,  3.1. 

There  are  numerous  sources  of  error  in  the  conclusions  drawn  from  statistical 
studies.  It  is  quite  unlikely  that  any  hospital  population  can  give  reliable 
information  regarding  the  existence  of  cancer  in  their  parents,  much  less  in 
their  other  relatives.  There  are  numerous  errors  both  of  omission  and  com- 
mission in  the  diagnosis  of  cancer.  The  nature  of  any  hereditary  element  in 
cancer  is  wholly  obscure  so  that  it  is  impossible  to  decide  whether  cancer  in 
cousins  and  aunts,  or  only  in  parents  should  be  considered,  whether  the  pre- 
disposition may  skip  generations,  whether  the  influence  affects  the  same 
organ  or  all  the  organs,  or  whether  the  influence  of  a  similar  environment, 
climate,  food,  and  habits,  may  not  submerge  any  form  of  heredity.  Con- 
sideration of  the  age  factor  completely  altered  the  conclusions  suggested  by 


THEORIES  OF  THE  NATURE  OF  CANCER  107 

Guillot's  statistics.  In  352  patients  he  found  a  cancer  history  in  10  per  cent. 
of  the  non-cancerous  and  in  17.4  per  cent,  of  the  cancerous.  But  the  average 
age  of  the  living  relatives  of  the  non-cancerous  was  37  years,  that  of  the  others 
52  years.  So  that  the  expectation  that  cancer  would  later  develop  in  the 
relatives  of  the  non-cancerous  before  their  average  age  reached  52  changed 
the  true  percentage  of  cancerous  relatives  of  the  non-cancerous  to  16,  or 
1.4  per  cent,  less  than  for  the  cancerous  group.  In  view  of  all  these  considera- 
tions it  must  be  confessed  that  the  statistics  of  cancer  heredity  in  the  present 
state  of  our  knowledge  are  inconclusive  or  even  worthless. 

The  evidence  presented  by  the  many  notable  cancer  families  seems  to  have 
a  different  value.  It  seems  impossible  to  attribute  to  coincidence,  or  envir- 
onment, or  erroneous  observation  the  remarkable  prevalence  of  cancer  in  the 
families  mentioned  by  Warren,  Broca,  Manichon,  Le  Tulle,  and  others.  These 
cases  seem  to  show  that  in  rare  instances  a  pronounced  hereditary  predispo- 
sition to  the  disease  exists.  It  is,  however,  important  to  emphasize  that  the 
history  of  these  families  indicates  that  when  an  hereditary  predisposition 
exists  it  displays  itself  in  unmistakable  form,  and  it  in  no  way  justifies  the 
assumption  that  hereditary  influences  prevail  for  cancer  in  general,  on  which 
point  the  evidence  is  wholly  negative.  These  family  histories  show  how  very 
uncommon  an  effective  hereditary  influence  really  is.  From  the  clinical  and 
statistical  evidence  therefore  one  must,  I  think,  subscribe  to  the  conclusions 
of  Le  Doux-Le  Bard,  (i)  Nothing  authorizes  us  to  affirm  that  cancer  is 
hereditary.  (2)  In  the  interests  of  the  public  this  doctrine  ought  to  be  com- 
bated. 

The  influence  of  heredity  upon  tumor  incidence  has  been  submitted  to 
experimental  test.  Bashford  and  Murray  were  able  to  increase  the  incidence 
of  mammary  cancer  in  340  mice  of  recent  cancerous  ancestry  to  18.2  per  cent., 
as  compared  with  an  incidence  of  8.6  per  cent,  in  223  mice  of  remote  cancerous 
ancestry. 

Tyzzer  has  conducted  breeding  experiments  with  the  offspring  of  a  female 
mouse,  suffering  from  a  cystadenoma  of  the  lung.  Of  100  offspring  of  this 
one  cancerous  parent  65  survived  six  months  and  3  more  than  two  and  a 
half  years.  Of  these,  20  (32  per  cent.)  developed  one  or  more  tumors,  17 
being  pulmonary  tumors.  Among  68  of  these  mice  born  of  cancer-free  par- 
ents 9  (13  per  cent.)  developed  tumors,  while  among  29  with  one  cancerous 
parent  n  (39  per  cent.)  developed  tumors.  The  increasing  frequency  of 
tumors  in  the  old  mice  (2  years)  of  this  family  indicated  that  cancer  was 
almost  inevitable  for  animals  which  survived  infectious  diseases.  While  no 
satisfactory  controls  were  secured  these  interesting  results  strongly  support 
the  hereditary  theory,  at  least  for  this  family  of  mice. 

Maud  Slye  has  conducted  elaborate  experimental  studies  on  the  influence 
of  heredity  on  the  incidence  of  mouse  tumors  and  has  proved  that  inbreeding 
of  tumor-bearing  animals  greatly  increases  the  incidence  of  tumors.  The 
material  used  in  these  studies  is  a  pedigreed  stock  of  mice,  in  her  hands  15 
years.  The  tumors  under  study  were  all  spontaneous,  arising  without  manipu- 
lation of  any  sort  except  that  of  selective  breeding.  The  work  has  now  yielded 
over  30,000  autopsies  and  over  4000  primary  spontaneous  tumors.  The 
results  led  her  to  the  following  conclusions: 

(i)  The  inheritance  behavior  of  neoplasms  is  that  of  a  Mendelian  re- 
cessive. (2)  Double  cancerous  parentage  yields  too  per  cent,  tumor  strains, 
except  where  some  individuals  die  of  infections  before  they  reach  the  cancer 
age.  (3)  Single  cancerous  parentage  yields  heterozygotes  (transmitting  but 
not  themselves  developing  cancer)  in  the  first  hybrid  generation.  These, 
whether  inbred  or  hybridized  with  other  heterozygotes,  yield  in  the  next 


108  NEOPLASTIC  DISEASES 

hybrid  generation  non-cancerous,  heterozygous  and  cancerous  progeny, 
approximately  in  the  proportion  of  i  :  2  :  i.  (4)  The  mating  of  a  cancerous 
with  a  heterozygous  individual  gives  approximately  50  per  cent,  cancerous 
and  50  per  cent,  heterozygous  offspring.  (5)  Double  non-cancerous  parentage 
yields  100  per  cent,  non-cancerous  strains.  (6)  The  tendency  to  cancer, 
therefore,  is  inheritable,  as  no  character  except  one  which  is  hereditary  can 
behave  in  this  manner.  This  segregating  out  of  a  character  is  the  test  of 
heredity.  (7)  The  tendency  to  tumors  of  specific  organs  and  of  specific  types 
is  also  inheritable.  For  example,  this  stock  has  yielded  strains  of  100  per  cent, 
lung  tumor,  or  100  per  cent,  alveolar  carcinoma  of  the  mammary  gland,  or 
50  per  cent,  liver  adenoma,  or  37  per  cent,  kidney  tumor. 

Other  geneticists,  however,  do  not  accept  all  of  Slye's  conclusions  from 
her  published  data.  They  are  inclined  to  believe  that  there  is,  no  doubt, 
a  susceptibility  to  cancer  in  various  families  and  strains  of  animals.  The 
method  of  inheritance,  they  believe,  does  not  follow  a  simple  Mendelian 
procedure,  but  is  probably  understandable  on  a  Mendelian  hypothesis  in- 
volving multiple  factors. 

While  there  are  certain  sources  of  error  in  the  experimental  studies  which 
suggest  themselves  to  the  general  pathologist,  it  may  be  assumed  that  these 
studies  have  demonstrated  the  prime  influence  of  heredity  under  the  condi- 
tions described.  Nevertheless,  the  writer  holds  that  it  is  still  necessary  to 
go  out  into  the  field  of  human  tumors  and  determine  by  observation  just 
how  far  any  hereditary  influence  proves  effective  in  the  causation  of  tumors. 
This  test  seems  reasonable,  since  there  is  abundant  clinical  evidence  of  the 
transmissibility  of  such  diseases  as  hemophilia,  glioma  retinae,  and  neuro- 
fibromatosis.  Clinical  and  statistical  studies,  however,  do  not  support  the 
view  that  heredity  plays  an  important  part  in  the  incidence  of  the  main  human 
tumors,  and  until  these  studies  bear  out  the  experimental  results,  the  con- 
clusions of  the  latter  must  be  limited  to  the  experimental  conditions  and  not 
applied  to  the  more  complex  field  of  human  disease.  Clinical  studies  indicate 
that  there  is  among  human  beings  a  general  susceptibility  to  tumors,  which 
in  rare  instances  has  become  pronounced  and  effective,  but  that,  as  a  rule, 
this  susceptibility  is  negligible  and  the  disease  does  not  develop  until  other 
exciting  factors,  which  are  the  real  effective  causes  of  the  disease,  are  brought 
into  play. 

It  should  be  noted  also  that  the  cancerous  predisposition  may  result  from 
factors  acting  in  each  case  in  utero,  that  is,  that  the  predisposition  may  be 
congenital  without  being  hereditary. 


CHAPTER  VII 
THE  SPECIAL  ETIOLOGY  OF  TUMORS;  TRAUMA 

While  one  general  and  essential  principle,  best  portrayed  in  the  theory 
of  cell  autonomy,  seems  to  underlie  the  inception  of  all  tumors,  yet  it  is  be- 
coming more  and  more  apparent  that  the  etiological  factors  are  variously 
combined  for  nearly  all  neoplasms.  In  this  sense  it  may  almost  be  said  tha't 
the  etiology  of  each  form  of  tumor  is  specific  and  that  a  practical  knowledge 
of  tumor  etiology  requires  a  minute  analysis  of  all  the  factors  concerned  in 
each  case. 

Thus  the  conditions  surrounding  the  inception  of  cancer  of  the  breast  are 
in  many  respects  quite  different  from  those  concerned  with  cancer  of  the 
tongue.  This  distinctive  quality  is  even  more  jobvious  in  the  clinical  course 
and  termination  of  different  malignant  tumors,  so  that  there  is  theoretical 
basis  for  and  practical  value  in  considering  each  tumor  as  a  distinct  clinical 
entity.  Well-known  examples  of  specific  etiology  are  seen  in  various  tumors 
connected  with  occupations,  as  #-ray  cancer,  multiple  epithelioma  of  the  skin 
of  workers  in  paraffin,  and  anilin  dyes,  scrotal  cancer  of  chimney-sweeps,  and 
the  rare  cancer  of  the  lung  in  metal  workers,  weavers,  and  cigar  makers. 

The  cumulative  effects  of  the  habits  of  the  individual  are  seen  in  smokers' 
cancer  of  the  lip,  pharynx,  and  larynx,  Kangri  and  Betel-nut  cancer  of  Indian 
natives,  and  cancer  of  the  skin  in  arsenic  eaters. 

Particular  forms  of  chronic  irritation  and  inflammation  precede  many 
well-known  clinical  forms  of  cancer,  as  epithelioma  of  tongue  from  jagged 
teeth,  cancer  of  skin  from  chronic  eczema,  indolent  ulcers,  burns,  or  along 
chronic  sinuses  from  necrosing  bone,  and  with  Paget's  disease  of  the  nipple. 

Specific  chronic  granulomas  occasionally  lead  to  cancer,  as  syphilitic 
psoriasis  linguae,  and  lupus  of  the  skin.  Sarcoma  also  develops  after  lupus 
and  syphilis  of  bones.  Chronic  inflammation  of  mucous  membranes  pre- 
cedes cancer,  as  in  uterus,  stomach,  urinary  passages,  nares,  and  with  chole- 
lithiasis. Chronic  inflammation  of  glandular  organs  frequently  forms  the 
essential  basis  of  cancer,  as  in  the  cirrhotic  liver,  contracted  kidney,  and 
hypertrophic  prostate.  Chronic  hyperplastic  and  benign  neoplastic  processes 
rather  rarely  become  transformed  into  malignant  tumors,  as  warts,  polyps, 
myoma  uteri,  and  simple  epithelial  cysts  of  many  organs.  Abnormal  involu- 
tion designates  the  conditions  leading  to  many  cancers  of  the  breast,  appendix, 
prostate,  and  thyroid.  Trauma  seems  to  be  the  sole  tangible  factor  in  originat- 
ing many  tumors  of  bone,  glia  tissue,  testicle,  and  many  other  organs. 

The  wide  differences  in  the  nature  of  the  embryogenic  disturbances  which 
lead  to  isolation  of  embryonal  cell  groups  and  tissues  set  apart  a  very  large 
class  of  tumors  whose  etiological  factor  is  distinctive  for  each  member  as 
well  as  for  the  entire  class.  Thus  branchiogenic  cancer,  Wilms'  renal  em- 
bryoma,  and  the  teratoid  testicular  tumors  which  are  probably  derived  from 
sex  cells,  deserve  to  be  considered  as  enjoying  quite  a  different  etiology. 

If,  as  seems  probable,  Hodgkin's  granuloma  becomes  transformed  into 
a  nearly  autonomous  lymphosarcoma,  there  is  very  little  resemblance  be- 
tween its  etiology  and  that  of  bilateral  lymphosarcoma  of  the  testis  of  a  child. 
If  abnormalities  of  the  lutein  secretion  enable  emboli  of  normal  chorionic 
cells  to  develop  malignant  tumors  there  is  little  wisdom  in  discussing  its 
etiology  with  that  of  smokers'  cancer  of  the  larynx.  The  two  diseases  are  as 

109 


110  NEOPLASTIC  DISEASES 

different  in  etiology  as  gout  and  erysipelas,  both  of  which  produce  exudative 
inflammations  of  the  skin. 

Thus  the  special  etiology  of  tumors  presents  extremely  numerous  and 
complex  problems  which  have  immediate  practical  bearing  on  diagnosis, 
treatment,  and  prevention,  and  which  are  probably  much  nearer  solution 
than  is  that  of  the  nature  of  the  neoplastic  process.  It  seems  important  to 
emphasize  the  separate  nature  of  these  departments  of  the  subject  of  etiology 
and  to  point  out  that  in  many  respects  our  knowledge  of  the  etiology  of  tumors 
is  very  clear  and  precise.  Yet  the  action  of  all  these  special  etiological  factors, 
as  irritation,  trauma,  and  inflammation,  is  mainly  secondary  and  indirect, 
and  without  combination  with  other  predisposing  conditions  they  are  incap- 
able of  inducing  tumor  growth.  It  is  possible  that  heredity  may  at  times 
furnish  one  of  these  predisposing  factors.  In  many  cases  the  above  special 
factors  exist,  but  no  tumor  develops. 

Therefore  the  special  etiology  of  tumors  can  deal  only  with  the  conditions 
under  which  tumors  arise,  but  not  with  the  intrinsic  properties  of  cells  which 
find  their  expression  in  the  tumor  process. 

Trauma. — Mechanical  trauma  is  an  important  factor  in  the  causation 
of  tumors.  From  the  scope  of  trauma  in  this  relation  should  be  excluded  the 
various  forms  of  chronic  irritation,  inflammation,  surgical  wounds,  cicatriza- 
tion, and  chemical  escharotics.  By  trauma  is  here  understood  a  single  or 
repeated  more  or  less  contusing,  crushing,  or  lacerating  mechanical  injury. 
This  much  discussed  subject  would  be  greatly  simplified  if  the  statistical  ten- 
dency were  replaced  by  clearer  ideas  of  the  results  of  trauma  in  different  tissues 
and  of  the  mechanism  by  which  such  lesions  lead  to  tumor  growth.  Studies  in 
this  field  are  as  meager  as  the  statistical  contributions  are  superabundant. 

Important  effects  of  trauma  here  are:  (i)  Solution  of  continuity,  minute  and 
gross;  (2)  separation  of  cell  groups  and  tissue  masses,  as  of  skin,  glands,  bone; 
(3)  necrosis  of  tissue;  (4)  confined  hemorrhage  requiring  absorption  or  encap- 
sulation; (5)  accelerated  regenerative  processes  with  hyperemia,  and  new 
growth  of  specific  cells,  blood-vessels,  and  supporting  tissue;  (6)  cicatrization. 

All  of  these  conditions  are  well-proved  elements  entering  into  the  causa- 
tion of  tumors,  and  the  failure  of  attempts  to  produce  tumors  by  experimental 
trauma  in  given  cases  does  not  reduce  their  importance  when  associated  with 
other  necessary  predisposing  factors.  When  one  or  several  of  them  meet  with 
the  relatively  rare  predisposing  conditions,  we  have  a  somewhat  satisfactory 
explanation  of  the  facts  observed  regarding  the  relation  of  trauma  to  tumors. 

The  predisposing  factors  take  many  forms:  (i)  There  may  be  a  benign 
or  a  minute  malignant  tumor  in  the  tissue  before  the  injury.  Many  patients 
with  cancer  of  the  breast  attribute  their  disease  to  some  form  of  injury.  Prob- 
ably very  few  of  these  tumors  are  the  direct  sequel  of  the  trauma,  but  a  slowly 
growing  cancerous  nodule  in  chronic  mastitis  may  be  accelerated  by  a  blow 
where  the  injury  alone  seems  to  be  the  immediate  cause  of  the  tumor.  In 
any  organ  a  preexisting  lesion  renders  the  effects  of  ordinary  injury  more 
severe  and  more  noticeable. 

2.  The  precancerous   condition  may  be  precipitated  into   a   malignant 
process  by  injury.    Examples  are  wounds  of  a  psoriatic  tongue  by  the  teeth, 
injuries  of  the  breast  altered  by  chronic  mastitis,  and  incomplete  surgical 
removal  of  indolent  ulcers,  mucous  polyps,  fistulous  tracts,  and  benign  tumors. 
Leukoplakia  of  the  tongue  is  said  never  to  develop  cancer  until  it  becomes 
complicated  by  cracks  and  fissures. 

3.  Misplaced  and  undeveloped  organs  are  predisposed  not  only  to  tumor 
growth  but  also  to  trauma.     The  results  of  this  unusual  combination  are 
seen  in  cancers  of  undescended  testes  and  supernumerary  breasts. 


THE  SPECIAL  ETIOLOGY  OF  TUMORS;  TRAUMA  111 

4.  Aberrant  quiescent  cell  groups  may  be  included  in  the  damaged  tissue. 
The  best  known  example  is  the  malignant  melanoma  arising  from  an  injured 
mole.     Definite  injury  frequently  precedes  the  appearance  of  the  various 
forms  of  teratoma  testis,  and  since  trauma  is  an  effective  method  of  producing 
artificial  parthenogenesis,  there  is  good  reason  to  believe  that  the  relation 
of  the  injury  to  the  tumor  is  in  this  case  direct,  for  these  tumors  develop 
from  immature  aberrant  sex  cells.    Throughout  the  entire  series  of  embryonal 
tumors  there  is  a  sound  basis  for  ascribing  more  than  ordinary  significance 
to  a  history  of  severe  or  mild  and  repeated  injury.    Ribbert  thinks  that  many 
adrenal  rests  are  incited  to  growth  by  trauma. 

5.  Normal  cells  under  the  conditions  established  by  trauma  develop  be- 
nign or  malignant  tumors.    There  seems  to  be  no  sufficient  reason  for  deny- 
ing the  relation  between  trauma  and  many  chondromas,  osteomas,  lipomas, 
fibromas,  and  fibromyxomas,  with  which  the  history  of  a  blow  is  rather  com- 
mon, and  there  is  little  ground  for  assuming  that  the  trauma  acts  on  any  but 
normal  cells.     Also  with  the  two  most  striking  forms  of  traumatic  tumors, 
gliosarcoma  and  osteosarcoma,  where  a  definite  history  of  injury  is  frequent, 
there  is  no  evidence  that  any  but  normal  cells  are  involved. 

The  character  of  the  injury  followed  by  tumor  growth  varies  widely. 
Traumatic  cancer  usually  appears  after  repeated  mild  injuries  often  amount- 
ing to  chronic  irritation,  while  sarcoma  commonly  develops  after  a  single 
blow.  Yet  many  cancers  have  appeared  after  single  injuries  (Ziegler,  Lowen- 
thal,  Jordan,  Segond).  Only  the  severer  injuries  are  capable  of  reaching  the 
deeper  tissues  from  which  sarcoma  develops.  Cancer  has  been  clearly  traced 
to  lacerations  by  rough  instruments,  rusty  nails  and  pins,  thorn  pricks,  insect 
bites,  surgical  wounds,  and  to  blows  without  visible  destruction  of  tissue. 

Fractures,  lacerations  of  deep  tissues,  contusions  and  concussion,  all  of 
which  are  apt  to  cause  hemorrhage,  represent  the  usual  type  of  injury  pre- 
ceding sarcoma  and  benign  mesoblastic  tumors. 

The  mechanism  by  which  injury  induces  tumor  growth  is  generally  obscure. 
The  traumatic  dermoid  clearly  originates  from  implanted  epidermis  and  fair 
success  has  attended  its  experimental  production.  Yet  it  has  been  abundantly 
proved  that  simple  misplacement  of  other  normal  tissue  cells  is  quite  inade- 
quate to  explain  tumor  growth.  Hyperemia  may  be  the  remaining  factor 
necessary  to  excite  the  proliferation  of  aberrant  rests,  and  precancerous  foci. 
Blood  extravasation  requiring  absorption  or  organization  creates  conditions 
especially  favorable  to  mesoblastic  overgrowth.  Certain  tissues  are  predis- 
posed to  excessive  overgrowth  in  the  presence  of  hemorrhage.  The  periosteum, 
the  tissues  of  the  scrotum  and  cord,  the  omentum,  and  the  pia-mater  fre- 
quently exhibit  very  active  overgrowth  of  tissue  following  hemorrhage,  yield- 
ing bulky  products,  which  have  the  gross  and  many  of  the  microscopical 
appearances  of  tumors.  Such  pseudosarcomas  are  especially  frequent  in  the 
scrotum.  Cornil  and  Berard  have  noted  the  very  active  proliferation  about 
traumatic  hematomas,  and  locate  the  early  sarcomatous  process  in  the  cells 
about  new  blood-vessels.  Some  early  sarcomas  of  the  brain  present  appear- 
ances implicating  the  new  vessels  in  the  sarcomatous  process. 

The  common  superfluous  callus  about  fractures  reveals  the  great  pro- 
liferative  capacity  of  periosteum,  and  Benecke  believes  that  the  regenerative 
process  in  periosteum  may  run  directly  into  sarcoma.  In  traumatic  myositis 
the  new  tissue  is  often  suggestive  of  sarcoma.  Yet  the  full  explanation  of 
traumatic  sarcoma  seems  to  require  the  assumption  of  special  local  or  general 
predisposing  factors  which  have  never  been  traced  in  microscopical  structure. 
The  chemical  composition,  blood-supply,  and  lymph  supply  of  brain  tissue 
are  peculiar,  but  give  no  clue  to  the  frequency  of  traumatic  gliosarcoma.  The 


112  NEOPLASTIC  DISEASES 

presence  of  necrotic  tissue  should  receive  attention  as  a  possible  specific  factor 
in  the  development  of  traumatic  tumors.  It  is  possible  that  products  of 
autolysis  or  decomposition  of  protein  tissue  may  exert  peculiar  influence 
on  regenerative  processes,  as  in  the  brain.  Kottnitz  cites  many  cases  of 
lipoma  in  which  a  traumatic  factor  appears  acting  directly  or  through  the 
nervous  system. 

Ribbert  admits  that  we  have  not  the  slightest  knowledge  why  trauma, 
which  affects  many  cell  types  in  large  areas,  excites  tumors  of  one  cell  type 
in  one  focus.  He  thinks  that  the  results  of  experimental  separation  of  cell 
groups  have  often  approached  the  condition  of  benign  tumors  some  of  which 
may  regress.  The  most  extensive  proliferation  is  obtained  by  partial  separa- 
tion of  tissues,  as  along  three  sides  of  a  square,  of  the  rabbit's  ear.  Epithelium 
completely  separated  dies,  but  regenerating  connective  tissue  is  much  more 
resistant. 

The  frequency  of  the  traumatic  origin  of  tumors  varies  with  different 
statisticians,  according  to  their  conception  of  trauma  and  their  critical 
standards.  Composite  statistics  vary  from  2.5  per  cent,  by  Kempf  to  44.7 
per  cent,  by  Lowenthal.  Of  6780  tumors  of  all  varieties  reported  in  the  litera- 
ture with  reference  to  trauma  494  or  7  per  cent,  were  regarded  as  of  traumatic 
origin.  Of  2641  cancers,  107,  5  per  cent.,  and  of  938  sarcomas  186,  or  about 
19  per  cent.,  were  classed  as  traumatic.  In  a  large  proportion  of  these  cases 
the  relation  of  the  trauma  was  extremely  uncertain.  The  figures  represent 
the  present  attitude  of  most  clinical  writers  which,  as  Lubarsch  and  Schimmel- 
busch  have  said,  is  often  extremely  uncritical.  Only  the  statistics  relating 
to  single  tumors  are  of  practical  value.  Of  55  melanomas  Werner-Rowe  found 
19  with  a  history  of  injury  of  a  mole. 

Of  glioma  of  the  brain  Adler  collected  1086  cases  of  which  8.8  per  cent, 
were  preceded  by  rather  definite  traumatic  history.  In  this  class  of  cases 
the  relation  between  the  trauma  is  often  clear,  the  symptoms  of  trauma 
merging  into  those  of  tumor  and  occasionally  a  scar  has  been  found  in  bone 
or  dura  directly  connected  with  the  tumor. 

There  are  important  medicolegal  aspects  of  the  relation  of  trauma  to 
tumors.  To  establish  the  relation  of  trauma  several  classes  of  evidence  are 
necessary,  as  is  recognized  especially  by  the  French  statutes. 

i.  The  authenticity  and  sufficient  importance  of  the  trauma.  (2)  Previous 
integrity  of  the  wounded  part.  (3)  A  reasonable  time  relation,  three  weeks 
to  three  years  or  more  in  certain  cases.  (4)  Continuity  of  pathological  changes 
or  symptoms  in  the  wounded  part  and  the  appearance  of  the  tumor.  (5) 
Microscopical  proof  of  the  existence  of  a  tumor. 

It  is  necessary  to  distinguish  also  between  complete  and  partial  liability. 
When  a  healthy  adult  receives  a  blow  on  the  head,  remains  unconscious  for 
days,  never  recovers  full  mentality,  shortly  develops  signs  of  brain  tumor, 
and  dies  in  a  few  months  of  gliosarcoma  of  suitable  size  and  location,  the 
liability  is  generally  accepted  as  complete.  When  a  patient  with  symptoms 
of  abdominal  disease  receives  a  blow  in  the  epigastrium  and  rapidly  succumbs 
to  carcinoma  of  an  abdominal  organ  it  is  reasonable  to  assume  that  the  trauma 
hastened  the  progress  of  an  existing  tumor.  As  Segond  states,  trauma  reveals, 
aggravates,  or  serves  as  a  pretext  for  the  origin  of  tumors;  so  that  in  each 
case  very  careful  consideration  of  all  circumstances  are  required  to  establish 
the  relation  of  the  injury. 

In  the  German  courts  definite  liability  has  been  assumed  for  cases  in 
which  the  connection  between  trauma  and  tumor  is  very  uncertain  and  in- 
capable of  proof,  as  with  carcinoma  of  colon  or  stomach  appearing  several 
years  after  a  blow  on  the  abdomen. 


CHAPTER  VIII 
THE  PARASITIC  THEORY 

The  parasitic  theory  is  the  oldest  hypothesis  of  the  origin  of  cancer.  It 
appealed  to  the  ancients,  was  tacitly  accepted  throughout  the  Middle  Ages, 
was  definitely  argued  by  modern  observers,  and  reached  the  height  of  its 
popularity  as  a  scientific  theory  about  1895,  but  during  the  last  fifteen  years 
it  has  rapidly  lost  ground,  and  today  few  competent  observers  consider  it 
as  a  possible  explanation  of  the  unknown  element  in  blastomatosis. 

The  data  concerning  the  parasitic  theory  fall  into  four  main  classes:  (i) 
Studies  of  the  incidence  of  cancer;  (2)  the  search  for  specific  parasites  in 
tumors;  (3)  the  experimental  production  of  tumors;  (4)  theoretical  considera- 
tion of  the  nature  of  cancer. 

The  Incidence  of  Cancer. — In  1809  Arnaudet  reported  that  in  certain 
rural  districts  in  Normandy  during  a  period  of  eight  years,  the  cancer  mor- 
tality reached  14.88  per  cent.  He  noted  the  occurrence  of  cancer  in  several 
members  of  the  same  household,  and  he  concluded  that  the  neighborhood 
of  a  cancer  patient  was  contaminated  through  the  water. 

Many  similar  reports  of  cancer  districts  and  cancer  houses  soon  appeared 
from  Guelliot,  Webb,  Fiessinger,  D'Arcy  Power,  Bosc,  and  others.  Behla 
found  the  cancer  mortality  of  the  low-lying  portions  of  Luckau  to  be  four 
times  that  of  the  central  portion.  He  noted  the  frequency  of  cancer  in  the 
dogs  of  the  town,  the  large  quantities  of  home-grown  vegetables  consumed 
by  the  cancer  families,  and  concluded  that  cancer  is  an  infectious  disease 
carried  to  its  victims  through  contamination  of  the  soil. 

In  1892  Haviland,  from  an  elaborate  analysis  of  the  English  census,  con- 
cluded that  cancer  is  a  disease  of  low-lying  districts  and  of  seasonably  flooded 
riparial  lands  where  subsoil  is  constantly  moist,  while  in  high  dry  localities 
it  is  rare. 

Very  minute  studies  of  cancer  localities  have  been  made  in  England  and 
other  countries  by  numerous  observers  all  tending  to  show  a  relation  between 
cancer  and  all  manner  of  local  peculiarities;  as  living  in  "old  and  cancer 
houses"  (Park),  "infected  streets"  (Mason),  houses  with  defective  plumbing, 
leaky  sewers  (Nason),  proximity  to  trees,  especially  large  ones  (Lloyd- Jones), 
collections  of  decaying  vegetable  matter,  stagnant  water  (Poppelman),  abun- 
dance of  certain  insects  (Bosc),  etc.  The  uncritical  character  of  these  observa- 
tions hardly  needs  comment.  Many  of  the  fallacies  involved  in  them  have 
been  pointed  out  by  Sticker  and  by  Prinzing. 

At  the  height  of  their  popularity  Symons  showed  that  there  were  no 
cancer  houses  in  Bath  where  cancer  mortality  was  the  highest  in  England. 
Out  of  this  fanciful  discussion  Williams  draws  the  sane  conclusion  that  cancer 
is  a  disease  of  civilization,  choosing  its  victims  from  the  well-to-do,  the  well- 
nourished  and  the  well-protected  against  infectious  diseases,  and  that  it 
flourishes  in  just  the  opposite  conditions  from  those  which  favor  the  spread 
of  tuberculosis.  At  one  time  there  was  a  tendency  to  report  small  epidemics 
of  cancer  among  men  (Webb,  Fiessinger),  and  to  point  out  its  epidemic  char- 
acter. Later,  epidemics  of  cancer  among  cattle  were  described  (Loeb),  or 
among  rats  and  mice  used  for  breeding  purposes  (Gaylord,  Borrel,  Loeb), 
for  which  old  age  and  inbreeding  are  sufficient  explanations.  Bashford,  in  a 
8  113 


114  NEOPLASTIC  DISEASES 

very  wide  experience  with  captive  rats  and  mice,  found  no  evidence  of  any 
"cage  infection." 

Epidemics  of  thyroid  cancer  among  artificially  bred  trout  have  menaced 
the  fish  industry  in  several  countries.  Pick  and  Plehne  concluded  that  it 
arises  from  overcrowding,  overfeeding,  and  inbreeding.  Gaylord  demon- 
strated the  true  cancerous  nature  of  a  certain  proportion  of  these  cases,  but 
Gudernatsch  pointed  out  the  remarkably  wide  distribution  of  the  thyroid 
lobules  in  many  species  of  fish  and  rendered  doubtful  the  neoplastic  character 
of  the  great  majority  of  the  "tumors."  Marine  and  Lenhardt  have  shown 
that  many  of  the  hyperplastic  thyroids  regress  under  proper  hygiene. 

Statistics  elaborately  presented  by  Williams  and  by  Hoffman  show  a  re- 
markable increase  in  the  recorded  deaths  from  cancer  during  the  last  50  years. 
In  England  in  1840  the  cancer  deaths  were  i  in  129  of  the  total;  in  1905,  i 
in  17.  Very  similar  indications  are  found  in  the  records  of  most  civilized 
countries  (Hoffman,  Lit.).  Williams  calculates  that  in  England,  1900,  i  in 
15  of  all  men,  and  i  in  9  of  all  women,  living  at  35  years  of  age  are  destined 
to  die  of  cancer.  The  increase  seems  to  be  affecting  men  more  than  women, 
although  in  England  cancer  is  now  a  more  fatal  disease  for  women  than  is 
tuberculosis.  The  increase  of  cancer  is  concomitant  with  a  decrease  of  tuber- 
culosis. 

Of  the  apparent  increase  in  cancer  deaths  a  considerable  proportion  must 
be  referred  to  improved  diagnosis.  Riechelman  shows  for  the  Berlin  hospitals 
that  there  was  still,  1902,  room  for  a  20  per  cent,  increase  in  the  recorded 
deaths  from  cancer  through  improved  diagnosis  alone.  The  remaining  por- 
tion must  be  largely  referred  to  the  longer  tenure  of  life  through  immunity  to 
infectious  diseases  and  improved  hygiene,  which  permit  a  larger  proportion 
of  persons  to  reach  the  cancer  age.  In  Prussia  vital  statistics  show  that  the 
average  person  lives  25  years  longer  than  in  1860.  Willcox  in  a  critical  analysis 
of  this  subject  shows  that  the  sources  of  the  recorded  increase  are  quite  com- 
plex, including  improved  diagnosis,  changes  in  age  composition  of  popula- 
tion, elimination  of  old  age  as  a  cause  of  death,  improved  registration,  and 
widening  of  the  definition  of  cancer. 

He  shows  that  the  increase  is  chiefly  of  inaccessible  cancers,  among  the 
lower  classes  of  society,  in  males  rather  than  in  females,  in  negroes  and  the 
foreign  born,  and  in  the  country  more  than  in  the  cities. 

The  impression  that  cancer  is  actually  increasing  to  a  slight  extent  which 
cannot  wholly  be  explained  by  the  above  factors  and  is  more  often  appearing 
at  earlier  ages,  is  probably  correct,  but  such  a  fact  cannot  stand  as  an  argu- 
ment for  the  parasitic  theory. 

The  contagiousness  of  cancer  was  at  one  time  supposed  to  be  proved  by 
clinical  observation.  Lusitanus  (1557)  claimed  to  have  observed  infection 
of  3  children  by  a  cancerous  mother.  Tulpius  reported  the  direct  transfer 
of  the  disease  between  human  beings.  In  the  i7th  and  i8th  centuries  cancer 
was  regarded  as  quite  as  infectious  as  phthisis,  with  which  it  was  often  con- 
founded. Lebert  and  Friedreich  believed  they  had  observed  cancer  infection 
of  the  fetuses  of  cancerous  mothers. 

The  numerous  observations  on  contact  infection  were  supposed  to  point 
to  a  parasitic  factor,  but  relatively  few  of  these  cases  seem  to  have  been  genuine, 
and  in  these  it  must  be  held  that  the  infecting  agent  is  the  cancer-cell.  Of 
the  many  cases  of  cancer  a  deux  reported  by  Budd  and  Guelliot  none  appears 
to  be  properly  attested,  while  Demarquay  found  that  in  only  i  of  134  cases 
of  cancer  of  the  penis  did  the  wife  have  cancer  of  the  uterus,  and  Bossi  re- 
ported that  of  1 80  husbands  of  women  with  uterine  cancer,  none  contracted 
the  disease.  The  attempts  of  Alibert,  Wickham,  and  Senn  to  inoculate  them- 


THE  PARASITIC  THEORY  115 

selves  with  cancer,  failed.  Finally,  it  is  the  universal  experience  of  surgeons 
that  the  disease  is  not  contracted  by  the  treatment  and  care  of  cancer  patients. 

The  conclusion  may  thus  be  drawn,  that  nothing  in  the  incidence  of  cancer 
points  to  its  infectious  nature. 

Microorganisms  in  Cancer. — With  the  advent  of  microbiology  each  new 
class  of  microorganisms  in  turn  was  isolated  from  cancer  tissue,  many  were 
grown  in  pure  culture,  and  some  were  claimed  to  reproduce  the  disease  upon 
inoculation. 

(a)  Bacteria. — Rappin,  Schill,  Francke,  Lampiasi,  and  others  made  un- 
warranted claims  for  the  data  regarding  the  bacteria  isolated  by  them  and 
they  were  soon  forgotten.     In   1887   Scheurlen  obtained  pure  cultures  of  a 
bacillus  from  mammary  cancer  and  with  it  claimed  to  have  produced  tumors 
of  the  breast  in  dogs.    Baumgarten  showed  this  bacterium  to  be  the  potato 
bacillus.    In  1890  Koubassoff  offered  a  complete  claim  of  evidence  for  a  thick 
motile  bacillus  from  gastric  cancer.     In  1910  Doyen  announced  his  Micro- 
coccus  neoformans  as  the  cause  and  cure  of  cancer.     It  was  soon  shown  that 
this  microorganism  had  nothing  to  do  with  cancer,  and  the  Societe  de  Chirur- 
gie  (1905)  reported  it  to  be  valueless  in  the  amelioration  of  the  disease.    These 
studies  led  to  certain  results  of  positive  value.    Shattuck  and  Ballance  showed 
that  non-ulcerated  tumor-tissue  could  easily  be  kept  sterile.     Verneuil  in 
necrotic  foci  and  Zahn  in  some  metastatic  growths  at  autopsy  found  many 
bacteria.     Richet  found  pyogenic  bacteria  common  in  cutaneous  cancers. 
Maragliano  often  found  staphylococci  in  the  blood  of  patients  with  ulcerating 
tumors,  even  without  fever,  but  never  with  non-ulcerating  growths. 

(b)  Cocvldia,  differing  in  many  details,  were  described  by  several  observers. 

Darier's  psorosperm  of  Paget's  disease  secured  much  support  from  Wick- 
ham,  and  the  histological  evidence  alone  sufficed  to  impress  many  with  the 
belief  that  this  structure  was  the  true  cause  of  this  and  other  cancers.  It 
was  repudiated  by  its  discoverer  in  1904. 

Thoma  (1888)  and  Sjobring  (1890)  described  much  the  same  intracellular 
and  intranuclear  structure  as  a  parasitic  coccidium. 

Metchnikoff  supported  Sudakiewitsch's  intracellular  coccidium. 

Adamkiewicz  asserted  that  all  cancer-cells  are  parasitic  coccidia  (Coc. 
sarcolytum),  giving  origin  to  a  specific  toxin  (cancroin)  and  much  this  same 
view  was  held  by  L.  Pfeiffer  and  J.  Clarke. 

(c)  Miscellaneous  Protozoa. — Other   observers   could   not   regard   all   the 
cancer-cells  as  alien  parasites,  but  certain  of  the  tumor-cells  they  identified 
as  parasitic  amebae  because  of  their  bizarre  forms  and  long  pseudopodia  which 
stretched  between  adjacent  cells.     These  were  the  Rhopalocephalus  carcino- 
matosus  of  Korotneff,  and  Cancriamceba  macroglossia  of  Eisen.     L.  Pfeiffer 
described  and  depicted  intracellular  structures  which  resembled  the  micro- 
sporidia  of  muscle-tissue. 

Podwyssoski  and  Sawtchenko  described  as  sporozoa  a  variety  of  free  and 
encapsulated  intracellular  structures  many  of  which  resembled  Sudakie- 
witsch's parasites.  Ruffer  and  Walker  improved  the  technical  methods  of 
demonstrating  the  cancer  bodies  and  endeavored  to  distinguish  between 
true  and  spurious  parasites.  Kahane  thought  he  detected  a  minute  proto- 
zoan in  the  circulating  blood  of  cancer  patients.  In  cancerous  ascitic  fluid 
Schaudinn  observed  a  large  ameboid  cell  which  he  named  Leydenia  gemmi- 
para.  Schiiller  traced  the  complete  cycle  of  a  minute  intranuclear  protozoon 
in  cancer-cells  which  differed  from  nearly  all  other  cancer  parasites. 

Bird's-eye  Inclusion. — From  the  beginning  of  the  search  for  the  cancer 
parasite  special  interest  always  centered  in  a  certain  intracellular  body  called 
the  "bird's-eve  inclusion." 


116  NEOPLASTIC  DISEASES 

This  body  appeared  in  the  cycle  of  many  of  the  parasites  described  by 
various  authors.  It  was  first  cautiously  suggested  by  Foa  as  the  probable 
cancer  parasite.  In  1902  Feinberg  made  a  final  effort  to  establish  specific 
features  in  this  body,  double  contour,  metachromatism  and  nucleus  sur- 
rounded by  a  clear  zone,  but  these  features  were  promptly  and  authorita- 
tively discarded  by  Hertwig. 

(d)  Mycetozoa. — L.  Pfeiffer  early  pointed  out  the  resemblance  of  many 
cancer  bodies  to  forms  of  mycetozoa,  especially  Plasmodiophora  brassicae. 
This  organism  was  first  described  by  Woronin  as  the  cause  of  club  root,  a 
common  disease  of  plants,  and  its  complex  cycle  was  worked  out  by  Nawas- 
chin.    Some  of  its  forms  closely  resemble  the  bird's-eye  inclusion  of  cancer, 
while  others  are  extremely  minute  and  difficult  of  detection  in  the  infected 
cells.    Behla  found  the  disease  common  in  the  gardens  of  his  cancer  houses 
in  Luckau.    Elaborate  attempts  to  demonstrate  that  this  or  a  similar  organ- 
ism is  the  cause  of  cancer  have  been  made  by  Behla,  Podwyssoski,  Feinberg, 
Gay  lord,  and  Robertson  and  Wade. 

Several  observers  claimed  to  have  secured  cultures  of  these  protozoa  and 
to  have  reproduced  tumors  by  inoculation  of  the  cultures  in  animals. 
Sjobring  used  a  medium  containing  ascitic  fluid,  peptone,  glucose,  and  soap 
made  from  human  fat,  and  claimed  to  have  isolated  his  rhizopod  from  human 
tumors.  Cultures  produced  tumor-like  growths  in  mice.  Yet  the  German 
pathologists  denied  that  the  growths  were  neoplasms  and  Israel  asserted 
that  the  rhizopods  were  fat  droplets.  By  the  inoculation  of  material  from 
club  root  Podwyssoski  and  Gaylord  produced  granulomatous  swellings  in 
animal  tissues,  the  cells  of  which  contained  the  englobed  parasites,  which 
closely  resembled  some  of  the  intranuclear  bodies  seen  in  cancer.  Yet  v. 
Tubeuf  and  others  have  inoculated  many  animals  with  club  root  and  failed 
to  produce  any'  lesions  resembling  neoplasms.  According  to  v.  Tubeuf  the 
histology  of  club  root  is  not  that  of  a  neoplasm,  the  tumor  resulting  from 
distentiori  and  degeneration  of  cells  surrounded  by  an  area  of  inflammatory 
overgrowth.  The  picture  of  infected  cells  in  club  root  distended  with  enormous 
numbers  of  very  definite  parasites  is  wholly  different  from  anything  seen  in 
cancer. 

Smith  has  shown  on  an  elaborate 'scale  that  Bacillus  tumefaciens,  isolated 
from  crown  gall,  is  capable  of  producing  a  variety  of  tissue  overgrowths  in 
plants  which1  he  regards  as  true  tumors,  both  simple  and  teratomatous.  Yet 
this  observer  fails  to  distinguish  between  chronic  productive  inflammation 
in  plants  and  neoplasia;  he  does  not  consider  that  even  in  animals  inflamma- 
tory hyperplasia  may  pass  into  neoplastic,  while  his  infectious  "embryomas" 
in  plants  cannot  have  any  relation  to  the  embryogenic  disturbances  known 
to  give  rise  to  teratomas  in  the  animal  body. 

Schiiller  claims  to  have  cultivated  his  protozoon  and  to  have  produced 
by  it  both  carcinoma  and  sarcoma.  Yet  no  one  else  has  been  able  to  find 
this  organism  in  cancer,  and  Schiiller's  technic  fell  under  suspicion  when 
Volcker  pointed  out  that  the  very  characteristic  large  forms  of  this  protozoon 
exactly  resemble  cork  cells. 

(e)  Spirocheta. — In  1905  Borrel  reported  the  occurrence  of  spirochetae  in 
2  mouse  tumors  without  attributing  to  them  etiological  significance.    Wenyon 
has  shown  that  mice  are  susceptible  to  blood  infection  by  these  organisms. 
Gaylord  and  Calkins,  finding  a  single  type  of  spirochetae  in  10  mouse  cancers 
and  in  1 6  transplants  therefrom,  suggested  that  the  spirochetae  were  the  cause 
of  the  tumors.    Yet  Gaylord  and  Clowes  succeeded  in  freeing  their  tumors 
from  spirochetas  by  treatment  with  KCN,  and  Tyzzer  found  many  tumors 
in  mice  not  infected  with  spirochetae.     In  35  human  tumors  and  25  in  the 


THE  PARASITIC  THEORY  117 

dog  I  found  spiral  organisms  only  on  ulcerated  surfaces  or  in  necrotic  areas. 
Similar  results  were  obtained  by  Mulzer  and  by  Lowenthal. 

(/")  Blastomycetes. — In  1890  Russell  fully  described  certain  small  and 
large  round  bodies  in  cancer-cells  which  stained  intensely  with  fuchsin  and 
which  he  recognized  as  parasitic  budding  fungi  or  yeasts.  Although  these 
bodies  had  long  before  been  noted  by  Fox,  and  Klein  and  Lubarsch  soon 
showed  that  they  were  found  in  many  normal  and  diseased  tissues,  the  yeast 
theory  of  cancer  was  taken  up  systematically  by  San  Felice  and  the  Italian 
school.  From  1895  up  to  the  present  time  San  Felice  has  devoted  much 
labor  to  the  support  of  this  theory.  He  experimented  first  with  a  culture 
obtained  from  fruits,  Saccharomyces  neoformans,  and  one  from  the  lymph- 
nodes  of  an  ox  dying  with  carcinoma  of  the  liver,  Saccharomyces  litoger.es. 
Later  he  obtained  cultures  from  human  tumors.  With  these  cultures  he 
produced  infection  of  many  animals,  chiefly  dogs. 

With  Saccharomyces  neoformans  he  thought  he  produced  a  sarcoma  in  the 
breast  of  a  bitch  and  in  many  other  animals,  but  most  of  the  Jesions  were 
clearly  inflammatory.  Saccharomyces  litogenes  produced  very  similar  lesions. 

Repeated  passages  increased  the  virulence  of  the  strains  and  their  neo- 
plastic  properties.  Cultures  from  human  tumors  were  non-pathogenic  for 
animals.  It  was  not  possible  to  recover  the  organism  from  the  tumors,  a 
result  which  San  Felice  attributed  to  the  death  of  the  yeasts  which  then 
assumed  the  form  of  fuchsin  bodies.  In  his  latest  studies  San  Felice  com- 
bines the  soluble  toxins  of  yeasts  with  the  living  cultures,  finding  that  the 
toxins  rather  than  the  bodies  of  the  organism  cause  proliferation  of  cells. 
Nevertheless  the  lesions  which  he  pictures  seem  to  have  the  features  of  infec- 
tious granulomas  and  not  those  of  tumors. 

Many  other  observers  claim  to  have  isolated  blastomyces  from  tumors 
and  produced  other  tumors  by  inoculation,  as  Plimmer,  Roncali,  Corselli 
and  Frisco,  Curtis,  Monsarrat,  Leopold,  Wlaeff,  Klein,  etc.  Against  their 
conclusions  stand  an  equal  number  of  very  competent  studies  which  show 
that  blastomyces  are  rarely  present  in  tumors  and  that  they  are  incapable 
of  producing  neoplastic  lesions.  Fouler  ton  and  Richardson  examined  several 
hundred  human  tumors  without  securing  a  single  yeast.  Their  rare  presence 
in  tumors  is  attributed  by  most  bacteriologists  to  secondary  infection,  and 
the  high  proportion  of  successful  cultures  secured  by  many  observers  is  clearly 
the  result  of  air  contamination.  Meser  found  lycopodium  seeds  from  the 
dressings  deep  within  the  tissue  of  carcinoma.  The  pathogenic  action  of  a 
number  of  yeasts  have  been  elaborately  studied  by  many  competent  observers, 
including  Mafucci  and  Sirleo,  Foulerton,  Rabinowitsch,  Petersen  and  Exner, 
and  Nichols,  none  of  whom  found  any  indication  that  these  organisms  can 
produce  tumors. 

The  various  blastomycetes  known  to  be  pathogenic  for  man  produce 
characteristic  granulomas,  but  not  tumors.  It  is  true  that  in  certain  chronic 
blastomycotic  lesions,  especially  of  the  skin,  considerable  hyperplasia  of 
epithelium  resembling  cancer  has  occasionally  been  seen,  but  there  is  no 
indication  that  this  hyperplasia  exceeds  that  observed  with  syphilis  and 
tuberculosis.  Genuine  cancer  sometimes  follows  such  lesions  and  yet  no  one 
supposes  that  the  tubercle  bacillus  is  the  cancer  parasite.  The  identity  of 
yeasts,  dead  or  alive,  with  Russell's  bodies  has  been  subjected  to  careful 
criticism  by  many  observers,  especially  by  Sternberg  and  Nichols,  who  con- 
clude that  there  is  no  adequate  proof  that  blastomyces  produce  any  consider- 
able proportion  of  the  fuchsin  bodies. 

Otto  Schmidt  claims  to  have  isolated  from  human  carcinoma  and  sarcoma 
an  organism  which  he  calls  Mucor  racemosus  and  which  he  believes  falls  in 


118  NEOPLASTIC  DISEASES 

the  class  of  mycetozoa.  With  this  organism  he  has  produced  10  sarcomas 
in  rats  and  mice,  some  of  which  he  has  transplanted  through  several  genera- 
tions, the  tumor  strain  finally  reaching  100  per  cent,  of  successful  implanta- 
tions. He  is  able  to  immunize  rats  against  the  organism  and  against  its  tumor- 
producing  properties,  and  rats  with  tumors  he  is  able  to  cure  by  inoculation 
with  killed  cultures  of  the  mucor.  Six  out  of  19  cancer  cases  at  the  Heidel- 
berg Institute  gave  what  he  regards  as  anaphylactic  reactions  against  the 
mucor.  Baisch  has  succeeded  in  verifying  some  of  Schmidt's  results.  On 
investigation  it  does  not  appear  how  often  Schmidt  secures  cultures  from 
human  tumors  nor  with  what  precautions  the  successful  cultures  were  obtained. 
The  mucor  cannot  be  identified  in  sections  of  the  tumors.  Some  of  the  grow- 
ing forms  of  the  parasite  Schuberg  regards  as  fat  droplets.  From  the  experi- 
mental tumors  the  parasite  is  not  recoverable.  Ten  tumors  were  produced, 
but  hundreds  of  animals  were  used  and  it  does  not  appear  that  the  propor- 
tion of  successful  results  greatly  exceeds  that  of  spontaneous  tumors  in  rats 
subjected  to  other  traumatic  influences.  The  cure  of  the  rat  tumors  is  accom- 
plished after  very  severe  intoxication  by  the  injected  cultures  and  the  death 
of  many  animals.  Schmidt  claims  to  have  cured  human  cancer  by  his  toxins, 
but  others  have  not  succeeded.  There  seem  to  be  no  grounds  for  accepting 
the  conclusion  that  human  patients  show  anaphylaxis  to  the  cultures  of  mucor. 
In  fact,  Schmidt  has  not  adduced  satisfactory  evidence  that  Mucor  racemosus 
has  anything  to  do  with  human  cancer.  What  he  seems  to  have  accomplished 
is  to  add  to  the  list  of  toxic  agents  that  are  known  to  excite  hyperplastic  in- 
flammation which,  especially  in  rats,  may  exhibit  metaplastic  changes  and 
possibly  pass  over  into  tumors.  He  has  not  apparently  controlled  his  work 
by  equally  energetic  efforts  to  produce  similar  changes  by  other  agents.  Yet 
his  observations  seem  to  fall  in  line  with  those  of  other  observers  who  by 
various  means  succeeded  in  causing  notable  hyperplasia  and  metaplasia  of 
animal  tissues,  as  Fischer  with  Sudan  III,  Jores  with  Scharlach  R  in  paraffin, 
Stohr  and  Stoeber  with  naphthalamin,  paratoluidin,  and  amidoazotoluol, 
and  Stoeber  and  Wacker  with  indol  and  skatol.  With  the  expressed  juice 
or  the  nucleoproteids  of  yeasts  Gaelotti  and  Pentimalli  have  also  produced 
a  considerable  variety  of  tumor-like  hyperplasia  in  dogs  and  rats,  but  they 
hesitate  to  assume  that  these  processes  are  identical  with  progressive  neo- 
plasms. It  is  even  more  doubtful  if  the  agents  they  used  actually  occur  in 
spontaneous  tumors. 

The  Experimental  Study  of  Tumors. — The  inoculability  of  carcinoma 
was  once  supposed  to  demonstrate  its  parasitic  nature.  Long  after  Peyrilhe's 
failure  several  experimenters  claimed  to  have  succeeded  in  transferring  cancer 
to  lower  animals  by  intravenous  inoculations  of  fresh  emulsions  (Langen- 
beck,  Follin,  Velpeau).  These  results  were  later  met  with  many  more  nega- 
tive reports  by  Virchow,  Weigert,  and  Billroth.  The  more  recent  claims  of 
successful  implantations  of  human  cancer  into  lower  animals  by  Boinet,  1894 
(epithelioma  into  dogs);  Juergens,  1896  (melanoma  into  rabbits);  Dagonet, 
1904  (epithelioma  into  a  rat);  and  Werner,  1907  (carcinoma  into  a  dog),  leave 
open  the  question  how  far  human  cancer  may  survive  in  these  animals.  Ex- 
tensive melanosis  of  the  organs  as  well  as  local  tumors  followed  the  inocula- 
tions of  human  melanoma  by  Goujon,  Lang  and  Bosc,  and  Vedel,  while  Pfeiffer 
thought  he  was  able  to  carry  his  melanoma  into  one  of  a  second  series  of  mice. 
Yet  Fischer  repeatedly  failed  to  transfer  melanoma  to  rats  and  Roux  and 
Metchnikoff  were  unsuccessful  with  the  chimpanzee.  In  none  of  the  suc- 
cessful cases  does  it  appear  that  the  resulting  process  was  anything  more 
than  a  local  or  general  reaction  to  the  cells  and  pigment  introduced.  While 
it  is  possible  that  the  reactions  observed  in  some  of  these  animals  must  be 


THE  PARASITIC  THEORY  119 

classed  with  the  tumor-like  processes  produced  by  chemical  agents  acting 
upon  tissue  cells  there  is  no  proof  that  the  injected  human  cells  multiplied 
during  the  considerable  periods  over  which  the  animals  were  observed. 

Firket,  Boinet,  Gaylord,  Lewin,  Bosc  and  Vedel,  and  others  claim  to  have 
produced  cancerous  nodules  by  inoculation  into  animals  of  various  human 
cancers.  While  it  is  impossible  to  detect  definite  fallacies  in  all  of  these  cases, 
especially  in  that  of  Dagonet,  there  are  many  difficulties  in  the  way  of  their 
acceptance.  A  much  greater  number  of  negative  results  are  recorded  by 
many  observers,  as  Shattuck  and  Ballance,  Fischel,  Sticker,  Hemmeter, 
and  many  others.  Herzog  found  that  the  nodules  first  forming  invariably 
disappeared  if  the  animal  survived  long  enough,  and  this  has  been  the  common 
experience  of  many  pathologists  working  in  this  field.  The  experience  of  the 
last  decade  with  transplantable  tumors,  showing  how  narrowly  balanced  is 
the  nutrition  of  tumor-cells,  renders  it  extremely  unlikely  that  human  tumor- 
cells  can  proliferate  extensively  in  distantly  related  animals.  The  frequency 
with  which  spontaneous  tumors  occur  in  laboratory  animals  has  been  greatly 
underestimated  by  most  observers,  but  has  been  clearly  pointed  out  by  Tyzzer. 

The  apparent  impossibility  of  inoculating  tumors  from  one  lower  animal 
to  another  of  the  same  species  long  stood  as  evidence  against  their  parasitic 
nature.  Since  the  transfer  of  tumors  among  lower  animals  has  become  ex- 
tensively practised  it  has  become  evident  that  this  inoculability  does  not 
favor  the  parasitic  theory,  but  rather  stands  strongly  against  it,  since  it  has 
been  shown  that  the  tumor-cells  are  transplanted  and  no  evidence  of  a  para- 
sitic agent  has  been  obtained.  It  is,  of  course,  conceivable  that  a  parasite 
is  transferred  with  the  cells  and  maintains  their  tendency  to  growth,  but  no 
evidence  of  such  a  parasite  has  thus  far  been  secured,  and  there  is  no  indica- 
tion of  the  existence  of  any  such  form  of  parasitism  anywhere  in  the  animal 
or  vegetable  kingdom  (Lubarsch). 

Therefore  the  results  of  the  study  of  transplantable  tumors  are  every- 
where regarded  as  a  new  and  serious  obstacle  in  the  way  of  the  parasitic  theory. 

The  development  of  epithelioma  following  x-ray  burns  is  a  phenomenon 
which  upon  analysis  seems  to  prove  that  this  tumor  develops  entirely  apart 
from  any  parasite  and  arises  through  slow  disturbance  of  the  nutrition  and 
mechanical  relations  of  the  epithelial  cells. 

Clunet  has  succeeded  in  producing  a  malignant  sarcoma  in  a  rat  by  re- 
peated exposures  to  x-ray  and,  in  a  case  reported  by  Senger,  round-cell  sarcoma 
seems  to  have  developed  after  a  lupus  cancer  treated  with  x-rays. 

Chemical  agents  of  great  variety  have  been  employed  by  many  observers 
to  produce  tumors  and  not  without  a  certain  success. 

Emanating  from  a  different  point  of  view,  but  falling  in  the  same  general 
class,  are  the  results  of  San  Felice,  Schmidt  and  Galeotti,  and  Pentemalli, 
previously  mentioned,  who  by  means  of  extracts  of  yeasts  seem  to  have  suc- 
ceeded in  rare  instances  in  producing  genuine  malignant  tumors  in  lower 
animals.  Since  the  great  majority  of  such  attempts  are  failures,  the  occa- 
sional success  may  be  accepted  without  in  any  way  involving  the  conclusion 
that  such  agents  are  commonly  at  work  in  producing  spontaneous  tumors  in 
man  or  animals.  They  seem  merely  to  illustrate  the  indirect  action  of  irritants 
on  predisposed  tissues,  which  is  a  principle  of  tumor  genesis  long  since  estab- 
lished by  clinical  and  pathological  studies  in  man. 

Likewise  the  striking  observations  of  Rous  that  filtered  extracts  of  a 
transplanted  and  very  virulent  sarcoma  of  chickens  causes  the  growth  of  the 
tumor  in  a  considerable  proportion  of  cases,  is  probably  to  be  classed  as  an 
instance  of  chemical  stimulation  of  cells. 

This  observation  has  the  additional  interest  that  the  chemical  deriva- 


120  NEOPLASTIC  DISEASES 

tives  of  this  tumor  possess  an  unusual  capacity  to  excite  the  neoplastic  hyper- 
plasia  and  recalls  the  well-known  observations  frequently  made  in  man, 
that  normal  cells  are  drawn  into  the  tumor  process  by  the  gradual  diffusion 
of  some  influence  from  the  tumor-cells.  As  an  alternate  hypothesis  one  may 
assume  that  an  invisible  microoorganism  passed  through  the  filter,  but  here 
again  the  evidence  of  the  existence  of  such  a  parasite  is  defective. 

There  are  several  other  observations  that  chemical  agents  arising  in  the 
course  of  tumor  growth  possess  a  notable  capacity  to  excite  tumor-like  growths 
of  tissue  cells,  and  it  seems  probable  that  in  some  instances  genuine  neoplasms 
have  been  produced  by  such  agents. 

By  repeated  subcutaneous  injections  of  extracts  of  human  cancer  filtered 
through  porcelain  Mayet  claims  to  have  produced  cancerous  lesions  in  white 
rats,  and  Francotte  and  DeRechter  report  similar  results  with  cancer  juice 
in  white  mice.  Hemmeter  by  local  injections  of  filtered  extract  of  cancer 
of  the  stomach  from  the  dog  has  produced  cancerous-like  proliferation  in  the 
walls  of  experimental  gastric  ulcers  in  the  dog. 

Theoretical  Objections  to  the  Parasitic  Theory.— It  is  often  assumed  that 
the  establishment  of  a  parasitic  cause  of  cancer  is  surrounded  by  no  more 
difficulties  than  those  which  beset  the  search  for  the  causes  of  syphilis  or 
other  infectious  diseases.  It  should  be  pointed  out,  however,  that  there  are 
many  theoretical  objections  which  would  render  unusually  difficult  the  estab- 
lishment of  any  cancer  parasite  even  though  supported  by  strong  objective 
data. 

The  known  infectious  diseases  display  features  of  incidence,  course,  and 
anatomical  character  which  sharply  separate  them  from  malignant  tumors. 
The  study  of  the  age  and  sex  incidence  of  cancer  presents  a  body  of  data 
which  reveals  a  fundamental  difference  in  the  etiology  of  cancer  and  all  known 
infectious  diseases.  The  distribution  of  cancer  is  as  wide-spread  as  inflam- 
mation in  general,  indicating  that  blastomatosis  is  not  a  subdepartment  of 
the  reaction  of  tissues  to  injury,  but  a  distinct  and  separate  phenomenon 
in  the  life  of  the  cell.  Over  against  degeneration  and  inflammation  stand 
regeneration  and  neoplasia.  The  anatomical  and  physiological  characters 
of  malignant  tumors  differ  essentially  from  those  of  known  infectious  proc- 
esses. The  isolation  of  the  cells  of  origin  of  tumors  is  wholly  different  from 
anything  recognized  in  parasitic  diseases.  The  abnormal  size  of  nucleus 
and  cell  body  revealing  overnutrition  is  contrary  to  the  rule  in  infectious 
processes.  The  types  and  degrees  of  metaplasia  observed  in  tumors  find  no 
parallels  in  inflammation.  The  progressive  growth  of  malignant  tumors 
reaches  a  degree  which  constitutes  it  a  different  pathological  entity  from  the 
regenerative  process  in  the  healing  of  wounds  and  the  reaction  to  irritants. 
Parasitic  diseases  cause  regressive  processes  in  the  infected  tissues  and  general 
deterioration  of  the  system  by  toxic  agents,  but  tumors  exert  no  deleterious 
action  on  the  system  or  on  the  organ  involved  or  even  on  the  cells  affected 
except  through  secondary  agencies.  The  metastases  of  tumors  reveal  con- 
ditions wholly  different  from  any  phenomena  observed  with  infectious  diseases. 
There  is  no  more  impressive  illustration  of  the  difference  between  tumors 
and  infectious  granulomas,  which  they  most  nearly  resemble,  than  the  com- 
parison of  the  fate  of  tumor-cell  emboli  and  of  emboli  from  a  tuberculous 
focus.  In  the  former  case  the  tumor-cells  grow  where  they  lodge,  receiving 
only  nutriment  from  the  blood  of  the  part  >  in  the  latter  case  the  embolic 
cells  die  and  the  transported  bacilli  excite  an  inflammatory  process  in  the 
adjacent  tissues.  Similarly,  transplantable  tumors  survive  in  the  progeny  of 
the  transferred  cells. 

It  is  conceivable  that  an  invisible  parasite  lives  with  the  tumor-cell 


THE  PARASITIC  THEORY  121 

stimulating  its  growth  and  nutrition,  but  there  is  no  evidence  of  any  such  form 
of  parasitism  anywhere  in  the  animal  kingdom.  Parasites  occur  in  mitotic 
cells,  especially  in  club  root,  but  this  process  is  not  a  tumor  (Tubeuf).  Where 
parasitism  is  known  it  is  at  the  expense,  usually,  of  the  life  of  the  cells,  while 
degenerative  processes  in  tumors  are  secondary. 

Weigert  and  Roux  assume  that  the  growth  capacities  of  the  cells  are 
determined  in  the  ovum  and  can  never  be  increased  except  by  fertilization, 
and  Ribbert  concludes  that  a  tumor-producing  parasite  is  therefore  incon- 
ceivable. Yet  it  must  be  admitted  that  the  growth  of  cells  is  greatly  influ- 
enced by  the  environment  and  that  peculiar  external  irritants  of  parasitic 
origin  may  greatly  stimulate  the  nutrition  and  growth  of  cells.  It  has  also 
been  assumed  that  tumors  result  from  release  of  the  restraints  of  growth, 
but  our  knowledge  of  the  nature  of  growth  restraints  seems  hardly  sufficient 
to  warrant  the  conclusion  that  parasites  may  not  be  concerned  in  abolishing 
these  restraints.  Biology  cannot  argue  'the  cancer  parasite  out  of  existence, 
but  it  can  demand  objective  data  in  its  support. 

The  general  facts  of  the  genesis  of  tumors  are  strongly  against  the  possi- 
bility of  a  parasitic  origin. 

Tumors  arise  in  some  instances  from  a  single  cell  (teratoma  testis),  in 
most  cases  from  a  narrowly  circumscribed  group  of  cells,  and  grow  chiefly 
or  exclusively  from  their  own  resources.  The  gradual  inclusion  of  neigh- 
boring cells  in  the  process  is  as  well  explained  by  the  diffusion  of  chemical  or 
other  influences  as  by  the  transfer  of  a  parasite,  while  there  is  much  evidence 
directly  in  favor  of  the  former  hypothesis.  The  embryonic  nature  and  isola- 
tion of  the  cells  of  origin  of  a  large  proportion  of  tumors,  as  embodied  in  Cohn- 
heim's  theory,  are  incompatible  with  a  parasitic  origin  of  such  tumors,  and 
yet  they  possess  all  the  qualities  of  malignant  neoplasms  which  are  not  known 
to  be  derived  from  embryonic  cells.  The  occurrence  of  highly  malignant 
congenital  tumors  in  several  members  of  the  same  family,  as  glioma  of  retina, 
reveals  an  embryogenic  and  hereditary  disturbance  as  the  essential  factor. 
Clinical  experience  strongly  impresses  the  importance  of  chemical  and 
mechanical  irritants  and  various  disturbances  of  nutrition  as  the  exciting 
causes  of  tumors.  Here  stand  the  numerous  list  of  occupational  cancers, 
from  paraffin,  anilin,  chimney-soot,  the  predisposing  influence  of  arsenic 
(Dubreuilh,  Hutchinson)  and  tobacco,  x-ray  cancers,  the  influence  of  chronic 
mechanical  irritation,  and  severe  trauma.  Likewise  clinical  observation  and 
anatomical  study  reveal  the  fact  that  cancers  which  are  not  of  embryogenic 
origin  do  not  arise  except  after  long  continuous  previous  change  in  the  tissue. 
These  changes  do  not  favor  the  establishment  of  any  known  form  of  parasit- 
ism, but  rather  suggest  disturbances  in  the  nutrition  and  function  of  the  cells. 
Thus  Billroth  expressed  the  conviction  that  without  previous  changes  in 
the  originating  tissue  cancer  does  not  exist,  and  his  report  of  an  epithelioma 
arising  after  many  years  over  most  of  the  area  of  an  extensive  scar  from  a 
burn,  well  illustrates  the  basis  for  his  belief. 

Few  writers  have  ventured  to  suggest  that  benign  tumors  can  be  of  para- 
sitic origin,  and  yet  occasionally  tumors  which  are  otherwise  indistinguish- 
able from  benign  growths,  as  adenoma  of  the  thyroid  and  leiomyoma,  may 
exhibit  all  the  characters  of  malignancy. 

The  developmental  history  of  many  tumors  exhibits  the  natural  unfolding 
of  embryonic  potencies.  However  extensive  may  be  the  scope  of  metaplasia 
in  tumors,  it  cannot  cover  the  facts  observed  in  the  field  of  malignant  tera- 
tomas.  The  teratomas  arising  from  sex  cells  yield  many  pure  forms  of  benign 
and  malignant  tumors,  on  the  one  hand,  and  highly  complex  structures  ap- 
proaching a  parasitic  fetus.  The  metastatic  cells  from  such  tumors  again 


122  NEOPLASTIC  DISEASES 

go  on  to  develop  specific  structures  in  lymph-nodes  and  distant  organs.  Thus 
in  a  metastasis  of  an  ovarian  teratoma  Lubarsch  observed  brain  tissue  and 
ependyma  in  orderly  arrangement.  Metastases  of  many  tumors  are  distinctly 
organoid  in  character,  maintaining  polarity  in  arrangement  and  functionating 
as  organs.  If  the  above  phenomena  are  of  parasitic  origin  then,  as  Wilms 
points  out,  the  whole  history  of  embryonic  development  must  be  conceived 
as  within  the  scope  of  parasitism.  Hopeless  dilemmas  arise  when  one  attempts 
to  conceive  of  the  necessary  properties  of  the  cancer  parasite.  It  must  pick 
out  minute  aberrant  groups  of  embryonic  cells  in  protected  situations  even 
in  the  fetus  of  a  healthy  mother.  Misplaced  and  embryonal  tissue  invaded 
by  metastases  escapes  infection  by  the  parasite.  Shaffer  and  Lubarsch  have 
described  misplaced  islands  of  gastric  mucosa  in  the  esophagus  invaded  by 
epithelioma  of  the  esophagus,  but  showing  no  hyperplasia.  Berent  observed 
a  misplaced  adrenal  rest  in  the  kidney  unaffected  by  a  metastatic  nodule 
from  epithelioma  of  the  jaw.  With  the  most  actively  growing  metastases 
adult  normal  tissues  are  not  infected,  but  as  a  rule  behave  passively.  In 
chorioma  the  parasite  invades  the  fetal  but  spares  maternal  tissues.  In  the 
metastases  of  melanoma  the  parasite  produces  extremely  rapid  proliferation 
of  cells  in  one  case,  or  it  remains  dormant  for  many  years. 

Contrary  to  all  known  forms  of  parasitism  the  cancer  parasite  stimulates 
growth  and  nutrition  of  cells  and  renders  them  viable  after  transplantation 
in  the  same  or  other  animals.  It  stimulates  the  absorption  of  nitrogen  by 
the  host  (Cramer)  and  fails,  except  through  secondary  influences,  to  exert 
any  toxic  or  deleterious  action  on  the  body. 

In  view  of  the  considerations  thus  briefly  reviewed  it  is  impossible  to 
regard  as  a  valid  hypothesis  the  conception  of  a  specific  group  of  parasites 
living  in  symbiosis  with  the  cancer-cell  and  stimulating  its  growth  and  nutri- 
tion. All  the  facts  are  reasonably  explained  by  regarding  the  cancer  parasite 
as  the  cancer-cell.  The  temporary  popularity  of  the  search  for  a  specific 
parasite  must  be  attributed  to  the  undue  influence  of  the  germ  theory  of 
disease  which  can  be  effectually  combated  only  by  further  knowledge  of  the 
biology  of  the  cell. 

The  Scope  of  the  Relation  of  Parasites  to  Cancer. — Although  the  concep- 
tion of  a  specific  cancer  parasite  living  in  symbiosis  with  the  cell  and  stimu- 
lating its  growth  is  without  definite  foundation  and  is  incompatible  with  the 
nature  of  many  tumors,  there  remains  a  certain  field  for  parasites  as  etiolog- 
ical  factors  in  tumors. 

In  the  familiar  coccidiosis  of  the  rabbit's  liver  parasitic  ova  excite  a  tumor- 
like  proliferation  of  the  bile-ducts.  The  process  is  strictly  dependent  upon 
the  presence  of  the  ova  and  regresses  when  these  are  removed,  and  hence 
it  is  not  a  true  tumor,  but  it  has  some  of  the  qualities  of  a  neoplasm  and  these 
are  dependent  on  a  parasitic  irritant. 

In  Bilharzia  infection  cancer  of  the  bladder  follows  in  a  certain  propor- 
tion of  cases.  Here  the  disease  is  true  cancer,  it  is  less  intimately  connected 
with  the  presence  of  the  parasite,  but  it  is  nevertheless  rather  obviously  a 
sequel  of  the  infection  and  reveals  a  peculiar  capacity  of  this  form  of  irritation 
to  produce  cancer. 

Lowenstein  has  described  papilloma  of  the  bladder  in  rats  infested  with 
Trichodes.  Primary  carcinoma  of  the  liver  in  cows  suffering  from  Distomia- 
sis  has  been  referred  to  the  irritation  of  this  parasite  (Haaland).  In  a  pap- 
illomatous  gastric  tumor  of  pigeons  Wasielewski  has  found  a  species  of  Dis- 
pharagus.  Brumpt  describes  an  adenoma  of  the  stomach  in  monkeys  as 
referable  to  infection  by  Physaloptera.  Febiger  has  fully  demonstrated 
the  relation  of  Spiroptera  to  a  gastric  carcinoma  in  rats.  Askanazy  attributes 


THE  PARASITIC  THEORY  123 

to  a  trematode,  Apistorchis  felineus,  an  etiological  relation  to  certain  hepatic 
carcinomas  in  man,  and  similar  relations  have  been  claimed  for  Distomum 
spatulatum  and  Japonicum  by  Katsurada  and  others. 

Many  observers  have  considered  the  possible  relation  of  trichinosis  to 
carcinoma,  and  several  have  stated  that  carcinoma  is  peculiarly  frequent  in 
chronic  trichinosis  (Langenbeck,  Babes).  I  rather  frequently  find  trichinae  in 
cancerous  tongues. 

Borrel  has  observed  several  cases  of  sarcoma  and  adenocarcinoma  of  the 
rat  in  which  a  nematode  worm  was  found  in  the  center  of  the  tumor.  Regaud 
and  Saul  have  reported  similar  cases  and  Bridre  found  several  sarcomas  in 
rats  growing  about  cysticerci.  Borrel  finds  acari  in  the  early  spontaneous 
lesions  of  the  lymphosarcoma  of  dogs.  In  12  early  epitheliomas  of  the  face  in 
man  he  found  numerous  acari  inclosed  in  the  tumor-cell  nests.  In  the  nipple 
of  certain  cases  of  Paget's  disease  and  cancer  of  the  breast  he  finds  acari  or 
another  animal  parasite,  Demodex  folliculorum.  Borrel  admits  that  these 
same  parasites  occur  not  infrequently  in  the  healthy  skin  or  nipple  where  they 
usually  produce  hypertrophy  of  the  sebaceous  glands.  These  ectoparasites 
he  regards  merely  as  the  carriers  of  the  true  cancer  virus. 

Saul  has  also  drawn  attention  to  the  occurrence  of  worms  in  mouse  tumors, 
and  in  two  human  ovarian  tumors  he  found  a  parasitic  mite,  Tarsonemus. 
It  has  been  suggested  that  the  Tarsonemus  gained  access  to  the  material 
after  its  removal  from  the  body. 

All  of  these  observations  indicate  that  animal  parasites  or  their  deriva- 
tives have  a  peculiar  capacity  to  excite  hyperplasia  in  the  tissues  they  infect. 
Yet  it  has  not  been  proved  that  they  are  present  in  any  but  superficial  tumors, 
or  that  their  presence  signifies  anything  more  than  a  secondary  invasion. 
Nor  is  it  known  that  the  tumor-like  processes  in  which  they  are  usually  found 
have  any  other  significance  than  the  hyperplasia  excited  by  sudan  III,  which 
regresses  upon  the  removal  of  the  irritant.  In  lower  animals  especially 
animal  parasites  of  the  skin  are  very  common,  while  cutaneous  tumors  are 
rare. 

Certain  manifestations  of  syphilis  have  a  close  though  indirect  relation 
to  tumors.  The  lingual  cancer  following  leukoplakia  may  be  regarded  as 
the  result  of  the  disturbed  nutrition  and  relations  of  the  epithelial  cells  long 
established  in  the  disease,  and  yet  the  frequency  of  this  form  of  cancer  re- 
veals a  certain  unusual  capacity  of  syphilis  to  excite  neoplastic  growth.  Like- 
wise the  syphilitic  sarcoma  described  by  Hansemann  shows  this  same  peculiar 
influence  exerted  on  mesoblastic  cells,  the  full  scope  of  which  is  possibly  not 
yet  recognized. 

Tuberculosis  in  several  of  its  phases  has  an  indirect  relation  to  certain 
tumors.  In  a  small  proportion  of  cases  of  lupus  epithelioma  develops  through 
long  disturbance  of  the  nutrition  and  relation  of  the  epithelial  cells  of  the 
affected  area.  That  there  is  something  specific  in  the  tuberculous  process 
is  suggested  by  the  greater  frequency  of  epithelioma  after  lupus  than  with 
simple  chronic  eczema. 

In  some  forms  of  tuberculous  lymphadenitis  tumors  of  endothelial  cells 
develop  under  conditions  strongly  suggesting  that  the  neoplasm  is  a  sequel 
of  the  tuberculous  infection.  Tuberculosis  may  cause  a  wide-spread  hyper- 
plasia of  the  lymphatic  tissues  of  the  body  with  miliary  lymphomas  in  many 
organs.  The  frequent  association  of  lymphatic  leukemia  with  tuberculosis 
has  suggested  to  many  that  this  disease,  which  has  several  characters  of  a 
neoplasm,  may  be  dependent  on  tuberculous  infection  or  intoxication.  Hodg- 
kin's  granuloma,  which  is  either  tuberculous  or  caused  by  a  related  organism, 
has  been  shown  in  several  cases  to  pass  over  into  a  sarcomatous  process. 


124  NEOPLASTIC  DISEASES 

Hence  the  sequels  of  both  syphilis  and  tuberculosis  have  a  definite  rela- 
tion to  tumors,  which  reveals  the  microorganisms  as  indirect  cancer  parasites. 
In  both  cases  the  resulting  tumor  process  seems  not  to  be  dependent  on  the 
presence  of  the  parasite,  but  to  arise  from  the  natural  momentum  of  the  dis- 
turbance originally  excited  by  the  parasite. 

In  the  lower  animals,  especially  in  rats,  the  momentum  of  inflammatory 
processes  which  may  lead  to  tumor  growth  seems  distinctly  less  dependent 
on  the  presence  of  the  parasites  than  in  man. 

In  plants  the  observations  on  crown-gall,  especially  those  of  Smith,  point 
to  the  conclusion  that  in  the  vegetable  kingdom  progressive  hyperplasias 
originally  excited  by  parasites  may  be  still  less  dependent  upon  their  con- 


FIG.  ii. — Growth  resulting  in  31  days  from  inoculation  in  sugar  beet  of  Bacillus  tume- 
faciens  obtained  from  poplar  gall.     (After  Smith.) 

tinued  presence  than  in  animals.  Levin  and  Levine  find  that  the  initial 
process  excited  by  Bacillus  tumefaciens  in  crown-gall  is  inflammatory,  while 
the  transformation  of  this  inflammatory  reaction  into  a  malignant  tumor- 
like  process  is  due  to  some  mechanism  within  the  host,  independent  of  the 
microorganisms . 

All  these  considerations  encourage  the  search  for  new  microorganisms 
which  may  have  a  special  capacity  to  excite  inflammatory  processes  which 
tend  to  go  on  to  tumor  growth,  but  they  offer  no  support  to  the  theory  of  a 
specific  cancer  parasite  living  in  symbiosis  with  the  cancer-cell  and  constantly 
stimulating  its  growth. 

The  results  in  this  field  show  that  parasites  may  be  concerned  only  with 


125 

the  inception  of  certain  tumors,  but  that  their  influence  cannot  explain  the 
continued  autonomous  growth  of  malignant  neoplasms,  wherein  lies  the  real 
mystery  of  the  cancer  process. 

The  study  of  the  parasitic  relations  of  cancer  suggests  the  following  classi- 
fication of  tumors  with  regard  to  their  possible  connection  with  a  parasitic 
origin : 

i.  Tumors  of  embryonal  origin  and  their  derivatives  to  which  Conheim's 
theory  applies,  and  to  which  parasites  have  no  relation  whatever. 


FIG.    12. — Centers  of  cell  proliferation  in  daisy  stem  inoculated   with  Bacillus  tume- 

faciens.     (After  Smith.) 

2.  Malignant  tumors  of  exposed  surfaces  or  internal  organs  with  which 
parasites  may  figure  as  occasional  indirect  or  direct  exciting  causes. 

3.  Sarcomas,  especially  those  of  lymphoid  type,  which  are  known  to  be 
the  sequel  of  infectious  diseases  or  on  account  of  their  imperfect  neoplastic 
qualities  may  probably  be  regarded  as  more  or  less  dependent  upon  the  presence 
of  parasites. 

4.  Tumors  of  lower  animals  in  which  the  momentum  of  a  parasitic  process 
tends,  more  than  in  man,  to  assume  autonomous  qualities. 


CHAPTER  IX 
EXPERIMENTAL  CANCER  RESEARCH 

EXPERIMENTAL  PRODUCTION  OF  TUMORS 

Among  the  various  fields  of  the  experimental  study  of  cancer  the  oldest 
and  probably  the  least  fruitful  is  the  attempted  experimental  production 
of  tumors.  Today  it  may  be  said  that  no  one  has  succeeded  in  producing 
cancer  under  conditions  that  are  strictly  experimental,  although  cancer  and 
sarcoma  have  been  observed  to  follow  #-ray  inflammation  in  man  and  ani- 
mals, and  Febiger  has  observed  the  development  of  cancer  on  chronic  gastritis 
produced  by  feeding  rats  with  cockroaches  infested  by  a  nematode  worm. 
Febiger's  work  may  probably  be  accepted  as  presenting  the  controllable 
conditions  of  an  experiment,  but  the  proportion  of  cancers  produced  was 
small. 

Efforts  to  produce  tumors  have  passed  through  several  phases  suggested 
by  theoretical  views  of  the  nature  of  tumors. 

i.  Transplantation  of  adult  tissues  or  cells  was  early  found  by  Zahn  and 
Leopold  to  result  in  eventual  and  usually  prompt  absorption.  Squamous 
epithelium  from  the  combs  of  fowls  Kaufmann  found  to  persist  for  an  un- 
usual period,  producing  small  cysts,  and  thus  duplicating  the  observed  mode 
of  origin  of  traumatic  epidermoids. 

Lengemann  followed  the  fate  of  misplaced  cells  of  liver,  kidney,  and  car- 
tilage. He  failed  to  observe  any  features  of  tumor  growth,  and  concluded 
that  misplacement  alone,  hyperemia,  or  partial  degeneration  of  the  cell  mass 
were  insufficient  to  excite  tumor  growth,  while  the  weakened  state  of  the 
animal  had  no  influence  on  the  fate  of  the  cells.  In  his  hands  salivary  gland 
and  thyroid  tissue  exhibited  the  greatest  proliferation. 

Stilling  chose  the  spleen  as  the  most  suitable  soil  and  after  transplanting 
fragments  of  uterine  muscle  and  mucosa  in  rabbits  found  in  some  cases  a 
growth  of  muscle-cells  far  exceeding  their  normal  limits  and  resembling  fibro- 
myoma,  and  in  other  cases  he  observed  the  development  of  large  cysts  lined 
by  proliferating  epithelium. 

Nichols  in  an  extensive  series  of  tests  found  definite  proliferative  powers 
of  adult  transplanted  cells  only  in  epidermis,  uterine  epithelium,  cartilage, 
and  placenta.  I.  Levin  used  cells  from  healing  wounds  without  result.  Pass- 
ing interest  was  excited  by  Lack's  report  that  multiple  carcinoma  developed 
in  a  rabbit's  abdomen  14  months  after  scraping  and  leaving  loose  germinal 
epithelium  from  the  ovary.  Yet  spontaneous  carcinomas  arise  in  this  region 
in  the  rabbit  (Boycott),  and  Fraenkel  failed  in  several  attempts  to  duplicate 
Lack's  results. 

Lubarsch  appears  to  have  encountered  a  similar  coincidence  in  finding 
a  large  renal  adenocarcinoma  in  the  kidney  of  a  rabbit  into  whose  kidney 
he  had  some  months  previously  transplanted  a  fragment  of  salivary  gland. 

Ribbert  implanted  portions  of  many  organs  in  the  peritoneum,  skin, 
anterior  chamber  of  eye,  and  lymph-nodes,  always  with  eventual  atrophy. 
He  concluded  that  fully  organized  tissue  masses  might  become  implanted  in 
these  new  positions  and  go  on  to  functionate.  The  transplantation  of  whole 
organs,  or  large  portions  of  ovary,  thyroid,  testis,  mamma  has  been  accom- 

126 


EXPERIMENTAL  CANCER  RESEARCH  127 

plished  by  many  observers.  The  transplanted  thyroid  may  relieve  myxe- 
dema  (Eiselsberg) ;  the  transplanted  ovary  is  said  to  have  led  to  pregnancy 
(Krauer);  the  testis  atrophies  without  necrosis;  and  transplanted  mammary 
tissue  has  secreted  milk  in  gestation  (Ribbert). 

2.  Transplantation  of  embryonal  tissues  has  been  pursued  to  a  formidable 
extent  with  the  general  result  of  showing  that  embryonal  tissues  exhibit  much 
greater  proliferative  capacity  than  adult,  but  still  lack  an  essential  factor 
in  tumor  growth.  Loeb,  however,  found  certain  adult  tissues  to  grow  better 
than  the  embryonal. 

Leopold  concluded  that  the  younger  the  embryo,  the  better  was  the  growth, 
while  Tisenhausen  specified  5  days  as  the  optimum  age  of  chick  embryos. 
Zahn  correlated  the  growth  with  the  extent  of  vascularization  of  the  trans- 
plant. Cartilage  is  said  to  have  increased  twenty  times  in  bulk  in  Nichols' 
animals,  and  Leopold  thought  he  obtained  true  chondromas.  Intermittent 
heating  of  the  organ  seemed  to  increase  the  growth  in  the  rabbit's  liver  of 
fragments  of  periosteum  injected  by  Birch-Hirschfeld  and  Garten.  Preg- 
nancy was  found  to  create  a  more  favorable  soil  in  the  work  of  Askanazy 
and  Jentzer  in  rats,  but  Shattock  found  it  less  favorable  for  cartilage  growing 
in  rabbits,  while  Rous  found  the  most  favorable  period  in  mice  to  be  after 
delivery. 

Successive  transfers  of  transplanted  tissues  at  8-day  intervals  seemed 
to  increase  the  growth  in  Wilms'  experiments  with  chicks,  but  an  opposite 
result  is  recorded  by  Fichera.  In  most  circumstances  transplanted  embryo- 
nal cells  exhibit  a  certain  amount  of  differentiation  as  well  as  of  growth,  but 
in  the  direction  of  normal  tendencies  rather  than  toward  tumor  growth. 

Transplantation  of  complex  tissues  or  portions  of  embryos,  intact  or  com- 
minuted, usually  results  in  abortive  teratoid  growths.  Freund  secured  such 
growths  in  74  per  cent,  of  rats  inoculated  intraperitoneally  with  emulsified 
rat  embryos.  Such  emulsified  cells  grew  for  6  weeks  in  rabbits  (v.  Hippel), 
or  8  weeks  in  chicks  (v.  Tiesenhausen),  but  gradually  regressed  after  6  to  12 
months.  Fichera  estimated  the  growth  in  rats  at  twenty  times  the  original 
bulk,  but  saw  no  resemblance  to  true  tumors.  Cartilage  and  epiblastic  tissues 
are  usually  the  most  active. 

Rous  mixed  embryo  with  tumor-tissue,  finding  that  both  components 
grew  in  association,  but  the  tumor-cells  soon  outgrew  the  normal  cells,  or 
both  failed  together,  but  growing  tumor-cells  did  not  stimulate  growth  in 
the  others. 

Traina  implanted  whole  limbs  and  complex  masses  of  embryonal  tissue 
in  the  ovaries  of  guinea-pigs  and  secured  striking  degrees  of  proliferation, 
but  no  tumors. 

The  negative  results  of  this  extensive  department  of  experimental  re- 
search become  easily  explicable  when  one  compares  the  obvious  crudity  of 
the  experiments  with  the  minute  analysis  of  pathological  data  bearing  on  the 
conditions  under  which  misplaced  cells  are  observed  to  give  origin  to  tumors. 
Thus  among  essential  conditions  for  the  neoplastic  growth  of  misplaced  cells 
are  the  following:  (i)  The  cell  group  must  not  possess  the  intrinsic  growth 
restraints  of  an  organ.  Otherwise  it  will  grow  or  functionate  as  an  organ. 
Evidently  there  is  a  nice  adjustment  between  the  demands  for  function  and 
the  capacity  for  growth  in  misplaced  cell  groups  that  develop  tumors.  (2) 
The  misplaced  tissue  should  not  be  completely  divorced  from  its  normal 
environment,  but  only  partially  so.  Otherwise  it  will  fail  to  receive  sufficient 
blood-supply  for  active  growth.  (3)  A  considerable  period  is  usually  neces- 
sary for  the  misplaced  cells  to  adjust  themselves  to  the  abnormal  environ- 
ment. Exceptions  to  this  condition  appear  probably  in  some  traumatic 


128  NEOPLASTIC  DISEASES 

sarcomas.  (4)  An  unusual  source  of  hyperemia  is  usually  necessary  for  tumor 
growth,  for  this  factor  facilitates  nutrition,  and  lessens  restraints  to  growth. 
(5)  The  misplaced  cells  must  possess  some  special  capacity  for  growth  either 
by  virtue  of  an  embryonal  character  or  from  the  retention  of  proliferative 
tendencies  of  more  than  ordinary  degree.  Thus  tumors  do  not  arise  indiffer- 
ently from  all  portions  of  an  organ,  but  from  the  cells  of  ducts  or  from  the 
germ  centers  of  lymph-nodes.  (6)  The  experimental  studies  ignore  the  im- 
portance of  the  preliminary  changes  which  are  observed  to  precede  the  develop- 
ment of  tumors  from  normal  or  misplaced  cells.  These  precancerous  stages, 
the  "indifferent  vorstadium"  of  Ribbert,  are  not  provided  in  the  experimental 
transplantation  of  tissue  cells. 

Some  of  these  objections  have  been  met  in  the  efforts  to  alter  the  char- 
acter and  accelerate  the  growth  of  cells  before  transplantation.  G.  Lewin 
injected  emulsion  of  a  human  ovarian  carcinoma  into  the  peritoneum  of  a 
dog.  After  several  weeks  the  omentum  was  found  studded  with  miliary 
nodules  which  seemed  to  be  of  inflammatory  character.  Those  were  again 
emulsified  and  injected  and  the  process  repeated  through  5  series  of  dogs, 
the  resulting  nodules  presenting  eventually  a  structure  which  Lewin  regarded 
as  sarcomatous.  These  observations  have  not  yet  been  verified. 

In  somewhat  the  same  manner  Stieve  produced  granulomatous  inflam- 
mation about  injections  of  infusorial  earth,  transplanted  this  granulomatous 
tissue,  and  saw  more  and  more  atypical  proliferation  approaching  that  of 
sarcoma. 

Influence  of  Lipoid  Solvents  on  Epithelial  Proliferation. — A  series  of 
experimental  studies  undertaken  from  various  viewpoints  have  indicated 
that  cells  treated  or  influenced  by  lipoid  solvents  tend  to  exhibit  increased 
and  atypical  proliferation. 

Reinke,  noting  atypical  epithelial  growth  after  the  injection  of  4  per  cent, 
ether  into  the  eye  of  a  salamander,  transplanted  the  proliferating  epithe- 
lium into  the  peritoneum  of  other  salamanders,  where  it  continued  to  grow 
more  atypically  so  as  to  resemble  carcinoma.  Askanazy  mixed  emulsion 
of  rat  embryos  with  ether  before  inoculation  and  secured  larger  teratoid 
tumors  than  by  means  of  untreated  embryos,  but  Freund  could  not  duplicate 
these  results. 

B.  Fischer  introduced  an  interesting  field  of  study  by  inoculating  under 
pressure  a  saturated  solution  of  scharlach  R  in  olive  oil  under  the  skin  of 
rabbits'  ears.  The  basal  epithelium  of  skin  and  hair  follicles  after  a  few  days 
began  to  proliferate  and  continued  to  grow  downward  inclosing  oil  globules 
and  producing  a  picture  resembling  epidermoid  carcinoma,  but  the  growth 
ceased  when  the  oil  had  been  absorbed.  In  the  mammary  gland  of  rabbits 
a  saturated  ethereal  solution  of  the  dye  produced  a  squamous  epithelial 
growth  replacing  gland  lobules.  Since  no  such  effect  followed  injection  of 
simple  oils  and  fats  Fischer  assumed  that  the  dye  contained  a  specific  chemo- 
tactic  substance  (attraxin)  stimulating  epithelial  growth.  Many  experi- 
menters verified  these  observations,  offering  various  explanations  of  the 
result.  The  wide  variety  of  materials  used  in  this  connection  and  the  general 
results  obtained  have  been  conveniently  tabulated  by  Haga. 

Meyer  found  that  when  the  arteries  of  the  ear  were  ligated  olive  oil  alone 
produced  the  results,  which  he  was  inclined  to  refer  to  chronic  inflammation. 
Stoeber  and  Wacker  found  certain  components  of  scharlach  R  and  sudan 
III  equally  effective,  and  by  using  5  per  cent,  solutions  of  indol  or  skatol  in 
rabbit  fat  they  produced  very  active  growth  more  closely  resembling  epi- 
dermoid carcinoma.  White  produced  the  usual  changes  with  oleic  acid,  and 
Benthin  used  a  great  variety  of  materials,  finding  that  the  best  were  sudan 


EXPERIMENTAL  CANCER  RESEARCH 


129 


III  and  scharlach  R.    These  dyes  have  shown  a  variable  influence  upon  trans- 
plantable  tumors  of  animals. 

In  the  mammary  glands  of  rats  (I.  Levin,  White),  in  the  kidneys  of  rab- 
bits (Meyer),  and  in  the  prostate,  seminal  vesicles,  liver,  and  lung  of  rats 
(Bullock  and  Rohdenburg)  injections  of  scharlach  R  have  produced  con- 
siderable atypical  proliferation  of  inflammatory  character,  but  much  less 


FIG.  13. — Atypical  epithelial  proliferation  of  epithelium  caused  by  injection  of  scharlach 

R.     (Bullock,  Rohdenburg.) 

marked  than  in  the  skin  of  the  ear.  Yet  Haga  succeeded  in  producing 
markedly  atypical  but  self-limiting  proliferation  in  the  tongue,  stomach, 
breast,  and  liver  of  rabbits,  which  in  some  cases  was  difficult  to  distinguish 
from  malignant  growth. 

Reviewing  these  results,  in  general  it  appears  that  the  property  of  certain 
lipoid  solvents  to  excite  epithelial  proliferation  has  been  established,  but  no 
true  tumors  have  been  produced  (Wacker,  Schmincke,  Lit.). 


FIG.  14.— Adenomatous  growth  of  the  rabbit's  stomach,  produced  by  feeding  lanolin. 

(After  Haga.) 

That  the  lipoid  solvent  property  is  an  essential  factor  in  the  result,  al- 
though suggested  by  much  collateral  evidence,  appears  uncertain.  J.  Loeb 
concluded  that  it  was  the  lipoid  solvent  properties  of  the  substance  employed 
that  produced  artificial  parthenogenesis.  The  theory  of  solution  of  a  lipoid 
cell  membrane  has  been  pursued  by  Clowes  as  the  key  to  atypical  cell  pro- 
liferation. Bullock  and  Rohdenburg  reject  this  theory  on  the  ground  that 
9 


130 


NEOPLASTIC  DISEASES 


all  lipoid  solvents  do  not  act  as  does  scharlach  R.  They  secured  considerable 
effect  from  injections  of  pine  tar,  indigo,  and  calomel,  in  oil,  and  they  refer 
all  the  effects  to  cell  death  and  regeneration.  Nevertheless  it  is  clear  that 
certain  fat  stains  exceed  all  other  irritants  so  far  tested  in  their  ability  to 
excite  epithelial  proliferation.  That  they  possess  somewhat  specific  properties 
in  this  respect  is  also  indicated  by  their  effective  use  to  stimulate  epithelial 
growth  of  ulcerating  surfaces. 

In  later  experiments  Bullock  and  Rohdenberg  by  injections  of  scharlach 
R  and  by  various  mechanical  irritants  succeeded  in  producing  the  morpho- 
logical picture  of  carcinoma  in  the  stomach  and  other  tissues  of  rats.  Not 
observing  metastases,  and  finding  that  continued  growth  was  apparently 


FIG.  15. — Epithelial  proliferation  of  lining  cells  in  ligated  duct  of  salivary  gland.     (After 

Ribbert.) 

dependent  upon  continuous  irritation,  they  hesitate  to  accept  the  condition 
produced  as  equivalent  to  true  experimental  carcinoma. 

Recently  Yamagiwa  and  Ichikawa  have  succeeded  in  producing,  first, 
precancerous  changes  and  in  7  cases  complete  carcinomas,  2  with  metastases, 
by  applications  of  coal-tar  over  periods  of  55  to  360  days  in  rabbits'  ears. 

Reviewing  the  results  obtained  by  many  observers  with  scharlach  R  and 
coal-tar,  it  seems  to  the  writer  that  the  processes  excited  must  be  regarded 
as  essentially  identical  with  certain  carcinomas  occurring  in  man,  and  as 
pointing  to  the  probable  mechanism  of  origin  of  such  tumors  in  man.  To 
demand  that  these  experimental  processes  must  continue  after  the  irritant 
is  removed  and  that  metastases  must  always  be  produced  is  to  ask  more 


EXPERIMENTAL  CANCER  RESEARCH 


131 


evidence  of  fully  developed  carcinoma  than  is  often  obtained  in  lesions  which 
are  regularly  observed  to  progress  in  man  to  a  fatal  issue.  The  lower  animals 
are  not  very  susceptible  to  carcinoma,  especially  to  epidermoid  carcinoma 
and  metastases  of  epidermoid  carcinoma  may  not  be  so  readily  established 
in  their  tissues  as  in  the  human  species.  Thus  the  general  object  of  the  experi- 
mental studies,  which  is  to  prove  that  carcinoma  may  be  induced  in  pre- 
viously normal  cells  by  continued  irritation,  seems  to  have  been  accomplished. 

After  exciting  proliferation  by  means  of  sudan  III,  Lamezan  and  Haga 
have  each  attempted  to  transplant  the  growing  cells  to  other  tissues  of  the 
same  animal  or  to  other  animals  of  the  same  species,  but  without  success. 

Chronic  Inflammation  in  the  Experimental  Production  of  Tumors. — 
Many  experimenters  have  employed  various  forms  of  chronic  inflammation  in 
the  endeavor  to  produce  tumors. 


FIG.  1 6. — Gastric  carcinoma  in  the  rat,  caused  by  infection  with  Spiroptera.     (After 

Febiger.) 

Ribbert  produced  small  but  typical  fibro-epithelial  papillomatous  tumors 
of  the  rabbit's  lip  by  repeatedly  scraping  the  regenerating  epithelium.  In 
many  organs  he  saw  atypical  growth  of  mechanically  displaced  epithelium, 
but  in  no  instance  was  a  true  tumor  observed.  One  of  his  most  notable  results 
was  obtained  by  ligating  the  ducts  of  salivary  glands  in  rabbits,  which  was 
followed  by  extensive  atypical  overgrowth  of  duct  epithelium  approaching 
the  appearance  of  duct  carcinoma. 

Brosch' assumes  that  preexisting  chronic  productive  inflammation  is  an 
essential  condition  in  the  experimental  production  of  tumors  by  means  of 
chronic  irritants.  After  cauterizing  and  crushing  a  portion  of  the  skin  of  the 
back  in  white  rats  he  rubbed  melted  paraffin  into  the  inflamed  area  over  a 
period  of  8  to  12  weeks  and  secured  atypical  epithelial  proliferation  closely 
resembling  beginning  carcinoma. 


132 


N EOF LA  S  TIC  DISEA  SES 


Cazin  employed  a  variety  of  traumatic  influences  in  the  unsuccessful 
effort  to  produce  cancer  from  normal  epithelium.  Over  a  period  of  5  months 
he  rubbed  soot  into  the  inflamed  skin  of  a  dog  without  producing  any  atypical 
proliferation. 

The  particular  chemical  agents  believed  to  be  responsible  for  many  of 
the  forms  of  cancer  observed  in  the  trades,  as  in  workers  in  paraffin,  coal- 
tar,  soot,  tobacco,  etc.,  have  been  rather  extensively  employed  in  the  study 
of  experimental  atypical  epithelial  proliferation,  but  in  no  case  has  a  pro- 
gressive tumor  resulted  (Haga,  Lit.).  Special  interest  attaches  to  the  rather 
notable  influence  of  tobacco  extract  in  exciting  epithelial  proliferation. 

Effect  of  Extract  of  Human  Tumors. — Wacker  and  Schminke  injected 
into  the  rabbit's  ear  fat  extracts  from  mammary  carcinoma,  chondroma,  and 
gastric  carcinoma,  and  secured  moderate  epithelial  proliferation.  I  have 
employed  the  alcoholic  extract  of  a  comedo-carcinoma  of  the  breast  in  intra- 


FlG.  17. — Position  of  spiroptera  in  center  of  carcinoma  of  stomach  in  rat.    (After  Febiger.) 

mammary  injections  in  the  rabbit,  securing  only  an  inflammatory  reaction. 
These  experiments  were  suggested  by  the  impression  that  the  extension  of 
comedo-carcinoma  in  the  breast  keeps  pace  with  the  diffusion  of  fatty  material 
in  the  obstructed  ducts. 

By  mixing  the  expressed  juice  of  carcinoma  tissue  with  sudan  III  and 
injecting  into  the  stomach  wall  of  rabbits  Haga  secured  well-marked  tume- 
factions of  the  mucosa  with  considerable  ingrowth  of  glandular  epithelium 
presenting  several  histological  characters  of  carcinoma. 

Experimental  Production  of  Tumors  by  the  x-Ray. — While  the  frequency 
of  development  of  carcinoma  from  x-ray  dermatitis  places  these  observa- 
tions virtually  in  the  experimental  class,  deliberate  employment  of  the  x-ray 
for  the  production  of  tumors  has  been  reported  by  Marie,  Clunet,  and  Raulot- 
La  Pointe.  These  authors  describe  the  exact  dosage  and  the  intervals  of 
treatment  followed  in  a  successful  effort  to  produce  a  malignant  tumor  in 


EXPERIMENTAL  CANCER  RESEARCH 


the  rat.    The  growth  was  a  spindle-cell  sarcoma  and  proved  transplantable 
in  other  rats. 

Febiger's  Experimental  Gastric  Carcinoma  in  the  Rat. — Having  dis- 
covered the  remains  of  a  nematode  worm  in  a  spontaneous  gastric  carcinoma 
in  a  rat,  Febiger  identified  this  parasite  as  one 
occurring  in  cockroaches  (Periplaneta  Americana 
and  P.  orientalis) .  He  designates  this  parasite  as 
Spiroptera  neoplastica.  It  was  later  found  to 
infect  other  hosts.  He  next  discovered  a  source 
of  infested  cockroaches  in  a  Danish  sugar  fac- 
tory and  by  feeding  a  series  of  rats  with  the 
bodies  of  these  insects  observed  the  develop- 
ment of  chronic  inflammation,  papillomatosis, 
and  carcinoma  of  the  stomach.  Of  62  rats  which 
survived  the  feeding  more  than  60  days,  12  de- 
veloped carcinoma.  The  interval  required  was 
as  brief  as  64  days,  and  in  one  case  metastases 
were  observed  after  104  days. 

The  inflammation  and  papillomatosis  affected 
a  large  portion  of  the  gastric  mucosa  and  reached 
such  an  extensive  grade  as  to  fill  or  even  occlude 
the  stomach.  Structurally  the  process  showed  extensive  papillary  overgrowth 
of  epithelium  with  marked  keratosis,  while  the  supporting  tissue  was  richly 
infiltrated  with  eosinophile  leukocytes.  From  this  lesion  there  was  progres- 


FIG.  18.- 


-Spiroptera  neoplastica. 
(After  Febiger.) 


WMK  .:! 


FIG.  19. — Structure  of  experimental  carcinoma  of  stomach  of  rat,  caused  by  Spiroptera. 

(After  Febiger. ) 

sive  invasion  of  the  mucosa  and  stomach  wall  by  proliferating  epithelial 
masses  producing  the  structure  of  carcinoma.  In  two  animals  pulmonary 
metastases  were  observed  in  which  tumor-cells  but  no  worms  or  ova  were 


134  NEOPLASTIC  DISEASES 

found.  In  the  gastric  tumor  numerous  spiropterae  with  ova  were  commonly 
present  within  the  proliferating  masses. 

This  brilliant  study  presents  an  experimental  production  of  a  well-recog- 
nized form  of  gastric  carcinoma  in  the  rat,  demonstrates  the  dependence 
of  the  malignant  tumor  upon  the  presence  of  a  nematode  worm,  and  reveals 
the  gradual  assumption  by  the  epithelium  of  the  power  of  independent  growth 
apart  from  the  irritant  originally  exciting  its  proliferation. 

There  appears  to  be  no  reason  for  introducing  the  idea  of  a  constitutional 
dyscrasia  in  the  particular  animals  yielding  the  carcinomas,  nor  for  assuming 
the  existence  of  a  microorganism  carried  along  with  the  nematode. 

M.  B.  Stark  has  studied  what  appears  to  be  an  hereditary  pigmented 
tumor  of  the  fruit  fly,  Drosophila.  This  condition  was  observed  by  Bridges, 
who  found  that  certain  black-spotted  male  larvae  invariably  died,  and  that  the 
lethal  factor  which  produced  the  tumor  is  sex-linked  in  inheritance,  being 
located  in  the  X-chromosome.  Stark  found  that  the  black  spots  were  com- 
posed of  polyhedral  and  spindle-cells  containing  pigment  which  gathered 
at  the  periphery  of  the  mass.  She  noted  that  the  tumors  caused  death  in 
about  15  hours,  that  the  removal  of  the  spots  prolonged  the  life  of  the  larvae, 
while  the  injection  of  tumor  emulsion  caused  the  death  of  normal  larvae  appar- 
ently from  toxic  action. 

TRANSPLANTATION  OF  TUMORS 

Between  Animals  of  Different  Species. — The  early  period  of  attempts 
to  transfer  cancer  from  human  beings  to  lower  animals,  from  the  time  when 
Peyrilhe's  servant  mercifully  terminated  the  sufferings  of  the  dog  into  which 
he  had  injected  cancer  emulsion,  down  to  the  present  date,  has  practically 
demonstrated  the  impossibility  of  this  mode  of  transfer.  The  numerous 
failures  recorded  in  the  literature  are  doubtless  far  exceeded  by  the  number 
of  unreported  experiments.  Even  using  anthropoid  apes  Metchnikoff  and 
Roux  and  Jobling  had  negative  results,  but  it  is  perhaps  not  to  be  assumed 
that  in  these  animals  whose  blood  relationship  to  man  is  comparatively  close, 
a  successful  transfer  may  not  prove  possible.  The  significance  of  the  few 
alleged  but  paradoxical  successes  has  already  been  considered. 

Between  Man  and  Man. — Cornil  reported  that  an  unnamed  surgeon 
grafted  a  fragment  of  spindle-cell  sarcoma  of  the  breast  into  the  other  breast. 
At  the  end  of  two  months  the  tumor  reached  the  size  of  an  almond  and  proved 
on  section  to  resemble  the  original  growth.  With  an  adenocarcinoma  a  similar 
result  was  obtained,  but  the  resulting  nodule  was  not  sectioned.  Fortunately 
no  other  clinical  record  of  successful  deliberate  transplantation  seems  avail- 
able (cf.  Milner).  Hahn  successfully  transplanted  a  portion  of  skin  containing 
a  carcinomatous  nodule. 

From  the  period  when  vaccine  treatment  was  very  widely  employed  I 
have  learned  of  4  cases  in  which  tumors  grew  from  injected  unkilled  cells  in 
the  vaccine,  some  of  which  were  mentioned  by  Coca.  The  study  of  spontaneous 
tumor  metastases  removes  the  necessity  of  experimental  evidence  in  this  field. 

Between  Related  Species  of  Lower  Animals. — The  early  observations 
on  transplantable  tumors  of  lower  animals  indicated  that  successful  grafts 
could  be  made  only  on  animals  of  the  same  species  and  even  then  only  under 
favorable  conditions,  but  later  studies  have  shown  that  the  suitability  of 
the  soil  is  of  somewhat  wider  scope  and  extends  with  some  tumors  to  closely 
connected  or  even  distantly  related  species.  Thus  Sticker  transferred  the 
lymphosarcoma  of  dogs  to  foxes;  v.  Dungern  carried  his  hare  sarcoma  into 
rabbits;  Funk  claims  to  have  secured  successive  transplants  of  rat  sarcoma 


EXPERIMENTAL  CANCER  RESEARCH  135 

in  rabbits  long  fed  on  emulsified  rat  sarcoma.  Murphy  was  able  to  culti- 
vate mouse  sarcoma  in  rats  subjected  to  repeated  x-raying  of  the  spleen,  but 
as  soon  as  the  lymphocytic  function  of  the  animals  was  restored  the  tumors 
regressed. 

Strauch  reports  an  anomalous  result  of  transplanting  Ehrlich's  mouse 
carcinoma  in  rabbit.  Three  weeks  after  inoculation  he  secured  in  the  rabbit 
a  well-defined  tumor  which  recurred  after  extirpation.  The  extirpated  tumor 
then  failed  to  grow  in  the  mouse,  but  produced  an  increasingly  malignant 
tumor  in  other  rabbits,  even  giving  metastases.  Happe  succeeded  in  trans- 
planting rat  sarcoma  into  the  lens  of  a  rabbit  where  it  grew  out  into  choroid 
and  retina. 

Thus  it  appears  that  the  viability  of  the  cells  of  certain  tumors  of  lower 
animals  is  somewhat  greater  than  once  seemed  likely,  but  is  nevertheless 
sharply  restricted  to  species  enjoying  a  definite  blood  relationship.  There 
seems  to  be  no  theoretical  difficulty  in  the  way  of  still  further  adaptation 
of  the  cells  of  one  animal  to  growth  in  related  species. 

Between  Lower  Animals  of  the  Same  Species. — It  is  highly  suggestive 
of  the  factors  determining  the  results  of  transplantation  of  tumors  that  the 
first  success  was  with  the  most  easily  transferable  growth,  the  lymphosarcoma 
of  dogs.  Yet  Novinsky  in  1876  had  only  2  positive  results  in  42  attempts. 
Hanau's  transplantation  (1889)  of  epidermoid  carcinoma  of  the  vulva  in  a 
rat  was  rather  more  impressive,  since  he  dealt  with  a  better  known  malignant 
tumor  and  secured  extensive  metastases.  Yet  Wehr  at  the  same  time  inter- 
preted the  lymphosarcoma  of  dogs  as  a  carcinoma,  obtained  metastases  in 
lymph-nodes  and  spleen  in  inoculated  dogs,  and  noted  spontaneous  regres- 
sions. In  1890  v.  Eiselsberg  succeeded  in  transferring  to  the  mesenteric 
tissues  a  spindle-cell  periosteal  sarcoma  from  a  rat. 

The  first  systematic  study  of  a  transplanted  tumor  and  one  which  revealed 
the  possibilities  of  this  method  of  study  was  that  of  Moreau  (1891).  A 
cylindrical  cell  carcinoma  of  a  mouse  he  carried  through  several  generations, 
the  tumor  gradually  losing  viability.  In  the  offspring  of  tumor  mice  as  well 
as  in  pregnant  animals  it  grew  more  rapidly.  Traumatism  produced  metas- 
tases which  were  otherwise  usually  missing.  Other  animals  were  insusceptible. 
The  tumor-tissue  when  not  ulcerated  was  free  from  microorganisms.  Firket 
carried  a  spindle-cell  sarcoma  through  3  generations  of  rats,  and  Velich  lost 
his  periosteal  spindle-cell  sarcoma  only  after  it  had  passed  8  generations, 
when  it  failed  to  survive  in  a  new  breed  of  rats. 

In  1901  and  1902  the  general  revival  of  interest  in  the  cancer  problem 
gave  to  the  studies  of  Loeb  in  America  and  Jensen  in  Denmark  a  special 
interest.  Loeb  (1900)  carried  a  cystic  sarcoma  of  the  rat's  thyroid  through 
40  generations  without  observing  change  of  structure  or  metastases,  and 
reported  observations  on  other  transplantable  rat  tumors.  Jensen  (1902  to 
1903)  reported  the  transmission  of  a  mouse  carcinoma  through  19  generations 
again  without  metastases.  Both  these  authors  convinced  themselves  that 
the  tumor  grew  from  the  transplanted  cells,  but  their  data  on  this  point  were 
not  decisive  and  Loeb  assumed  the  existence  of  an  agent  apart  from  the  cells. 
Jensen  found  the  tumor-cells  very  susceptible  to  heat,  light,  drying,  and 
antiseptics,  but  was  able  to  preserve  their  viability  for  18  days  at  — 1°  C. 
He  further  announced  that  he  had  seen  the  regression  of  large  tumors  in  mice 
receiving  injections  of  antiserum  prepared  in  the  rabbit.  Borrel  strengthened 
the  evidence  in  favor  of  the  carcinomatous  nature  of  the  mouse  tumors  by 
observing  numerous  metastases  in  lungs  and  lymph-nodes.  With  these  and 
other  studies  shortly  following  the  modern  field  of  experimental  cancer  re- 
search definitely  opened. 


136  NEOPLASTIC  DISEASES 

Of  the  permanent  results  of  this  new  era  of  experimental  research  it  is 
too  early  to  speak  with  certainty.  In  many  respects  the  recent  work  has 
deepened  our  insight  into  the  conditions  of  growth  of  tumors,  especially  the 
narrow  range  of  their  viability  and  at  the  same  time  their  apparently  un- 
limited capacity  for  growth  in  suitable  environment.  Particularly  fortunate 
are  the  conditions  provided  for  the  detection  of  any  immunity  factors  that 
may  be  concerned,  and  yet  progress  in  this  field  has  perhaps  been  more  limited 
than  in  others.  It  is  apparent  that  many  phenomena  encountered  in  the 
study  of  transplanted  tumors  and  hastily  interpreted  as  new  observations 
had  long  before  been  fully  recognized  in  spontaneous  human  tumors  by 
those  familiar  with  this  field.  Many  observations  on  change  of  structure, 
the  apparent  discrepancy  between  histological  appearance  and  biological 
behavior,  the  mechanism  of  tumor  regression,  the  conditions  governing 
metastasis,  the  elements  contributing  to  cachexia,  have  proved  little  more 
than  welcome  reappearance,  under  experimental  conditions,  of  facts  and 
principles  previously  established  in  the  human  subject.  The  study  of  trans- 
plantable  tumors  has  shed  no  light  on  the  histogenesis  or  mode  of  origin  of 
neoplasms.  In  the  field  of  practical  therapeutics  it  has  opened  up  many 
new  trails  which  unfortunately  have  led  mostly  astray.  Chief  among  the 
less  important  results  is  the  further  evidence  supplied  by  the  extension  of 
the  work  to  various  lower  animals  that  different  tumors  are  often  quite  differ- 
ent clinical  and  pathological  entities,  and  that  observations  on  one  may  not 
safely  be  applied  to  another. 

The  problems  arising  in  the  study  of  transplanted  tumors  may  now  be 
considered  in  brief  detail.  For  a  full  discussion  of  this  subject  cf.  Woglom. 

Problems  of  Transplantable  Tumors. — Nature  and  Origin  of  the  Tumors. — 
Many  doubts  were  first  expressed  regarding  the  malignancy  and  even  of 
the  neoplastic  nature  of  the  transplantable  tumors.  Yet  it  has  been  abun- 
dantly shown  that  the  chief  tumors  in  mice  often  exhibit  infiltrative  growth 
and  metastases.  Bashford,  Murray,  and  Cramer  described  in  detail  local 
infiltration  and  metastases  in  the  Jensen  tumor,  and  Apolant  showed  that 
this  type  of  growth  developed  when  the  tumor  met  dense  resisting  tissues. 

Murray  found  pulmonary  metastases  in  about  50  per  cent,  of  his  spon- 
taneous tumors,  but  they  were  often  microscopic.  The  significance  of  the 
morphology  of  these  tumors  must  also  be  regarded  as  unequivocal.  When 
the  whole  list  of  mouse  tumors  now  described  is  considered,  it  appears  that 
this  animal  is  subject  to  a  considerable  variety  of  tumors  comparable  to  those 
of  man,  and  a  standard  of  tumor  morphology  for  this  animal  has  been  estab- 
lished. 

The  origin  of  the  chief  mouse  tumor  has  been  shown  by  Bashford  and 
Murray  and  Apolant  to  be  from  widely  scattered  mammary  tissue.  Many 
other  mouse  tumors  have  been  described  and  traced  to  their  probable  origin, 
as  epidermoid  carcinoma  of  the  mouth  (Borrel,  Haaland),  adenocarcinoma 
of  intestine,  carcinoma  of  stomach,  adenoma  of  liver,  spindle-cell  sarcoma  of 
renal  region  (Bashford,  Murray,  and  Cramer),  chondroma  (Ehrlich),  adeno- 
carcinoma of  kidney,  adenocarcinoma  of  ovary,  melanoma,  myoma  uteri, 
adenocarcinoma  of  sebaceous  glands,  and  many  others  (Haaland,  Tyzzer). 
Apolant  thought  that  95  per  cent,  of  mouse  tumors  arise  in  the  mamma, 
but  in  Tyzzer's  series  of  70  tumors  of  mice  74  per  cent,  arose  in  the  lung. 

In  the  rat  the  series  of  observed  tumors  is  almost  equally  extensive. 
Loeb's  tumor  was  a  spindle-cell  growth  apparently  sarcomatous  arising  in  the 
thyroid.  Other  sarcomas  are  described  by  Herzog  and  by  Jensen.  Stohr 
reports  a  fibro-epithelioma  of  the  tongue,  Flexner  and  Jobling  an  adeno- 
carcinoma of  the  seminal  Vesicle;  and  Lewin  and  Michaelis  a  mammary 


EXPERIMENTAL  CANCER  RESEARCH  137 

carcinoma;  Gaylord,  a  spindle-cell  sarcoma.  Many  of  these  tumors  have 
been  extensively  transplanted. 

In  the  dog,  mammary  carcinoma  is  a  common  tumor  which  presents 
many  peculiarities  but  all  the  essential  features  of  malignancy.  It  has  been 
transplanted  in  the  Loomis  Laboratory  by  Teague  into  animals  weakened  by 
distemper.  The  infectious  lymphosarcoma  of  dogs  has  been  variously  inter- 
preted. It  is  a  large  round  or  rather  polyhedral  cell-growth  probably  arising 
from  the  reticulum  cells  of  the  lymph-node.  Beebe  and  the  writer  have 
shown  in  bacteria-free  transplants  that  it  arises  from  the  transplanted  cells. 
Whatever  may  be  the  conditions  surrounding  the  inception  of  this  tumor, 
when  fully  developed  it  presents  all  essential  features  of  a  malignant  neo- 
plasm. Many  efforts  to  cultivate  bacteria  have  failed,  and  spirochetse  occur 
only  on  ulcerating  surfaces.  The  conditions  permitting  transplantation 
are  similar  to  those  observed  with  other  tumors. 

In  the  fowl  lymphocytomas  with  and  without  leukemia  are  comparatively 
common.  In  Wernicke's  summary  of  the  recorded  tumors  of  fowl  it  is  seen 


FIG.  20. — Structure  of  nodule  of  lymphosarcoma  of  dog  3  days  after  transplantation. 
Note  line  of  separation  between  tumor-cells  and  host's  tissues. 

that  a  considerable  variety  of  new  growths  has  been  observed.  Ehrenreich 
found  7  tumors  of  carcinomatous  or  sarcomatous  type  among  1000  old 
chickens.  An  attempt  to  transplant  one  of  the  carcinomas  failed.  Pick 
observed  an  epidermoid  carcinoma  of  the  mouth;  Tyzzer  reports  myxosar- 
coma  of  the  thigh  and  leiomyoma  of  the  mesentery.  Fujinami  and  Inamoto 
have  described  a  myxosarcoma  which  was  readily  transplantable  and  pro- 
duced numerous  metastases  in  the  inoculated  fowl. 

Rous  has  described  3  chicken  sarcomas,  spindle-cell  and  osteochondro- 
matous,  all  of  which  are  transplantable.  The  juice  from  the  spindle-cell 
sarcoma  strained  through  a  Berkefeld  filter  (No.  5,  medium)  as  well  as  the 
dried  and  powdered  tumor-tissue  reproduced  the  growth.  The  effective 
agent  remained  in  the  dried  tissue  for  7  months,  but  was  destroyed  by  a  tem- 
perature of  55°  C.,  and  would  not  pass  a  Chamberland  bougie  (F.  i).  It 
was  very  susceptible  to  antiseptics.  Quite  remarkable  was  the  increase  in 
viability  of  this  tumor,  for  while  it  was  at  first  transferred  with  great  diffi- 


138 


NEOPLASTIC  DISEASES 


culty,  it  eventually  gave  100  per  cent,  of  successes  in  Plymouth  Rocks.  It 
could  not  be  transplanted  to  other  fowl. 

In  animals  inoculated  with  the  juice  secondary  tumors  very  often  devel- 
oped at  points  of  trauma,  but  always  much  more  slowly  than  in  animals 
inoculated  with  cells.  Filtrates  from  the  spindle-cell  tumor  and  from  the 
chondroma  reproduced  only  the  original  tumor.  It  thus  appears  that  in 
Rous'  sarcoma  a  tumor-producing  agent  can  be  separated  from  the  tumor- 
cells  by  coarse  filtration.  The  nature  of  this  agent  has  not  been  determined. 

It  seems  probable  that  the  action  of  this  agent  may  be  compared  to  that 
of  substances  diffusing  from  certain  human  tumors  into  surrounding  tissues 
and  causing  peculiar  collateral  hyperplasia  and  even  the  gradual  transforma- 
tion of  normal  into  tumor-cells.  It  may  also  be  pointed  out  that  various 
chemical  agents  have  been  shown  to  be  specially  adapted  to  the  excitation 


FIG.  21. — Section  of  a  pulmonary  metastasis  of  Rous'  chicken  sarcoma. 

of  atypical  overgrowth  of  cells.  Another  factor  of  undetermined  value  may 
be  a  peculiar  quality  in  the  reaction  of  chicken  tissues  to  irritants.  The 
principles  of  avian  pathology  are  not  as  yet  fully  expounded.  It  is  of  little 
moment  to  inquire  whether  or  not  the  Rous  sarcoma  is  a  true  tumor.  It 
is  obviously  not  a  simple  inflammation,  but  enjoys  several  essential  features 
of  a  neoplasm.  At  present  it  must  be  regarded  as  a  disease  sui  generis  with- 
out exact  parallel  in  other  animal  species. 

In  rabbits  a  considerable  number  of  tumors  have  been  described,  but 
none  appears  to  have  been  extensively  transplanted.  In  the  hare  v.  Dungern 
and  Coca  discovered  a  slowly  growing  spindle-cell  sarcoma  in  the  skin  of  the 
ear.  It  contained  spindle-cells  mingled  with  large  polyhedral  eosinophile 
cells  and  somewhat  resembled  a  granuloma.  It  proved  readily  transplantable 
in  rabbits,  and  from  the  serum  reactions  of  the  inoculated  animals  the  authors 
concluded  that  the  tumor-cells  even  in  late  generations  retained  the  properties 


EXPERIMENTAL  CANCER  RESEARCH  139 

of  hare  protein.  The  significance  of  these  serum  reactions  is,  however,  open 
to  doubt. 

Fate  of  the  Transplanted  Tumor. — The  demonstration  of  the  survival  of 
the  tumor-cells  in  the  transplanted  tumor  has  been  a  highly  important  result 
of  experimental  studies,  since  it  establishes  an  essential  distinction  between 
neoplasms  and  infectious  processes.  The  principle  had,  of  course,  been  pre- 
viously demonstrated  by  observations  on  metastatic  processes  in  human 
subjects  by  the  experimental  evidence  has  been  more  decisive.  Observations 
at  intervals  upon  the  implanted  tumor  grafts  have  shown  for  the  tumors 
of  Jensen,  Loeb,  Ehrlich,  the  lymphosarcoma  of  dogs,  and  Rous'  chicken 
sarcoma,  that  while  the  central  portions  of  the  mass  suffer  simple  necrosis, 
the  peripheral  cells  stimulate  the  formation  of  new  blood-vessels  and  the 
multiplication  of  fibroblasts,  and  with  this  support  they  multiply  and  pro- 
duce the  new  tumor.  This  reaction  has  been  attributed  to  somewhat  specific 
formative  powers  acting  on  fibroblasts  or  angioblasts  and  producing  chiefly 
connective -tissue  or  granulation  tissue  about  the  tumor  graft  (Ehrlich,  Gierke). 
A  leukocytic  or  a  lymphocytic  reaction  is  also  observed,  especially  when 
there  is  much  necrosis  in  the  graft,  or  when  it  is  infected.  Much  exudative 
inflammation  often  interferes  with  implantation.  V.  Dungern  and  Coca 
describe  a  phagocytic  absorption  of  tumor-cells  in  the  hare  by  means  of  large 
mononuclear  leukocytes,  which  interfere  with  implantation.  The  stroma 
of  the  transplanted  tissue  usually  undergoes  hyaline  transformation  and 
absorption,  but  in  some  cases  it  may  be  preserved  for  a  certain  period.  Thus 
Beebe  and  the  writer,  in  the  lymphosarcoma  of  dogs,  found  on  the  third  day 
arterioles  in  the  graft  filled  with  circulating  blood.  Progressive  proliferation 
of  the  transplanted  stroma  has  not  been  satisfactorily  traced. 

The  time  required  for  the  appearance  of  proliferation  varies  greatly  with 
different  tumors.  It  may  be  visible  in  24  to  48  hours.  A  palpable  tumor 
seldom  appears  before  10  days,  usually  it  may  be  detected  in  2  -or  3  weeks, 
but  occasionally  is  delayed  for  months  (Bridre,  Stohr). 

Adaptation. — Great  variation  in  the  proportions  of  successful  transplants 
has  nearly  constantly  appeared.  Nearly  all  observers  found  difficulty  in 
securing  the  first  graft,  while  subsequent  generations  have  usually  followed 
much  more  readily,  so  that  some  tumors,  as  the  Buffalo  rat  sarcoma,  have 
eventually  yielded  100  per  cent,  of  "takes."  Careful  analysis  of  the  condi- 
tions of  successful  transplantation  has  been  necessary  in  order  to  determine 
whether  the  differences  were  due  to  an  increase  in  the  growth  capacity  of  the 
cells  or  to  some  peculiar  adaptation  to  the  experience  of  transplantation.  The 
former  possibility  led  to  the  employment  of  Ehrlich  of  the  conception  of 
increased  virulence. 

It  was  soon  shown  that  the  chief  factors  resided  in  the  transplanted  cells, 
since  within  the  range  of  animals  commonly  employed  the  increase  in  number 
of  successful  grafts  and  in  their  rate  of  growth  was  invariable.  Preliminary 
heating  to  39°  to  41°  C.  or  exposure  to  mercuric  chloride  or  iodide,  yielded 
a  larger  percentage  of  takes  in  the  experience  of  Clowes  and  Baeslack.  Heat 
beyond  45°  C.  or  a  few  minutes'  exposure  to  20°  C.  kills  most  tumor-cells 
(Jensen,  Loeb).  Yet  Ehrlich  transplanted  a  carcinoma  kept  for  2  years  at 
—10°  C.,  although  the  tumor  soon  ceased  to  grow.  Liquid  air  at  a  tempera- 
ture of  — 195°  C.  failed  to  kill  all  cells  in  the  experiments  of  Moore  and  Walker, 
while  Gaylord  and  Haaland  eliminated  the  carcinomatous  elements  from  a 
mixed  carcinosarcoma  by  heating  to  44°  C.  for  30  minutes.  With  the  excep- 
tion of  Rous'  chicken  tumors  it  has  always  been  found  necessary  to  transplant 
intact  cells,  while  extensive  comminution  or  drying  abolished  growth.  Most 
tumor-cells  are  comparatively  resistant  to  ordinary  antiseptics. 


140  NEOPLASTIC  DISEASES 

Spontaneous  fluctuation  in  growth  energy  of  the  implanted  tumor  has 
been  assumed  in  order  to  account  for  variations  in  the  results  of  implanta- 
tion. As  stated  by  Bashford,  Murray,  and  Cramer,  "considerable  varia- 
tions in  success  attend  the  inoculations  of  one  and  the  same  tumor  at  different 
times.  Thus  one  series  of  inoculations  may  give  a  small  percentage  of  slow- 
growing  tumors  which  at  a  subsequent  period  may  begin  to  grow  rapidly 
or,  on  transplantation,  while  still  growing  slowly,  give  a  high  percentage 
of  quickly  growing  tumors."  From  a  large  series  of  inoculation  experiments 
taking  into  account  the  percentage  of  "takes"  and  the  rate  of  growth,  these 
authors  constructed  curves  showing  rhythmic  variations  in  growth  energy. 

It  is  thus  interesting  to  note  that  in  this  experimental  field  conclusions 
may  be  drawn  which  support  clinical  observations  frequently  made  in  the 
human  subject,  that  the  rate  of  growth  of  many  tumors  varies  at  different 
periods  of  their  course.  Whether  the  two  sets  of  observations  are  exactly 
parallel  may  be  doubted.  It  may  further  be  concluded  from  clinical  and 
pathological  study  that  the,  rate  of  growth  of  different  portions  of  the  same 
tumor  varies  enormously,  the  active  portions  being  usually  peripheral,  that 
one  tumor  may  be  active- while  another  neighboring  mass  is  quiescent,  that 
superficial  tumors  may  regress  when  internal  metastases  are  active,  and  that 
in  general  the  rate  of  growth  of  tumors  is  subject  to  fluctuations  from  a  great 
variety  of  factors  which  are  chiefly  dependent  on  the  uncertain  nutrition 
of  both  tumor  and  host.  Under  these  complex  conditions  it  is  extremely 
difficult  to  determine  whether  anything  properly  designated  as  increased 
virulence  or  adaptation  of  tumor-cells  has  so  far  been  demonstrated  in  the 
experimental  field.  On  the  contrary,  it  would  appear  that  successive  trans- 
plantation involves  a  process  of  sifting  out  the  more  viable  cells  and  providing 
for  them  a  highly  favorable  soil. 

Uniformity  in  technic  of  transplantation  is  an  obvious  essential  in  a  com- 
parison of  results.  Emulsions  of  cells  in  salt  solution,  or  thin  slices  of  tissue, 
are  chiefly  employed,  and  in  either  case  it  has  been  found  that  an  optimum 
quantity  exists,  viz.,  i  to  2  cm.  of  emulsion  and  i  or  2  cubic  millimeters  of 
tissue.  Larger  amounts  may  yield  initially  larger  tumors,  but  in  many  cases 
subsequent  standstill  or  regression  are  observed. 

With  large  doses  it  has  been  assumed  that  partial  immunity  resulted 
from  absorption  of  much  of  the  tumor-tissue. 

The  site  chosen  for  inoculation  is  ordinarily  the  subcutaneous  tissue,  into 
which  the  tumor  material  is  injected  or  implanted.  The  internal  organs, 
especially  the  spleen,  have  proved  less  suitable  (Goldmann).  Uhlenhuth 
secured  grafts  by  rubbing  an  incised  wound  with  the  Jensen  rat  sarcoma, 
and  Beebe  and  the  writer  transferred  the  dog  sarcoma  in  this  same  manner, 
which  is  apparently  the  natural  mode  of  transfer  of  this  disease,  during  coitus. 

Influence  of  Variations  in  the  Soil. — That  slight  variations  in  the  tissues 
of  the  host  greatly  influenced  the  results  of  transplantation  was  very  early 
noted.  Not  only  was  the  same  species  of  animal  required,  but  the  results 
were  more  successful  in  animals  of  exactly  the  same  color  and  antecedents. 
Brown  and  wild  strains  differed  in  susceptibility  from  white  and  domesticated 
families.  Rous  found  it  impossible  to  transfer  his  chicken  sarcoma  at  first 
to  any  but  Plymouth  Rocks,  preferably  of  the  same  brood.  Haaland  found 
it  impossible  to  propagate  on  Danish  mice  fed  on  grain  a  Berlin  tumor  coming 
from  mice  fed  on  milk.  Many  others  have  had  difficulty  in  transferring 
propagable  tumors  from  the  animals  of  one  country  to  those  of  another. 

The  influence  of  diet  has  since  been  shown  to  be  highly  important.  Beebe 
and  Van  Alstyne  were  able  to  render  rats  highly  refractory  to  the  Buffalo 
sarcoma  by  a  previous  course  of  carbohydrate-free  diet.  They  have  also 


EXPERIMENTAL  CANCER  RESEARCH  141 

shown  that  the  course  of  this  tumor  is  distinctly  retarded  by  carbohydrate- 
free  diet,  and  accelerated  by  buty rates  among  the  fats.  Sweet  also  has  ob- 
served increased  resistance  to  implantation  in  animals  on  a  carbohydrate-free 
diet.  That  these  rules  may  not  hold  for  all  tumors  is  highly  probable  and 
specifically  shown  by  Woglom's  negative  results  in  carcinoma.  Benedict 
brought  about  the  complete  regression  of  large  sarcomas  in  rats  rendered 
diabetic  by  phloridzin. 

Simple  restriction  of  food  has  been  shown  by  Moreschi  to  retard  the 
growth  of  implanted  tumors.  With  the  Flexner-Jobling  rat  carcinoma  Rous, 
however,  failed  to  influence  the  growth  by  restricted  diet. 

By  substituting  lime  substances  for  the  usual  diet  Sweet,  Corson,  and 
Saxon  rendered  rats  markedly  insusceptible  to  implanted  sarcoma,  and  when 
a  graft  succeeded  in  such  animals  its  growth  was  accelerated  by  return  to 
normal  diet.  Castration  also  favored  growth.  Centanni  reports  that  a  diet 
of  wheat  bread  and  corn  but  without  green  food  renders  mice  highly  insus- 
ceptible to  tumor  implantation.  Oser  and  others  find  that  tumors  grow 
better  in  splenectomized  animals. 

Cholesterol  administered  subcutaneously  in  doses  of  40  mgm.  at  intervals 
of  2  to  3  days  was  found  by  Robertson  and  Burnett  to  decidedly  accelerate 
the  growth  of  carcinoma  in  rats.  These  results  were  confirmed  by  Sweet, 
Corson,  White,  and  Saxon.  Tethelin,  the  active  principle  of  the  anterior 
lobe  of  the  pituitary  gland,  was  found  to  have  a  similar  effect,  and  since  both 
these  substances  contain  a  hydroxy-benzol  group,  Robertson  and  Burnett 
concluded  that  the  accelerating  influence  resided  in  the  hydroxy-benzol 
radical.  An  increased  cholesterol  content  of  the  blood  has  been  found  in 
certain  cases  of  cancer  by  Luden. 

Spontaneous  absorption  of  implanted  tumors  was  first  recorded  by  Loeb 
and  its  comparative  frequency  and  the  increased  resistance  to  reinoculation 
were  emphasized  especially  by  Clowes  and  Baeslack.  About  23  per  cent,  of 
tumors  derived  by  Gaylord  and  Clowes  from  the  Jensen  tumor  were  found 
to  regress,  and  Bashford  reported  as  high  as  50  per  cent.  Most  of  the  regress- 
ing tumors  have  never  reached  a  large  size,  but  some  very  large  growths  appear 
to  reach  a  critical  point  beyond  which  nutrition  fails  and  complete  absorption 
follows.  It  is  a  notable  fact  that  during  absorption  the  animals  do  not  suffer 
from  intoxication  and  that  recovery  may  be  complete.  The  histological 
changes  in  regressing  tumors  vary  widely.  A  simple  necrosis  is  often  the 
primary  event  followed  by  absorption  and  fibrosis,  or  a  progressive  fibrosis 
may  overtake  the  tissue  and  lead  to  gradual  atrophy  of  tumor-cells.  Phago- 
cytic  processes  by  mononuclear  cells  are  frequently  observed  (Gaylord, 
Clowes,  Bashford). 

Structural  Changes  in  Propagated  Tumors. — While  many  tumors  maintain 
a  uniform  structure  through  many  generations,  some  carcinomas  have  ex- 
hibited notable  changes  in  structure  which  are  difficult  to  interpret.  As  a 
rule  these  changes  duplicate  those  observed  in  the  human  subject,  and  on  the 
whole  they  appear  to  be  less  violent  than  are  frequently  observed  in  human 
material.  Thus  Bashford's  study  of  85  propagable  tumors,  35  of  which  had 
been  in  cultivation  for  3  years,  revealed  the  usual  series  of  minor  changes  in 
the  size  and  structure  of  alveoli,  appearance,  and  disappearance  of  various 
forms  of  epithelial  metaplasia,  formation  of  bone  and  cartilage  in  sarcomas 
and  variations  in  vascularity.  Metastases  were  not  always  more  atypical 
than  the  original  growth.  Apolant  was  disposed  to  attribute  the  reversion  of 
a  solid  carcinoma  to  an  adenoma  to  increased  resistance  in  partly  immunized 
animals,  a  conclusion  from  which  Murray  dissents. 

Considering  the  variation  observed  in  propagable  tumors  in  comparison 


142  NEOPLAST1C  DISEASES 

with  the  structural  changes  in  recurrent  human  tumors  the  entire  scope 
appears  very  much  more  restricted  in  the  lower  animals  than  in  man. 

The  most  important  change  credited  to  the  propagable  tumors  is  the 
sudden  assumption  of  malignant  neoplastic  properties  by  the  previously 
normal  stroma.  This  change  was  first  observed  by  Ehrlich  and  Apolant 
in  the  tenth  generation  of  an  adenocarcinoma  of  the  mouse.  A  reverse  trans- 
formation, viz.,  the  disappearance  of  spindle-cells  from  an  adenocarcinoma, 
is  also  recorded  by  Apolant,  but  in  this  instance  it  was  concluded  that  the 
spindle-cells  were  merely  altered  epithelium. 

Many  later  observations  of  the  development  of  sarcoma  in  carcinoma 
have  been  recorded  in  both  rats  and  mice  (Loeb,  Lewin,  Bashford,  Russell). 

The  change  appears  to  occur  rather  suddenly  after  the  8th  to  toth  or  later 
generations.  Russell  fixed  the  period  at  which  the  change  usually  appears 
at  the  55th  to  6oth  day  of  propagation  and  states  that  it  is  independent  of 
the  number  of  transfers.  When  once  established  it  is  usually  progressive 
and  in  certain  cases  the  spindle-cell  tissue  has  eliminated  the  other  element, 
or  both  structures  persist  together,  or  separate  strains  of  sarcoma  and  carci- 
noma are  obtained.  The  rate  of  growth  of  the  mixed  tumors  appears  in- 
creased rather  than  diminished.  In  metastases  either  sarcoma  or  carcinoma 
were  encountered,  but  the  sarcomatous  element  when  present  was  more 
prominent  in  metastases  (Haaland,  Clunet). 

Several  theories  have  been  advanced  in  explanation  of  the  sarcomatous 
transformation  of  mouse  carcinoma. 

It  was  at  first  considered  possible  that  the  growths  were  originally  mixed, 
but  this  theory  was  abandoned  for  lack  of  evidence. 

Most  observers  have  concluded  that  the  sarcoma  represents  a  neoplastic 
transformation  of  the  stroma  of  the  host  caused  by  a  stimulation  of  stroma- 
cells  by  the  epithelium.  The  exact  nature  of  this  stimulus  is  not  clearly 
defined,  but  it  has  been  conceived  as  a  sort  of  growth  stimulus  possibly  carried 
by  chemical  derivatives  of  the  epithelium. 

Repeated  transplantations  are  not  necessary.  Both  Haaland  and  Russell 
describe  in  detail  the  appearance  of  foci  of  overcellular  stroma  located  in  the 
center  of  carcinoma  nodules,  the  increase  of  mitotic  figures  in  the  stroma- 
cells,  the  survival  of  these  altered  stroma-cells  in  grafts  and  their  rapid  in- 
crease until  they  overgrow  the  epithelial  elements.  Haaland  describes  peculiar 
halos  of  large  cells  surrounding  epithelial  groups,  and  intermediate  between 
epithelium  and  stroma-cells.  Others  have  failed  to  trace  the  spindle-cells 
to  either  stroma  or  epithelium. 

The  third  possibility,  which  seems  to  the  writer  to  have  been  too  hastily 
dismissed,  is  that  the  spindle-cells  are  altered  epithelium.  Such  transforma- 
tions are  relatively  common  in  the  early  or  advanced  stages  of  many  human 
tumors  and  especially  in  recurrences  after  operation,  and  this  fact  estab- 
lishes a  probability  that  a  similar  change  in  mouse  tumors  has  a  similar  signifi- 
cance. On  the  other  hand,  there  is  no  parallel  in  human  pathology  for  the 
development  of  sarcoma  in  stroma  supporting  carcinoma,  so  that  observa- 
tions in  mice  would  introduce  a  new  principle  into  oncology.  In  man  spindle- 
cell  transformation  usually  goes  with  increased  growth  and  malignancy,  and 
such  is  the  case  in  mice.  It  is  difficult  to  conceive  how  an  original  carcinoma 
can  be  made  to  yield  all  its  growth  energy  to  normal  stroma-cells  and  com- 
pletely retire  from  the  field,  yet  this  anomalous  result  appears  to  be  reached 
in  the  pure  sarcomas  developing  from  mouse  carcinoma.  The  crucial  evidence 
is  that  presented  by  Haaland  and  Russell  of  gradual  transformation  of  stroma 
into  sarcoma.  Yet  the  interpretation  of  transitional  pictures  is  notoriously 
hazardous,  and  few  observers  have  been  able  to  convince  themselves  that 


EXPERIMENTAL  CANCER  RESEARCH  143 

it  actually  occurs.  Orth  thought  that  Lewin's  sarcoma-cells  represented 
granulation  tissue.  I  have  examined,  through  the  kindness  of  Woglom, 
several  cases  purporting  to  show  the  sarcomatous  transformation  of  stroma- 
cells,  but  have  been  forced  to  draw  from  these  sections  the  opposite  conclu- 
sion, viz.,  that  the  spindle-cells  were  derivatives  of  epithelium.  Since  such 
an  interpretation  is  at  least  admissible,  it  may  be  urged  that  further  evidence 
is  required  before  the  sarcomatous  transformation  of  mouse  carcinoma  can 
be  accepted  as  proved. 

Resistance. — In  the  elucidation  of  the  factors  concerned  in  natural  and 
acquired  resistance  to  tumor  implantation  the  experimental  studies  have 
opened  up  a  new  and  highly  fruitful  field.  The  results  apply  strictly  to  the 
artificial  conditions  in  normal  animals  receiving  tumor  grafts,  but  not  them- 
selves developing  spontaneous  tumors.  It  has  repeatedly  been  shown  that 
animals  resisting  implantation  may  often  develop  spontaneous  tumors  (Bash- 
ford,  Thorel,  Clunet).  Likewise  very  young  animals  which  do  not  develop 
cancer  may  prove  very  favorable  soil  for  implantation.  This  principle  re- 


FIG.  22. — Halos  of  pale  cells  surrounding  epithelial  cell  groups,  in  the  sarcomatous 
transformation  of  carcinoma  in  the  rat.     (After  Haaland.) 

appears  in  the  rapid  growth  of  many  carcinomas  occurring  in  human  sub- 
jects of  youthful  age.  The  problem  of  the  continued  growth  of  a  tumor  is 
therefore'  quite  different  from  that  of  its  inception.  It  follows  also  that  an 
animal  may  be  susceptible  to  one  tumor  while  insusceptible  to  another,  and 
it  is  equally  clear  that  the  body  tissues  of  animals  in  general  are  very  favor- 
able soil  for  the  growth  of  lawless  cells  which  must  therefore  be  restrained 
by  purely  local  factors. 

Natural  Resistance. — Age  has  been  shown  to  have  no  definite  influence 
on  the  susceptibility  to  certain  tumor  grafts,  since  both  young  and  old  animals 
have  proved  suitable  for  experimental  studies.  Most  observers  have  pre- 
ferred stock  from  4  to  8  weeks  of  age  (Haaland,  Albrecht,  Hecht). 

Racial  differences  were  believed  to  account  for  the  capricious  behavior 
of  many  tumors  when  transferred  from  animals  of  one  country  to  those  of 
another.  Yet  it  has  appeared  that  many  indications  of  resistance  seemingly 
referable  to  racial  differences  were  the  result  of  altered  diet,  and  Gierke 
strongly  supported  this  view.  In  many  instances  strange  animals  at  first 


144  NEOPLASTIC  DISEASES 

resistant  soon  became  susceptible  when  housed  under  the  same  conditions  as 
the  animals  furnishing  the  graft  (Stohr,  Cuenot,  Mercier).  For  absolutely 
comparable  results  the  use  of  animals  of  one  litter  or  parentage  is  probably 
advisable. 

Good  health  appears  to  favor  the  growth  of  tumor  grafts  and  poor  con- 
dition to  retard  it.  Yet  Teague  succeeded  in  transplanting  mammary  carci- 
noma of  dogs  only  in  animals  weakened  by  distemper.  Observations  on  the 
effect  of  pregnancy  are  conflicting,  Moreau  and  Herzog  finding  acceleration, 
while  Haaland,  Bridre,  and  Cuenot  saw  retardation  of  growth  in  gestation. 

Slye,  comparing  mammary  tumor  growth  in  two  series  each  of  30  mice, 
found  that  without  exception  the  amount  of  tumor  grown  by  a  female  while 
reproductive  was  strikingly  less  than  during  her  non-reproductive  period. 
Similar  results  were  observed  during  gestation.  Reproductive  females  bear- 
ing small  tumors  of  slow  growth  were  often  observed  to  succumb  rapidly  to 
their  tumors  after  the  birth  of  the  last  litter. 

Acquired  Resistance. — The  first  observations  concerning  acquired  resist- 
ance were  made  by  Gaylord,  Clowes,  and  Baeslack,  who  noted  frequent 
spontaneous  regression  of  the  Jensen  rat  tumor  and  also  the  insusceptibility 
of  these  recovered  animals  to  reinoculation.  Similar  results  were  soon  re- 
ported by  many  observers  with  various  tumors  and  the  question  arose 
whether  the  diminishing  proportion  of  successful  takes  in  reinoculated  animals 
was  due  to  a  gradual  sifting  of  naturally  immune  animals  or  to  active  im- 
munity caused  by  repeated  absorption  of  the  tumor  grafts.  The  latter  theory 
was  strongly  supported  by  Bridre,  who  found  that  by  inoculating  very  large 
doses  his  resisting  animals  rapidly  became  quite  immune.  Michaelis,  Borrel, 
and  Ehrlich  verified  these  results.  It  next  became  apparent  that  the  resist- 
ance thus  established  while  most  pronounced  against  the  tumor  employed 
extended  also  but  to  a  lesser  degree  to  other  tumors.  Ehrlich  was  inclined 
to  believe  that  the  resistance  was  practically  universal  (pan-immunity). 

That  the  actual  temporary  growth  of  tumor-cells  was  necessary  to  excite 
the  resistance  was  strongly  suggested  by  its  failure  to  appear  in  animals 
treated  by  tumor-cells  killed  by  heat  or  mercuric  chlorid  (Clowes) ;  or  killed 
by  chloroform  (Michaelis);  or  treated  with  the  filtrate  of  tumor  emulsion 
(Bridre);  or  by  cells  injured  by  grinding  and  freezing  (Haaland).  Whether 
the  principle  has  been  fully  established  is  perhaps  doubtful. 

Normal  tissue  cells  are  almost  equally  effective  in  exciting  resistance, 
as  first  shown  by  Bashford  using  red  corpuscles,  and  later  by  Schone,  using 
liver,  testis,  or  emulsion  of  mouse  embryo;  by  Borrel  and  Bridre,  with  spleen, 
liver,  or  testis;  by  Higuchi  with  blood-free  placenta.  With  lactating  mouse 
breast  Moreschi  secured  variable  results.  Both  Russell  and  Woglom  pro- 
duced the  resistant  state  by  emulsions  of  embryo  skin  and  Woglom  ascertained 
that  the  immunity  reached  a  maximum  10  days  after  inoculation,  remained 
high  until  the  twenty-fourth  day,  and  vanished  about  the  seventy-fifth  day. 

Devitalization  of  the  normal  tissue  cells  generally  robbed  them  of  their 
immunizing  power,  while  Woglom  showed  that  injection  of  the  animal's 
own  tissues  were  ineffective. 

When  these  experiments  were  transferred  to  tumor-bearing  animals  the 
results  became  less  definite,  although  Russell  considerably  reduced  the  pro- 
portion of  successful  secondary  inoculations  when  the  reimplantation  was 
preceded  by  an  injection  of  tumor  or  embryo-emulsion.  The  practical  test 
of  these  methods  in  animals  with  spontaneous  tumors  proved  entirely  fruit- 
less in  the  hands  of  Haaland  who  failed  by  this  form  of  vaccination  to  influence 
the  growth,  prevent  post-operative  recurrence,  or  diminish  metastases  from 
spontaneous  tumors.  Likewise  in  the  human  subject,  vaccination  therapy 


EXPERIMENTAL  CANCER  RESEARCH  145 

employed  on  a  vast  scale,  while  attended  by  some  paradoxical  successes,  has 
failed  to  establish  its  usefulness  (Coca). 

Passive  Resistance. — Attempts  to  convey  actively  acquired  resistance 
to  other  animals  has  not  been  distinctly  successful.  The  use  of  the  serum 
of  resistant  animals  has  usually  failed  to  render  new  animals  passively  re- 
sistant to  inoculation  (Michaelis,  Ehrlich,  Haaland).  Repeated  reinocula- 
tions  of  immune  rats  by  Uhlenhuth  failed  to  render  their  serum  effective  in 
preventing  successful  inoculation  in  fresh  animals  receiving  first  serum  and 
then  tumor,  or  serum  and  tumor  together.  Bridre  prepared  in  sheep  and  fowl 
an  antiserum  against  mouse  cancer  which  did  not  retard  and  even  appeared 
to  accelerate  tumor  growth.  This  method  has  been  extensively  employed  in 
human  therapy  using  as  antigen  either  the  whole  tumor  or  various  protein 
fractions,  with  uncertain  results  (Vidal,  Beebe,  Berkeley). 

Nature  of  the  Factors  in  Resistance. — The  blood-serum  having  failed  to 
yield  proof  of  possession  of  the  immunity  factors,  it  became  evident  that 
resistance  to  tumor  implantation  must  be  of  more  complex  nature  than  that 
excited  by  bacteria.  In  this  emergency  Ehrlich  pronounced  his  theory  of 
athrepsia  to  account  for  the  failure  of  tumor  grafts  to  grow  in  resistant 
animals.  Having  found  that  mouse  carcinoma  after  surviving  in  rat  tissues 
for  a  week  may  then  be  successfully  restored  to  active  growth  by  returning 
the  graft  to  the  mouse,  he  succeeded  in  conducting  a  series  of  zig-zag  transfers 
from  mouse  to  rat  to  mouse,  etc.,  without  permanent  injury  to  the  tumor. 
From  this  data  he  argued  (i)  that  there  were  no  cytolytic  agents  in  the  rat, 
otherwise  the  tumor-cells  would  have  been  injured,  and  (2)  that  the  mouse 
graft  failed  to  grow  in  the  rat  after  a  few  days  sojourn  because  it  soon  ex- 
hausted a  specific  nutritive  substance,  which  was  not  the  nutritive  molecule 
itself,  but  acted  as  a  stimulus  to  nutrition.  Replacements  in  the  mouse  pro- 
vided new  supplies  of  the  ^-substance.  This  theory  abandoned  the  idea  of 
antagonistic  substances  in  the  resistant  animal  and  substituted  the  concep- 
tion of  an  inert  lack  of  nutriment  as  the  factor  in  resistance.  -  The  theory 
was  possibly  a  correct  interpretation  of  the  experiments  cited,  but  failed  to 
meet  the  conditions  in  animals  of  the  same  species.  Here  two  valid  objec- 
tions were  soon  raised  by  many  authors  (Uhlenhuth,  Borrel,  Hertwig  and 
Poll,  Bashford).  It  has  been  shown  (i)  that  a  tumor-bearing  animal  may 
usually  be  reinoculate'd,  both  tumors  advancing  or  regressing  together,  the 
one  not  interfering  with  the  nutrition  of  the  other;  and  (2)  that  when  a  second 
inoculation  fails  it  is  usually  due  to  an  immunity  excited  by  the  partial  absorp- 
tion of  the  original  graft. 

While  thus  failing  to  account  for  actively  produced  resistance  Ehrlich's 
athreptic  theory  has  served  to  emphasize  the  probable  importance  of  the 
nutritive  qualities  of  the  soil  as  opposed  to  antagonistic  substances  in  the 
blood  of  resistant  animals. 

A  further  illustration  of  this  principle  may  be  found  in  the  experiment  of 
Beebe  and  Crile  who  regularly  caused  the  disappearance  of  the  lymphosar- 
coma  of  dogs  by  exsanguinating  the  animals  and  immediately  transfusing  them 
with  the  blood  of  resistant  dogs.  Here  it  may  be  assumed  that  an  antago- 
nistic substance  was  carried  over  in  the  blood,  but  it  is  simpler  and  equally 
reasonable  to  suppose  that  the  transfused  blood  was  better  adapted  to  the 
normal  than  to  the  tumor-tissue,  and  that  its  presence  turned  the  balance  of 
nutrition  in  favor  of  the  normal  tissues  and  against  the  tumor,  which  then 
suffered  slow  atrophy  and  absorption.  Rather  specific  evidence  against  the 
purely  athreptic  nature  of  tumor  immunity  has  appeared  in  the  successful 
cultivation  of  rat  and  mouse  tumor-cells  in  various  alien  plasmas  (Lambert, 
Hanes). 

10 


146 


NEOPLASTIC  DISEASES 


Cultivation  of  tumor-cells  in  vitro.  The  conditions  requisite  for  the  prolonged  sur- 
vival or  actual  multiplication  of  tissue  and  tumor-cells  in  vitro  seem  to  be  a  fluid  medium 
permitting  of  nutrition  and  diffusion,  fixed  points  of  attachment  for  the  cells,  and  a 
suitable  temperature.  Nutrient  fluids  exactly  homogeneous  with  those  to  which  the 


FIG.  23. — Cultivation  of  mouse  carcinoma-cells  in  blood-plasma.     (Lambert  and  Hanes.) 


cell  has  been  adapted  are  not  necessary.  These  conditions  were  partially  provided  by 
Loeb  who  saw  slight  spreading  of  epithelial  cells  over  the  surface  and  into  clefts  of  an 
agar  medium. 


FIG.  24. — Rat  sarcoma,  growing  in  pigeon  plasma. 

Vol.  2.) 


(Lambert,  Hanes,  Crocker  Reports, 


The  fixed  points  of  support  were  missing  in  the  circulating  whole  blood  used  by 
Beebe  and  the  writer,  and  we  secured  only  prolonged  survival  of  dog  tumor-cells.  An 
adaptation  of  Harrison's  technic  by  Burrowes  proved  successful  in  his  hands  and 
Carrel's  in  permittng  definite  multiplcation  of  tissue  cells  in  the  fibrin  meshes  of 
coagulated  plasma,  and  this  method  had  been  extensively  used.  Epithelial  cells  grow 


EXPERIMENTAL  CANCER  RESEARCH  147 

out  in  coherent  sheets  from  the  parent  mass,  while  mesoblastic  cells  tend  to  grow  out 
in  long  sprouts  or  become  widely  scattered.  The  importance  of  the  results  of  experi- 
mental cultivation  of  tissue  and  tumor-cells  in  vitro  has  not  been  as  great  as  might  have 
been  anticipated,  but  it  has  been  shown  that  these  cells  are  capable  of  living  in  much 
more  varied  media  than  once  seemed  likely,  and  that  the  natural  immune  substances 
supposed  to  exist  in  the  serum  of  refractory  animals  has  little  influence  on  the  growth. 
Tumor-cells  as  a  rule  seem  to  be  less  capable  of  survival  or  growth  than  corresponding 
normal  tissue  cells,  and  only  after  some  difficulty  has  Burrowes  succeeded  in  cultivating 
certain  human  tumor-cells. 

Hypersusceptibility. — Various  observers  have  reported  phenomena  sug- 
gesting hypersusceptibility  to  tumor  growth  in  animals  receiving  grafts, 
emulsions,  or  saline  extracts  of  tumors,  but  the  data  are  insufficient  to  estab- 
lish the  existence  of  a  specific  hypersensitization  (Woglom,  Lit.). 

The  mechanism  by  which  the  resistant  animal  aborts  the  tumor  graft 
offers  suggestive  evidence  regarding  the  nature  of  the  immunity  factors. 
In  resistant  animals  the  unsuccessful  graft  fails  to  excite  the  specific  stroma 
reaction  and  remains  unprovided  with  the  necessary  channels  of  nutriment. 
Russell  examining  grafts  in  refractory  animals  at  intervals  found  that  the 
surviving  cells  continued  to  proliferate  from  7  to  10  days,  but  instead  of  excit- 
ing an  active  growth  of  fibroblasts  they  became  sharply  separated  from  the 
host's  tissues.  He  concluded  that  there  must  be  present  in  resisting  animals 
something  which  inhibits  the  chemotactic  influence  of  the  cancer-cell  upon 
the  connective  tissues  of  the  host.  Inflammatory  reaction  has  also  been 
shown  to  be  responsible  for  the  failure  of  grafting  in  resistant  animals, 
v.  Dungern  and  Coca,  studying  the  inoculation  site  in  immune  animals,  and 
in  regressing  sarcoma  in  the  hare,  observed  that  the  necrosing  graft  gathered 
large  numbers  of  macrophages  in  vessels  and  tissue  spaces,  as  well  as  many 
lymphocytes  and  plasma-cells,  which  attacked  and  absorbed  the  tumor- 
cells.  Since  this  reaction  failed  in  susceptible  animals  they  interpreted  it 
as  a  phenomenon  of  hypersusceptibility  or  allergic,  provided  by  the  previous 
immunizing  dose.  Burgess  examining  grafts  in  non-susceptible  Japanese 
mice  observed  at  first  the  formation  of  the  usual  vascular  stroma,  but  after 
a  week  an  inflammatory  reaction  ensued  yielding  polynuclears,  eosinophils, 
lymphocytes,  and  plasma-cells,  which  shut  off  the  blood-supply  and  induced 
fibrosis.  Da  Fano  also  noted  a  rich  exudate  of  lymphocytes  and  plasma- 
cells  about  the  inoculated  tumor  in  immunizing  animals.  In  splenectomized 
animals  Apolant  finds  that  very  slight  immunity  to  tumors  can  be  excited, 
and  Baeslack  observed  marked  fall  in  the  circulating  lymphocytes  in  sus- 
ceptible animals  with  growing  tumors,  and  a  steady  increase  in  resisting 
subjects  with  regressing  tumors.  Murphy  finds  that  the  chicken  embryo 
possesses  no  means  of  preventing  growth  of  implanted  rat  tumor  until  the 
chick  hatches  and  develops  spleen  and  lymphocytes,  but  if  the  embryo  receives 
a  fragment  of  adult  chicken  spleen  or  bone-marrow  along  with  the  tumor 
graft  the  latter  fails  to  grow.  After  subjecting  the  rat  spleen  to  the  #-ray 
he  found  that  the  animal  supported  the  growth  of  alien  tumor-tissue  for  a 
considerable  period  and  until  the  spleen  recovered  its  lymphocytogenic  func- 
tion. 

All  these  observations  lend  important  support  to  the  view,  long  since 
established  in  human  pathology,  that  the  lymphocyte  is  an  important  agent 
of  defense  of  the  organism  against  tumor  growth. 

Some  light  but  no  complete  elucidation  of  the  nature  of  tumor  immunity 
has  been  furnished  by  collateral  studies  on  tissue  immunity. 

Antibody  production  has  been  demonstrated  against  various  tissue  cells 
injected  into  foreign  species,  as  tracheal  epithelium  (v.  Dungern),  or 
spermatozoa  (Metalnikoff).  These  observations  may  justify  the  use  of 


148  NEOPLASTIC  DISEASES 

antisera  prepared  in  lower  animals  against  human  carcinoma  tissue  or  its 
derivatives. 

Antibody  production  has  been  demonstrated  against  an  animal's  own 
tissues,  injected  either  into  the  same  individual  or  into  other  animals  of  the 
same  species.  Thus  Adler  prepared  an  autospermatoxin  in  guinea-pigs  and 
Halpern  showed,  by  complement  deviation,  the  development  of  antibodies 
against  an  animal's  own  kidney,  pancreas,  and  spleen.  These  observations 
further  support  the  view  that  a  human  tumor-bearing  subject  may  to  some 
extent  be  immunized  by  injections  of  his  own  tumor-tissue. 

A  certain  relationship  has  been  found  between  the  same  organs  in  differ- 
ent species  of  animals,  as  with  the  testis  (v.  Dungern  and  Hirschfeld  Schenk), 
and  with  the  sexual  cells  of  fish  (Dunbar). 

Nevertheless  in  the  sera  of  animals  rendered  immune  to  transplantable 
tumors  there  has  been  no  satisfactory  demonstration  of  specific  cytolysins, 
agglutinins,  or  precipitins.  Nor  have  complement  deviation  tests  in  such 
sera  been  clearly  successful. 

Lambert  and  Hanes  were  able  to  cultivate  rat  sarcoma  cells  in  the  plasma 
of  rats  immunized  against  this  sarcoma,  although  the  sera  of  immunized 
alien  animals  inhibited  the  growth  while  the  normal  alien  sera  did  not. 

The  serological  evidence  therefore  points  to  some  other  form  of  immunity 
and  this  is  apparently  to  be  found  in  the  local  and  general  hypersensitization 
produced  in  the  immunized  animals  elicited  by  absorption  of  regressing  or 
inoculated  tumor-tissue,  v.  Dungern  and  Coca  with  the  hare  sarcoma,  and 
Weil  with  the  Flexner-Jobling  rat  carcinoma  demonstrated  anaphylactic 
reactions  in  the  inoculated  animals  and  a  local  inflammatory  allergetic  reac- 
tion to  inoculation.  This  conception  of  tumor  immunity  is  in  accord  with 
the  fact  that  complete  resistance  to  implantation  of  a  virulent  sarcoma  may 
exist  in  animals  bearing  an  actively  growing  tumor  of  the  same  sort. 


SPECIAL  ONCOLOGY 

CHAPTER  X 

FIBROMA 

Fibroma  is  a  term  applied  to  tumors  composed  chiefly  of  connective  tissue. 

Many  of  these  tumors  are  composed  exclusively  of  connective  tissue  and 
are  designated  as  pure  fibromas.  More  of  them  are  covered  by  hypertrophic 
lining  epithelium,  as  in  papillary  fibroma,  or  contain  glandular  structures, 
adenofibroma.  In  the  nerve-trunks  they  may  show  atrophic  nerve-fibers 
for  which,  and  on  account  of  their  origin,  they  are  called  neurofibroma. 


FIG.  25. — Benign  pigmented  nbro-epithelial  wart.     (Photo  by  B.  H.  Buxton.) 

Blood-vessels  may  be  very  abundant  or  the  lymph-vessels  may_be  in  excess, 
in  angio fibroma  and  lymphangio fibroma.  Neoplastic  connective  tissue  is 
also  observed  in  various  other  benign  and  some  malignant  tumors,  as  in  fibro- 
lipoma,  fibrochondroma,  etc. 

The  gross  appearance  of  true  fibromas  is  usually  characteristic.  They 
are  circumscribed,  encapsulated,  usually  lobulated,  firm  or  soft  tumors,  and 
on  section  exhibit  a  grayish  translucent  appearance.  The  blood  content 
varies,  but  is  usually  slight.  Secondary  changes  yield  corresponding  altera- 
tions in  texture.  Multiplicity  is  a  striking  feature  of  neurofibromas  both  in 
the  skin  (fibroma  molluscum)  and  in  the  organs.  From  this  characteristic 

149 


150  NEOPLASTIC  DISEASES 

appearance  there  are  all  gradations  merging  toward  the  products  of  chronic 
inflammation.  In  some  very  early  fibromas  of  breast  and  kidney  the  isola- 
tion of  the  tumor  nodule  is  imperfect,  although  the  later  stages  of  such  growths 
are  well  encapsulated.  There  is  no  sharp  dividing  line  between  chronic  pro- 
ductive inflammation  and  fibroma,  although  characteristic  examples  of  each 
are  widely  separate.  The  inflammatory  nodule  merges  insensibly  with  the 
surrounding  tissue,  its  histology  lacks  the  definite  features  of  a  neoplasm 
and  it  occurs  under  clinical  conditions  which  supply  the  inflammatory  agent, 
as  in  chronic  mastitis,  and  chronic  rhinitis.  Yet,  as  Ribbert  remarks,  the 
longer  an  inflammatory  nodule  persists,  the  more  in  some  cases  it  may  ap- 
proach the  quality  of  a  neoplasm.  It  must  be  admitted  that  chronic  pro- 
ductive inflammation  may  pass  insensibly  into  fibroma,  a  fact  most  frequently 
illustrated  with  some  forms  of  local  elephantiasis. 

The  structure  of  fibromas  varies  greatly,  but  it  commonly  presents  fibro- 
blasts,  fibrils,  blood-  and  lymph- vessels. 

Soft  fibromas  contain  a  considerable  proportion  of  cells  lying  in  a  soft 
matrix  which  is  often  edematous.  Much  vascularity  also  reduces  the  con- 
sistence. Hard  fibromas  contain  fewer  cells  and  firmer,  more  abundant  matrix 
which  is  often  hyaline.  In  very  dense  fibromas  arising  from  periosteum  and 
tendons  very  few  cells  may  be  present  and  wide  areas  of  hyaline  matrix  are 
observed.  The  consistence  is  also  affected  by  calcification,  mucoid  degenera- 
tion, and  the  formation  of  cysts. 

The  cells  of  genuine  fibromas  are  usually  larger  and  more  numerous  than 
in  adult  connective  tissue.  In  actively  growing  fibromas  the  chromatin 
content  of  the  nuclei  is  also  increased  and  the  tissue  has  a  distinctly  neoplastic 
character.  Even  in  some  hard  fibromas,  as  in  keloid,  the  cells  may  be  of  large 
size  throughout,  but  in  many  cases  the  active  cells  may  be  limited  to  the 
periphery  or  to  isolated  foci  chiefly  about  vessels,  while  the  main  portions 
of  the  tumor  are  acellular.  The  arrangement  of  the  cells  is  uniform  and  is 
determined  by  pressure  or  by  the  presence  of  originating  structures  as  blood- 
vessels or  nerve-trunks,  or  gland  alveoli. 

With  an  increasing  proportion  of  cells,  diminution  of  matrix,  and  irregu- 
larity in  size  and  shape  of  the  cells,  the  tumors  show  more  active  growth 
and  a  tendency  to  recurrence,  and  to  these  tumors  the  term  fibrosarcoma  is 
given.  In  distinguishing  fibroma  from  sarcoma  Borst  relies  chiefly  on  irregu- 
larity in  size  and  shape  of  the  cells  as  well  as  overgrowth  of  nucleus  and 
absence  of  definite  stroma.  When  the  bulk  of  cells  greatly  exceeds  the  matrix 
the  tumors  are  usually  of  active  growth  and  require  careful  removal  to  pre- 
vent recurrence. 

The  matrix  of  fibromas  varies  greatly.  In  many  cases  it  has  the  characters 
of  embryonal  connective  tissue;  in  keloid  it  is  hyaline;  in  dense  tumors  it 
may  be  very  firm  but  fibrillar;  and  it  is  often  edematous  and  infiltrated  with 
leukocytes. 

The  fibroglia  fibrils  of  Mallory  are  regularly  present  and  may  be  very  long 
and  quite  abundant.  They  are  best  demonstrated  in  material  promptly 
fixed  in  Zenker's  fluid  and  stained  by  a  mixture  of  anilin  blue,  0.5;  orange 
G,  2.0;  oxalic  acid,  2.0;  water,  100.  The  bundles  of  wavy  collagen  fibrils  are 
abundant  chiefly  in  hard  fibromas.  Ribbert  regards  the  matrix  of  fibromas 
as  a  product  of  cell  activity,  but  not  as  a  derivative  of  cell  processes.  The 
fibrils  he  considered  to  be  the  result  of  cell  activity  upon  a  secretory  product 
which  has  many  of  the  qualities  of  fibrin,  but  with  an  altered  staining  reaction. 
This  origin  would  explain  the  great  length  of  many  fibrils,  the  great  bulk  of 
the  matrix,  and  the  presence  of  many  fibrils  and  much  matrix  with  very  few 
cells.  Elastic  fibrils  are  usually  scanty. 


FIBROMA  151 

Secondary  changes  occur  in  the  matrix,  including  hyaline  transformation, 
calcification,  fatty  and  mucoid  degeneration,  edema,  and  necrosis,  and  in 
connection  with  bone,  ossification.  Also  the  remnants  of  invaded  structures 
may  be  included  in  fibromas,  as  fat-cells,  which  may  be  incited  to  prolifera- 
tion, gland  alveoli,  muscle-cells,  and  nerve  fibrils.  By  metaplasia  portions  of 
fibromas  may  be  converted  into  cartilage  or  bone. 

Blood-vessels  occur  in  normal  form  and  number,  or  as  irregular  thin-walled 
spaces,  or  as  sinuses  lined  by  endothelium  alone.  In  angiofibroma  the  vessels 
are  very  abundant.  They  appear  as  irregular  spaces  and  canals  lying  in  the 
connective  tissue,  they  are  lined  by  a  moderate  number  of  flat  or  cubical 
endothelium,  but  the  connective  tissue  is  the  predominant  element.  Some 
authors  include  among  fibromas  the  majority  of  angiomas.  It  seems  better, 
however,  to  separate  from  fibromas  all  very  vascular  tumors  in  which  blood- 
vessels form  a  predominant  organoid  unit.  Fibroma  is  a  histioid,  not  an 
organoid,  tumor. 

Lymph-vessels  are  commonly  present  in  fibromas.  In  keloid  the  lymph 
spaces  are  so  prominent  as  to  suggest  for  this  tumor  the  term  lymphangio- 
fibroma.  In  local  elephantiasis  which  is  closely  related  to  fibroma  the  dilated 
lymph-vessels  are  numerous.  Edema  and  lymph-cysts  form  from  obstruction 
to  the  lymph  flow. 

The  natural  history  of  fibroma  is  that  of  a  slowly  growing  tumor  progress- 
ing steadily  or  intermittently  over  many  years.  In  many  instances,  as  in 
neurofibroma,  there  is  a  natural  tendency  for  the  tumor  to  reach  a  certain  size 
and  then  to  remain  stationary,  probably  from  mechanical  interference  with 
blood-supply.  In  very  large  fibromas,  as  of  breast,  skin  and  ovary,  hyaline, 
calcific  and  necrotic  areas  bear  witness  to  the  regressive  tendency  that  over- 
takes this  type  of  tumor.  A  spontaneous  cure  may  thus  be  accomplished. 
In  a  large  fibroma  of  the  quadriceps  tendon  I  have  seen  almost  complete 
destruction  and  permanent  arrest  of  growth  by  central  softening.  Many 
mammary  fibromas  suffer  hyaline  change  and  arrest  of  growth. after  15  to  20 
years.  Kosinski  has  reported  complete  spontaneous  atrophy  of  neurofibro- 
mata.  Sarcomatous  transformation  is  very  rare,  but  occurs  with  neuro- 
fibroma. In  the  mixed  adenofibroma  of  breast  cancerous  changes  may  de- 
velop in  the  epithelium.  Recurrence  after  operation  is  characteristic  of  keloid, 
but  usually  consists  of  an  extension  of  the  tumor  process  over  formerly  intact 
areas. 

Origin  of  Fibromas. — The  exact  point  of  origin  of  most  fibromas  is  still 
undetermined.  That  many  of  them  arise  from  misplaced  islands  of  tissue, 
according  to  Cohnheim's  theory,  is  very  probable.  Chiari  observed  a  con- 
genital polypoid  fibroma  at  the  perineal  raphe,  and  Ribbert  has  seen  a  fibroli- 
poma  in  the  same  situation.  Arnold  described  a  congenital  chondrofibroma 
of  the  skull  which  he  referred  to  a  disturbance  in  the  development  of  the 
cranium.  In  several  reported  fibromas  of  the  testis  there  were  elements 
suggesting  that  the  tumor  represented  a  one-sided  development  of  a  teratoma. 
Certain  fibromas  in  the  adult  appear  in  the  region  of  embryonal  clefts  where 
superfluous  cells  may  be  supposed  to  exist.  In  the  breast  Williams  found 
evidence  that  14  per  cent,  of  the  adenofibromas  of  this  organ  arise  from 
embryonal  rests,  and  the  frequent  association  of  chondroma  and  osteoma 
with  fibroma,  especially  in  the  dog's  breast,  favors  this  view. 

For  other  fibromas  one  must  apply  the  theory  of  local  irritation  and  dis- 
turbance of  nutrition,  as  in  keloid,  which  commonly  follows  scarring;  in  papillary 
fibromas  and  adenofibromas  of  mucous  membranes,  which  are  associated 
with  catarrhal  inflammation;  and  in  fibromas  of  periosteum  and  joint  areas, 
which  may  follow  repeated  trauma. 


152 


NEOPLASTIC  DISEASES 


In  a  third  group  the  clinical  features  point  to  a  congenital  or  acquired  local 
predisposition,  of  which  multiple  neurofibroma  is  the  best  example.  Ele- 
phantiasis seems  to  exhibit  a  general  predisposition  often  combined  with  the 
effect  of  recurring  inflammation. 

It  is  especially  in  the  second  and  third  etiological  classes  that  one  encoun- 
ters the  less  definite  tumor-like  processes  which  it  is  sometimes  difficult  to 
classify,  and  in  which  one  must  recognize  the  cumulative  influence  of  inflam- 
mation and  chronic  disturbance  of  nutrition  and  the  passage  of  inflammatory 
into  self-perpetuating  neoplastic  processes. 


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FIG.  26. — Fetal  fibro-adenoma  of  breast  in  a  girl  of  18  years.    The  tumor  grew  rapidly, 
measured  9  cm.,  was  soft,  bluish,  resembling  sarcoma. 

Clinical  Types  of  Fibroma.- — The  clinical  types  of  fibroma  are  numerous 
and  some  of  them  form  characteristic  clinical  entities  which  not  only  illus- 
trate the  peculiarities  of  this  group  of  neoplasms,  but  throw  light  on  the  nature 
of  tumors  in  general. 

NEUROFIBROMATOSIS 

Tumors  of  the  peripheral  nervous  system  form  a  very  important  and 
complex  group  of  neoplasms  of  frequent  occurrence  and  varied  clinical  course. 

A  satisfactory  classification  of  these  tumors  is  difficult,  owing  to  the  com- 
plex structure  of  the  nerve  trunks,  and  the  uncertainty  of  the  source  of  the 
supporting  cells  which  accompany  nerve-fibers,  such  as  the  cells  of  the  sheath 
of  Schwann,  the  neurilemma,  the  endoneurium,  and  the  lymph  sheaths  of 
nerve  trunks,  all  of  which  participate  in  tumor  growth. 

In  one  general  group  the  growth  affects  the  connective-tissue  structures 


FIBROMA  153 

of  the  nerve,  epineurium,  perineurium,  and  endoneurium,  the  specialized 
nerve  elements  undergo  atrophy,  the  tumors  are  fibrous  in  character,  and 
they  are  commonly  classed  with  the  fibromas. 

In  another  group  there  is  extensive  overgrowth  of  specialized  nerve  struc- 
tures, axis-cylinders,  and  myelin  sheaths,  and  these  tumors  are  designated 
as  neuromas.  Virchow  recognized  these  main  classes  as  false  and  true  neuromas. 

In  many  cases,  especially  the  more  actively  progressive,  there  is  over- 
growth of  both  nervous  and  supporting  elements,  which  are  difficult  to  trace 
in  the  tumor,  so  that  a  complex  histogenesis  must  be  recognized,  and  these 
tumors  do  not  readily  fall  in  either  of  the  above  groups.  Moreover,  there 
may  be  one  type  of  tumor  in  the  skin,  mainly  fibrous,  and  others,  mainly 
nervous,  in  the  deeper  regions  (Genersich,  Herxheimer). 

All  these  considerations  indicate  that  neurofibromatosis  in  all  its  forms 
is  essentially  one  and  the  same  disease,  and  that  the  underlying  factor  is  a 
disturbance  in  the  relations  between  the  fetal  ectoderm  and  the  tissues  which 
it  innervates. 

In  most  of  the  cases  it  is  the  motor  and  sensory  nerves  which  are  involved, 
in  some,  to  what  extent  is  not  yet  clear,  the  sympathetic  system  is  concerned. 


FlG.  27. — Recurrent  neurogenic   sarcoma   of   forearm.      Diffuse   invasion  of  skin  and 
muscle.     A  new  tumor  arising  in  upper  segment  of  nerve  trunk. 

It  is  probable  that  the  great  majority  of  fibromas  and  fibrosarcomas  of 
the  skin  and  deeper  tissues  of  limbs  and  trunk  are  of  neurogenic  origin. 

While  theoretical  considerations  favor  the  classification  of  all  tumors  of 
nerve  trunks  and  filaments  in  one  group,  there  are  practical  advantages  in 
separating  the  more  fibrous  growths  from  those  in  which  specialized  nerve 
structures  are  prominent. 

Adopting,  for  the  present,  this  latter  point  of  view,  the  neurofibromas 
will  be  described  as  a  type  of  fibroma,  while  the  others  will  be  considered  in 
a  separate  chapter  in  connection  with  tumors  of  brain  and  spinal  cord. 

Fibrous  tumors  of  the  nerve  trunks  and  filaments  appear  under  two  main 

forms:  v 

1.  Cutaneous    neurofibroma.      Single.     Multiple   (Fibroma    molluscum}. 

Recklinghausen's  disease.  . 

2.  Neurofibroma  of  the  subcutaneous  and  deeper  nerve  trunks, 
form  neurofibroma.    Visceral  neurofibroma.    Neurofibrosarcoma. 

Cutaneous  Neurofibroma.  Fibroma  Molluscum— This  most  frequeni 
tumor  of  the  skin  occurs  as  a  single  nodule,  more  often  as  very  numerous 


154  NEOPLASTIC  DISEASES 

projecting  nodules,  sometimes  associated  with  slight  local  or  general  pig- 
mentation. Recklinghausen  showed  that  the  tumors  arise  from  the  cutaneous 
nerve  filaments,  a  conclusion  which  had  been  suggested  by  some  previous 
writers  and  has  been  fully  verified  by  many  later  studies. 

The  peculiar  clinical  characters  of  the  disease  were  fully  described  by 
Kolliker,  1860;  Hitchcock,  1862;  Virchow,  1863;  Murray,  1873;  Atkinson, 
1875;  Balzer,  1879;  and  Winiwarter,  1876;  but  Recklinghausen  in  1882  traced 
degenerating  nerve-fibers  in  several  cases  and  stated  that  all  these  tumors 
arise  from  nerve  trunks  or  filaments.  An  extensive  literature  has  accumulated 
on  this  subject  and  has  been  reviewed  more  recently  by  Bruns,  Thomson, 
Adrian,  Sarazanes,  Verocay,  and  Herxheimer  and  Roth. 

In  typical  fibroma  molluscum  the  tumors  are  multiple  and  they  may  be 
so  numerous  as  to  nearly  cover  the  surface  of  the  body.  Very  often  a  single 
nodule  attracts  attention,  but  others  may  be  found  on  careful  search.  They 
may  be  as  small  as  a  pin-head,  more  often  the  size  of  a  pea,  occasionally  they 


<m^'#P'&t 


K  •        •  < . -  '       » 

FIG.  28. — Structure  of  a  recurrent  neurofibroma  of  skin. 

form  broader  flat  elevations.  Developing  in  the  subcutaneous  tissue  they 
may  reach  several  centimeters  in  diameter,  and  rarely  they  attain  larger  dimen- 
sions. A  few  become  pendulous,  and  complete  extrusion  has  been  observed. 
All  portions  of  the  integument  may  be  affected  from  the  scalp  to  the  soles 
of  the  feet,  while  in  some  cases  the  mucous  and  serous  membranes  and  internal 
organs  are  involved. 

In  the  skin  they  lie  in  the  derma  or  just  beneath  it,  where  they  form  hard, 
movable  and  often  painful  nodules,  of  irregular  distribution.  Pigmentation 
of  the  overlying  skin  or  other  regions  is  often  marked,  so  that  the  disease  is 
designated  as  pigmented  neurofibromatosis. 

Typical  fibroma  molluscum  may  be  complicated  by  other  forms  of  neuro- 
fibroma or  neurosarcoma,  as  in  the  cases  of  Genersich  and  Herxheimer. 

The  structure  presents  interlacing  hyaline  fibers  between  which  lie  few 
or  many  compressed  tumor  cells.  The  interlacing  structure  is  usually  very 
characteristic.  The  proportion  of  cells  to  intercellular  fibers  varies  widely, 


FIBROMA  155 

the  older  tumors  being  almost  completely  fibrous.  Nerve-fibers  in  stages 
of  degeneration  and  atrophy  may  usually  be  demonstrated.  The  larger 
tumors  frequently  involve  other  structures  of  the  skin,  as  the  sebaceous  and 
sweat  glands.  They  may  be  quite  vascular,  and  many  authors  trace  a  con- 
nection between  neurofibroma  and  angiofibromas  and  nevi.  They  are  some- 
times associated  with  xanthoma  (Delore,  Poncet)  and  with  multiple  lipoma 
(Vallas,  Mouchet).  Some  early  lesions  suggest  an  origin  from  the  connective 
tissue  about  sweat  glands,  but  even  here  the  process  has  been  traced  to  nerve 
filaments  probably  belonging  to  the  sympathetic. 

The  exact  nature  of  the  cells  involved  in  neurofibromas  is  not  easily  deter- 
mined and  probably  not  uniform.  Herxheimer  and  Roth  conclude  that  the 
small  dermal  tumors  are  chiefly  fibromas.  In  the  larger  growths  they  find 
that  the  cells  of  the  sheath  of  Schwann  and  of  the  endoneurium  multiply. 
Concentric  groups  of  cells  which  are  so  characteristic  of  this  tumor  they 
interpret  as  endothelium  of  the  nerve  sheaths.  In  the  ganglionic  lesions 
the  endothelium  of  the  capsules  of  the  ganglion  cells  multiples  actively.  In 
fact,  all  the  elements  of  the  nerve  filament  or  nerve  trunk  except  the  ganglion 
cells  and  nerve  fibrils  participate  in  the  tumor  process. 

According  to  Verocay's  conception  the  tissue  of  neurofibroma  is  not  con- 
nective, but  consists  of  nerve  cells  or  their  embryonal  equivalents  which  have 
not  been  properly  employed  in  the  development  of  the  nervous  system.  He 
therefore  suggests  the  term  "neurinoma."  The  validity  of  this  view  depends 
on  the  nature  of  the  cells  of  the  sheath  of  Schwann.  If  these  are  specialized 
nerve  or  glia  cells  Verocay's  interpretation  would  seem  acceptable,  but  it 
seems  probable  that  this  author  has  chiefly  studied  tumors  which  belong 
with  the  true  neuromas  and  their  derivatives. 

Clinical  Course. — The  single  nodules  in  the  skin  are  of  slow  growth,  may 
undergo  fibrosis,  and  are  usually  excised  without  recurrence.  When  the 
nodules  are  very  numerous  they  cannot  well  be  excised,  and  the  patient  often 
presents  other  general  stigmata  of  Recklinghausen's  disease.  "  Bruns  calcu- 
lates that  about  8  per  cent,  of  the  cases  of  multiple  neurofibroma  are  com- 
plicated by  other  phases  of  the  disease  and  eventually  die  from  extensions 
of  the  tumors.  These  cases  belong  to  a  group  in  which  the  larger  nerve  trunks 
are  involved  and  they  deserve  separate  consideration. 

The  typical  molluscum  persists  for  many  years  with  slow  increase  in  the 
size  and  number  of  tumors,  but  without  notable  change  in  character. 

Neurofibroma  of  the  Deeper  Nerve  Trunks.  Visceral  Neurofibroma. 
Neurofibrosarcoma. — In  a  numerous  group  of  cases  the  subcutaneous  and 
deeper  nerve  trunks,  and  especially  the  peripheral  portions  of  the  nerve  trunks, 
are  the  seat  of  single  or  multiple  tumors  which  are  usually  more  cellular  than 
the  cutaneous  fibromas,  and  carry  a  much  more  serious  prognosis. 

In  the  simplest  form  the  tumor  is  a  firm  movable  mass  lying  in  the  sub- 
cutaneous tissue,  well  circumscribed,  of  moderate  dimensions,  slow  growth, 
and  often  permitting  successful  excision. 

Very  often,  however,  the  single  subcutaneous  tumor  is  associated  with 
other  growths  which  appear  later  in  the  course  of  the  same  nerve  trunk.  Or 
the  single  superficial  tumor  is  followed  after  excision  by  another  growth  at 
or  near  the  original  site.  The  subcutaneous  and  intermuscular  regions  of  the 
arm,  leg,  popliteal  space,  neck,  or  back  are  favorite  seats  of  such  multiple 
tumors  with  recurrence  after  operation. 

In  certain  cases  the  external  tumors  are  associated  with^  multiple  small 
or  single  large  tumors  of  the  deep  nerve  trunks,  which  project  into  the  pleural 
or  peritoneal  cavities,  or  externally,  and  give  the  impression  of  being  metastatic 
growths. 


156 


NEOPLASTIC  DISEASES 


The  plexiform  or  cirsoid  neurofibroma  occurs  in  the  subcutaneous  tissues 
of  face,  scalp,  buttock,  or  other  regions,  and  produces  a  bulky  ill-defined 
swelling  in  which  the  thickened  nerve  trunks  may  be  detected  by  palpation. 
On  dissection  many  of  the  coiled  and  thickened  nerve  trunks  may  be  un- 
raveled. The  blood-vessels  may  be  abundant  and  dilated.  On  microscopic 
section  one  finds  diffuse  and  nodular  swelling  of  the  nerve  trunks  due  to  in- 
crease of  the  cells  within  the  epineurium  and  to  mucous  degeneration.  The 
fibrous  tissue  about  the  nerves  and  vessels  and  throughout  the  fat  tissues 
may  be  increased  and  infiltrated  with  mucus.  Local  recurrence  is  very  fre- 
quent and  sarcomatous  changes  have  occurred  in  several  cases,  so  that  simple 

surgical  interference  is  generally  contrain- 
dicated.  Many  other  peculiarities  are  illus- 
trated in  the  cases  collected  by  Reckling- 
hausen  and  later  writers. 

There  is  considerable  variety  in  the 
structure  of  the  larger  tumors  of  nerve 
trunks.  Some  exhibit  overgrowth  of  nerve 
elements  and  medullated  nerve-fibers,  and 
belong  in  the  class  of  true  neuromas.  Most 
of  them  are  rather  cellular  but  fibrous,  and 
show  no  reproduction  of  nerve-fibers,  but 
they  lack  encapsulation,  they  recur  locally 
with  great  persistence,  so  that  the  patient 
eventually  loses  the  limb  after  repeated  ex- 
cision, or  his  life  from  metastatic  growths. 
They  are  therefore  properly  designated  as 
neurosarcoma.  Local  recurrence  is  observed 
with  some  rather  fibrous  tumors  of  this  class. 
Or  the  cells  are  much  more  numerous  than 
the  fibers  and  appear  as  elongated  spindle- 
cells  arranged  in  intertwining  fascicles,  and 
the  tendency  to  recurrence  is  more  marked. 
Very  cellular  growths  present  larger  poly- 
hedral or  multipolar  cells  with  little  stroma. 
Giant-cells  may  be  prominent.  Myxomatous 
changes  are  frequently  observed,  so  that  the 
suspicion  arises  that  most  of  the  recurring 
myxomas  of  the  skin  and  fasciae  may  originate 

FIG.  29.— Hard  recurrent  fibro-  from  nerve  trunks.  In  actively  growing 
sarcoma  of  popliteal  space.  Prob-  neurosarcoma  the  cells  are  very  numerous, 
ably  neurogenic.  small,  spindle  or  rounded  in  form,  and  devoid 

of  definite  stroma. 

The  clinical  course  of  neurofibrosarcoma  of  the  deeper  nerve  trunks  is 
generally  unfavorable.  The  small  tumors  may  begin  to  grow  slowly  and 
some  appear  to  reach  a  natural  limit.  Many  of  them  progress  by  successive 
involvement  of  more  central  portions  of  the  condemned  nerve  trunk.  A  high 
proportion  recur  after  each  operation,  with  increasing  extensions,  more  active 
proliferation  of  cells  of  more  atypical  quality,  and  eventually  calling  for 
amputation  of  the  limb.  Even  wide  excision  may  fail  to  remove  the  danger  of 
local  return,  while  new  tumors  continue  to  develop  higher  up  the  nerve  trunk. 
The  usual  postoperative  recurrence  presents  an  indurated  scar,  firmly 
adherent  to  an  underlying  mass  which  extends  widely  in  and  between  the 
muscles,  along  the  fasciae,  and  even  to  the  bone,  which  restricts  movement, 
is  accompanied  by  much  pain,  and  is  quite  impossible  of  excision. 


FIBROMA  157 

In  such  conditions  it  is  difficult  to  distinguish  between  local  recurrence 
and  the  development  of  new  tumors.  The  cellular  growths  invade  the  sub- 
cutaneous and  deep  veins,  and  produce  pulmonary  metastases  which  often 
reach  large  dimensions.  Such  metastases  may  exist  when  the  local  tumor  is 
not  regarded  seriously  or  when  amputation  is  advised. 

The  serious  nature  of  the  deeper  neurofibromas  is  very  imperfectly  realized 
by  most  surgeons,  so  that  the  number  of  victims  of  this  disease  is  much  larger 
than  is  generally  believed.  The  primary  attack  on  these  tumors  must  be 
undertaken  with  great  caution.  Little  aid  in  their  control  can  at  present  be 
expected  from  the  ordinary  methods  of  employing  x-ray  or  radium  as  an 
adjuvant  to  surgery.  Probably  the  best  plan  of  treatment  is  to  apply  radium 
or  x-ray  to  the  limit  of  skin  tolerance,  followed  by  excision  of  the  tumor  and 
the  use  of  radium  in  the  fresh  wound.  The  persistent  use  of  the  x-ray  may 
effect  a  cure. 


•  .  ^ 

pIG>  20.  —  Markedly  fasciculated  structure  of  a  neurosarcoma.     Neurofibroma  of  skin. 

Visceral  Neurofibromatosis.  —  The  internal  nerve-trunks  and  filaments 
may  be  the  seat  of  large  plexiform  or  small  multiple  fibromas.  In  the  intestinal 
form  the  tumors  may  occur  at  any  point  from  the  lips  to  the  anus.  Certain 
cases  of  macroglossia  have  been  found  to  be  diffuse  neurofibromatosis  and 
related  to  elephantiasis  especially  of  the  lymphangiectatic  type  (Virchow). 
Sarazanes  has  collected  cases  in  which  the  tumors  occurred  in  the  tongue, 
stomach,  jejunum,  ileum,  colon,  vagina,  and  bladder.  In  Robin's  case  there 
was  a  large  tumor  of  the  solar  plexus.  Lotzbeck  has  described  several  large 
tumors  pressing  upon  the  lumbar  spine  and  arising  from  the  lumbar  plexus, 
and  Czerny  observed  a  case  involving  both  lumbar  and  sacral  plexuses. 
Pomorski  describes  a  remarkable  case  in  which  multiple  tumors  projected 
into  the  pleural  cavity  arising  from  the  intercostal  nerves.  Herxheimer  and 
Roth  describe  a  remarkable  case  presenting  multiple  fibromas  of  skin  of  upper 
half  of  trunk;  fibromas  of  intercostal  and  lumbar  nerves;  small  sarcoma  of 
lumbar  plexus  passing  into  a  large  pelvic  tumor;  tumor-like  thickenings  of 


158  NEOPLASTIC  DISEASES 

terminal  filaments  of  the  sympathetic  and  lumbar  intervertebral  ganglia; 
tumor  mass  with  chromaffin  cells  in  adrenal  medulla;  multiple  subserous 
nodules  in  jejunum;  miliary  endotheliomas  of  spinal  dura. 

In  a  well-defined  group  of  cases  the  sympathetic  system  is  the  chief  or 
exclusive  seat  of  the  lesions  (Czerny,  Adrian).  In  the  case  of  Simon  and 
Hoche  the  mesentery  was  much  thickened  and  beset  with  many  fine  nodules. 

Several  cases  with  adrenal  tumors  and  pigmentation  serve  to  explain  the 
long-suspected  relation  to  Addison's  disease  (Chauffard,  Suzuki,  Hoffmann, 
Kawashima,  Vignolo-Lutati).  The  tumors  of  the  adrenal  are  composed  of 
medullary  chromaffin  cells.  Gliomas  of  the  central  nervous  system  have 
been  observed  in  a  few  cases  (Verocay). 

Elephantiasis. — It  has  long  been  recognized  that  there  exists  a  close  con- 
nection between  multiple  tumors  of  nerve-trunks  and  some  forms  of  ele- 


-Oj  -V.**. 


FIG.  31. — Neurofibromatosis.  Detail  of  process  in  nerve-filaments.  In  the  center, 
proliferation  of  sheath-cells;  in  intermediate  zone,  endothelial  cells;  in  peripheral  arear 
fibroblasts.  (After  Herxheimer.) 

phantiasis.  The  nature  of  this  relation  remains  ill-defined,  but  it  is  strongly 
suggested  by  the  occurrence  of  multiple  fibromas  in  many  cases  of  elephan- 
tiasis, by  the  hereditary  and  congenital  character  of  both  conditions,  by  the 
occasional  presence  in  both  of  pigmentary  changes  in  the  skin,  and  by  the 
partial  histological  resemblance  of  the  structure  of  the  affected  tissues.  The 
result  of  recurrent  inflammation  and  lymph  stasis  are  the  two  main  factors 
which  separate  non-parasitic  elephantiasis  from  fibromatosis. 

Elephantiasis  or  diffuse  fibromatosis  affects  the  skin  over  large  areas,  as 
of  an  entire  limb,  or  occurs  in  more  circumscribed  form  when  its  neoplastic 
characters  are  more  distinct.  It  is  acquired  and  sporadic  or  congenital  and 
endemic.  Beginning  early  it  produces  a  soft  mucinous  thickening  or  in  later 
periods  the  tissue  is  firmer  or  sclerosed  (elephantiasis  molle  and  durum).  The 
lymph-vessels  are  commonly  increased,  enlarged,  or  may  be  cystic  (ele- 
phantiasis lymphangiectatica). 


FIBROMA  159 

Hygroma  cysticum  (Wernher)  is  a  circumscribed  form  of  congenital  lymph- 
angiectatic  elephantiasis  appearing  in  the  neck,  sacral  and  perineal  regions 
of  fetuses,  infants,  and  children.  The  blood-vessels  are  sometimes  much 
increased  (elephantiasis  telangiectatica,  elephantiasis  angiomatosa) .  In 
some  remarkable  cases  the  skin  of  the  entire  limb  was  greatly  swollen,  dark 
blue,  and  composed  of  many  thickened  varicose  veins  often  containing  phle- 
boliths  (Rokitansky,  Pitha,  Leisrink,  Unna).  All  structures  of  the  skin  may 
be  involved  and  there  is  increase  of  connective  tissue  diffusely  and  about 
nerves,  vessels,  and  glands.  The  sweat-glands  may  be  hypertrophic.  The 
epidermis  may  be  thickened,  pigmented,  and  corrugated,  and  in  the  remark- 
able form  of  congenital  ichthyosis  it  is  hypertrophic  and  extensively  horni- 
fied.  In  cases  reported  by  Naegeli  and  by  Morgan  elephantiasis  was  associ- 
ated with  tumor-like  thickening  of  the  nerve-trunks  supplying  the  area.  In 
several  cases  reported  by  P.  Bruns  the  elephantiasis  was  associated  with 
definite  neurofibromatosis.  In  certain  cases  usually  congenital  the  thick- 
ened skin  falls  in  overlapping  folds  like  drapery  (Mott)  and  for  these  cases 
the  terms  pachydermia  or  pachydermatocele  are  employed.  Jordan  dis- 
tinguished two  types  of  congenital  elephantiasis,  one  of  which  is  chiefly  a 
diffuse  neurofibromatosis,  the  other  involving  nerves,  other  cutaneous  struc- 
tures, and  the  muscle-tissue.  In  each  case  the  blood-vessels  gave  origin  to 
the  new  tissue. 

In  most  cases  of  acquired  elephantiasis  the  nerve-trunks  play  a  subordi- 
nate part  and  the  process  involves  all  the  cutaneous  structures,  yet  in  many 
cases  of  long-standing  neurofibromatosis  similar  extension  of  the  hyperplastic 
process  is  observed.  The  clinical  history  indicates  that  this  extension  is 
chiefly  owing  to  recurrent  inflammation  and  lymph  stasis.  Thus  the  disease 
commonly  progresses  with  repeated  attacks  of  erythema  or  erysipeloid,  and 
it  may  develop  in  the  course  of  chronic  suppuration.  These  observations 
early  led  to  the  assumption  that  elephantiasis  was  of  infective  origin  and 
confusion  arose  between  elephantiasis  arabum  (diffuse  fibromatosis)  and 
elephantiasis  graecorum,  which  was  true  leprosy.  Carter  has  pointed  out 
many  points  of  resemblance  between  the  two  types,  especially  in  the  nerve 
lesions,  and  shown  that  true  elephantiasis  may  complicate  leprosy.  Today 
both  leprosy  and  filariasis  may  be  readily  separated  from  the  other  causes 
of  elephantiasis. 

These  clinical  relations  of  elephantiasis  as  well  as  the  histological  structure 
demonstrate  that  the  process  is  not  a  true  neoplasm,  but  belongs  in  the  class 
of  fibromatoid  reactions  of  predisposed  subjects  to  chronic  disturbance  of 
nutrition. 

Neuropathic  papilloma  (Gerhardt),  Nevus  unius  lateris  (Barensprung), 
Nevus  linearis  (Unna),  Nerve  nevus  (Simon). — This  lesion  occurs  as  multi- 
ple flat  or  bean-shaped,  warty  outgrowths  of  hypertrophic  dermal  papillae. 
They  follow  the  distribution  of  definite  cutaneous  nerves  like  herpes  zoster 
and  may  be  more  numerous  along  Voight's  lines  bounding  the  distribution 
of  the  nerves  (Philipson).  They  may  occur  on  any  portion  of  the  body  and 
even  in  the  buccal  mucosa  (Pott).  In  some  cases  they  are  extensively  pig- 
mented (Schonberg). 

The  condition  is  hereditary  (Haegele)  and  often  congenital,  but  may 
appear  as  late  as  the  2;th  year.  The  onset  may  be  rather  acute,  as  in  Beigel's 
case,  but  the  course  is  chronic,  reaching  a  standstill  or  spontaneously  regres- 
sing (Neumann).  Pain  may  be  pronounced,  and  paresis  and  paralysis  may 
develop. 

The  histology  shows  an  acute  stage  followed  by  chronic  connective  over- 
growth of  dermal  papillae,  but  the  structure  varies  greatly  and  there  are  no 


160  NEOPLASTIC  DISEASES 

reports  to  indicate  that  the  process  is  a  true  tumor.  In  Elliot's  case  there 
was  cystic  distention  of  the  cutaneous  glands.  The  overlying  epithelium 
may  be  hypertrophic.  Recklinghausen  states  that  the  growth  affects  the 
terminal  filaments  of  the  nerves,  that  it  follows  neuritis  and  is  related  to 
ichthyosis  with  which  it  may  be  associated.  Unna  doubts  this  relation.  Al- 
though the  condition  is  vaguely  defined  it  appears  to  represent  most  clearly 
the  influence  of  nervous  disorder  upon  fibromatosis. 

General  Etiology. — In  the  origin  of  the  foregoing  types  of  cutaneous 
fibromas  many  complex  factors  seem  to  be  concerned,  most  of  which  center 
in  the  nervous  system.  Together  they  constitute  a  somewhat  definite  clin- 
ical entity  or  dyscrasia  to  which  the  term  neurofibromatosis  may  be  applied. 
The  congenital  and  slightly  hereditary  character  is  prominent  in  all  the  forms 
of  fibromatosis,  suggesting  the  existence  of  abnormal  qualities  in  the  connect- 
ive tissues  of  these  subjects.  The  unfolding  of  the  dyscrasia  often  proceeds 
in  a  somewhat  orderly  manner.  Thus^  Debove  observed  pigmented  plaques 
at  birth,  small  tumors  of  the  skin  at  5  years  of  age,  and  tumors  of  the  nerves 
at  8.  Yet  in  most  cases  the  pigmentation  and  the  tumors  appear  simul- 
taneously at  a  later  age,  10  to  30  years  (Marie).  French  authors,  especially 
Sarazanes,  emphasize  the  nervous  symptoms  observed  in  many  cases,  and 
point  to  the  pain,  anesthesia,  defects  of  special  senses,  neuroses,  epilepsy, 
mental  disturbances,  idiocy,  fragility  of  the  bones,  and  infantilism  and  mal- 
formations, as  evidence  of  general  and  especially  of  nervous  deficiency  in  the 
subjects  of  neurofibromatosis.  Various  digestive  disturbances,  jaundice, 
urobilinuria,  and  alterations  of  nitrogenous  metabolism  have  been  cited  in 
support  of  the  theory  of  general  dyscrasia.  Feindel  and  Oppenheim  describe 
marked  forms  of  neurofibromatosis,  in  which  the  general  symptoms  are  present 
with  punctate  or  lenticular  pigmented  spots  in  the  skin,  while  the  tumors  are 
absent,  scanty,  or  appear  later. 

For  general  fibromatosis  various  theories  of  origin  have  been  assumed,  as 
the  theory  of  recurrent  or  chronic  infection  as  suggested  by  the  recurrent 
inflammatory  processes  in  elephantiasis  and  its  resemblance  to  leprosy.  The 
theory  of  auto-intoxication  is  suggested  by  many  constitutional  symptoms 
and  especially  by  certain  cases  of  neurofibroma  which  clinically  resemble 
Addison's  disease  (Chauffard,  Bernard).  Feindel  points  out  that  the  pig- 
mentation and  tumors  may  date  from  pregnancy,  and  alcoholism  and  over- 
use of  arsenic  have  been  reported  as  exciting  causes.  Brickner  has  described 
in  pregnancy  a  peculiar  punctate  pigmentation  of  the  skin  which  seems  to 
fall  with  neurofibromatosis.  It  is  generally  assumed  that  the  victims  of 
fibromatosis  are  the  subjects  of  a  congenital  malformation  of  the  ectoderm 
which  under  a  great  variety  of  exciting  causes  may  slowly  or  rapidly  develop 
one  or  more  of  the  manifestations  of  the  disease.  The  great  mass  of  data 
that  has  accumulated  in  this  field  seems  to  call  for  a  general  assent  to  this 
hypothesis,  but  there  is  danger  that  the  conception  of  the  scope  of  this  dyscrasia 
may  be  extended  over  too  many  pathological  phenomena. 

Keloid  (*y//>y,  tumor)  or  cheloid  (yji't.rh  claw)  is  a  peculiar  overgrowth 
of  hyaline  connective  tissue  developing  in  the  skin  of  predisposed  subjects 
after  trauma  or  scarring.  The  traumatic  origin  is  usually  obvious,  as  in 
the  extensive  scarring  of  burns.  More  localized  keloids  occur  in  which 
it  is  difficult  to  trace  the  probable  traumatic  origin,  and  these  are  called 
spontaneous. 

The  subjects  of  keloid  may  exhibit  a  special  predisposition  to  overgrowth 
of  connective  tissue  after  injury  and  in  the  negro  this  predisposition  is  racial. 
The  character  of  the  trauma  is  diverse.  Extensive  burns  by  heat  or  escha- 
rotics  are  specially  prone  to  develop  keloid,  but  needle  punctures  (Gumbel) , 


FIBROMA 


161 


scratches,  vaccination,  repeated  pressure  of  heavy  weights,  and  surgical  wounds 
have  preceded  the  condition. 

The  typical  keloid  has  a  characteristic  structure  and  consists  of  anasto- 
mosing strands  of  thick,  hyaline,  collagenous  matrix  between  which  lie  many 
well-nourished  fibroblasts.  Small  well-developed  blood-vessels  are  present, 
and  lymph  spaces  may  be  so  prominent  as  to  lead  to  the  use  of  the  term 
lymphangiofibroma  for  some  cases  of  keloid.  Elastic  fibers  are  missing. 
Glandular  structures  of  the  skin  are  pushed  aside  and  this  fact  leads  Goldman 
to  conclude  that  the  growth  of  the  tumor  is  chiefly  central.  The  periphery  is 
not  well  defined,  but  is  often  more  cellular,  with  thinner  fibers  than  the  cen- 
tral portions.  Yet  this  feature  is  not  so  pronounced  as  to  deprive  the  growth 


FIG.  32. — Structure  of  a  keloid. 

of  its  circumscribed  character  or  to  invalidate  the  statement  of  Ribbert  that 
keloid  grows  largely  from  its  own  resources.  Secondary  changes  are  chiefly 
those  of  increasing  hyalinosis. 

Keloid  occurs  in  the  form  of  a  broad  flat  elevated  firm  thickening  of  scar 
tissue  which  gradually  extends  over  a  considerable  area,  or  as  more  circum- 
scribed projecting  or  even  polypoid  outgrowths.  The  overlying  epidermis 
is  usually  shiny,  atrophic,  and  separated  from  the  tumor  by  a  thin  layer  of 
cutis.  The  natural  history  is  of  a  slowly  progressive  growth  which  tends  to 
involve  the  whole  area  of  affected  scar  tissue,  or  remains  limited  to  the  seat 
of  a  trauma.  After  extirpation  it  often  develops  anew  in  predisposed  tissues, 
but  never  produces  metastases.  It  may  be  made  to  disappear  under  pressure. 
11 


162  NEOPLASTIC  DISEASES 

The  neoplastic  properties  in  keloid  are  not  pronounced.  Especially  at 
its  inception  it  belongs  in  the  group  of  fibrous  overgrowths  which  depend 
upon  chronic  disturbance  of  nutrition.  Yet  it  sometimes  possesses  consider- 
able momentum  of  growth,  its  cells  exhibit  nuclear  hypertrophy,  and  especially 
in  the  so-called  spontaneous  circumscribed  forms,  it  may  sometimes  be  re- 
garded as  an  imperfect  neoplasm.  The  remarkable  case  of  Porter's,  in  which 
a  very  bulky  keloid  of  face  and  arm  developed  in  ten  months  after  a  burn, 
suggests  both  the  neoplastic  nature  of  the  process  and  a  predisposition  to 
the  disease. 

Xanthoma,  or  xanthelasma,  as  named  by  Wilson  and  Smith,  is  a 
common  brownish-yellow  tumor  of  the  skin  appearing  most  frequently  in  the 
eyelids  (92  per  cent.,  Poensgen),  but  occurring  in  multiple  form  in  other 
regions  (xanthoma  multiplex,  generalized  xanthoma).  It  may  appear  first 
in  the  eyelid,  later  in  other  localities  (Korach)  and  like  multiple  fibroma  often 
follows  the  course  of  cutaneous  nerves,  especially  along  Voight's  lines  (Kob- 
ner),  and  symmetrically  along  folds  of  the  skin.  Apparently  similar  growths 
have  been  described  in  the  respiratory  and  pharyngeal  mucosa,  the  serous 
membranes,  endocardium,  tendon  sheaths,  on  the  cornea,  and  in  the  pancreas 


FIG.  33. — Tumor-like  keloid  following  needle  puncture.     Remained  stationary  after   a 
few  months  of  rapid  growth.     (After  Brenizer,  A.  S.,  61.) 

in  diabetes.  According  to  Unna  generalized  xanthoma  is  sharply  separated 
anatomically  from  xanthoma  palpebrarum. 

In  the  skin  the  growth  is  flat  (xanthoma  planum)  or  bean  shaped  (xan- 
thoma tuberosum)  or  polypoid  and  pendulous.  Usually  of  small  size,  they 
occasionally  reach  considerable  dimensions  (Poensgen,  Ehrmann).  They 
are  often  congenital,  but  rather  more  frequent  in  adults  and  old  persons. 
It  was  shown  by  Chambard  that  general  xanthoma  may  develop  in  the  course 
of  icterus  or  with  other  diseases  of  the  liver  and  with  diabetes  (xanthoma  dia- 
beticorum).  Not  a  few  subjects  of  early  xanthoma  later  develop  diabetes, 
yet  Johnston  and  Torok  separate  the  skin  affection  in  diabetes  from  the  com- 
mon xanthoma  vulgare.  The  diabetic  lesion  may  be  transitory,  while  the 
other  is  permanent. 

In  some  cases  xanthoma  tuberosum  is  associated  with  nevi,  vascular  and 
pigmented,  illustrating  a  congenital  predisposition,  and  this  fact  may  support 
Borst's  conclusion  that  the  two  conditions  are  anatomically  related.  Xan- 
thoma may  also  be  associated  with  multiple  lipomas  (Ehrmann).  Virchow 
regarded  xanthoma  tissue  as  intermediate  between  connective  and  fat  tissue 
and  employed  the  term  fibroma  lipomatodes,  believing  that  the  cells  were 


FIBROMA  163 

derived  from  fibroblasts.  The  histological  and  clinical  features  point  to  the 
existence  of  a  peculiar  formation  of  lipoids  in  the  cells  of  a  fibroma  under 
the  influence  of  a  local  nervous  and  a  general  metabolic  disorder.  In  xan- 
thoma  palpebrarum  the  deposit  of  lipoids  precedes  the  tumor  growth  and 
first  appears  as  yellow  streaks  along  the  blood-  and  lymph-vessels  and  muscle- 
fibers. 

The  structure  of  xanthoma  is  characterized  chiefly  by  the  great  abundance 
of  lipoid  globules  in  large  swollen  polyhedral  and  smaller  spindle-shaped  cells. 
This  material  is  an  orange-yellow  lipochrome;  more  of  it  is  stained  by  sudan 
III  than  by  osmic  acid,  and  Stoerk,  with  Pinkus  and  Pick,  have  showed  that 
the  globules  are  doubly  refractive  and  of  myelin  nature  or  probably  a  choles- 
terin  fatty  acid  ester.  The  central  cells  may  become  greatly  distended  with 
this  material,  while  the  peripheral  cells  may  show  the  spindle  shape  of  grow- 
ing fibroblasts.  Much  fatty  detritus  may  accumulate  in  these  tumors  and 
giant-cells  similar  to  those  in  epulis  and  containing  or  surrounding  iatty 
crystals  or  masses  may  form  (Teuton).  In  such  cases  the  tumor  may  resem- 
ble a  spindle-  and  giant-cell  sarcoma.  I  have  seen  such  a  tumor  from  the 
peroneal  tendon  sheath  of  a  diabetic  subject  who  also  showed  xanthoma 
palpebrarum. 

Waldeyer  early  showed  that  the  first  changes  in  xanthoma  palpebrarum 
consist  in  the  appearance  of  fatty  globules  in  certain  perivascular  groups  of 
star-shaped  fibroblasts.  Many  authors,  including  Borst,  trace  the  xanthoma 
cells  to  the  lymph  endothelium  and  he  also  finds  a  close  structural  resem- 
blance between  some  xanthomas  and  pigmented  nevi.  Hallopeau  and  Torok 
consider  the  cells  as  equivalent  to  embryonal  fat-cells  which  they  may  strongly 
resemble.  Waldeyer  found  many  plasma-cells  about  the  vessels  of  the  eye- 
lid and  believes  that  these  become  infiltrated  with  fat.  Hebra,  Wilson,  Geyer, 
and  others  have  observed  a  proliferation  of  the  sebaceous  glands,  and  Knauss 
of  the  hair  follicles,  sweat-glands,  and  blood-vessels.  Pollitzer  in  cases  of 
xanthoma  palpebrarum  traces  the  fatty  cells  to  degenerating  fibers  of  the 
orbicularis  muscle,  and  he  would  separate  this  lesion  from  xanthoma  multiplex, 
which  he  regards  as  a  fibroma  or  keloid  undergoing  fatty  degeneration.  Unna 
also  traces  a  close  connection  between  the  fatty  cells  of  early  xanthoma  palpe- 
brarum and  the  muscle-fibers  of  the  orbicularis  which  lie  close  to  the  skin, 
but  he  considers  the  fat  to  be  a  deposit  from  the  lymph-vessels. 

It  thus  appears  that  many  different  anatomical  elements  may  be  con- 
cerned in  the  clinical  lesions  of  xanthoma,  and  that  not  all  of  the  clinical 
forms  have  a  relation  to  tumors.  Some  of  them,  however,  are  certainly  neo- 
plastic  and  fibromatous.  Since  the  fatty  change  seems  to  be  identical  in 
nature  wherever  it  occurs  there  would  seem  to  be  room  for  the  term  xan- 
thomatosis  as  applying  to  this  process  wherever  it  occurs  and  without  limitation 
to  a  specific  anatomical  lesion. 

FIBROMA  OF  BONES,  PERIOSTEUM,  AND  FASCLE 

Tumors  of  this  class  are  comparatively  rare,  but  of  very  general  distri- 
bution. From  the  maxillae,  especially  the  superior,  fibromas  arise  and  reach 
moderate  dimensions,  projecting  into  the  mouth  with  ulceration  of  the  mu- 
cosa,  or  beneath  the  skin.  In  the  interior  of  the  maxillae  fibromas  may  develop 
from  disturbances  in  the  formation  of  the  teeth  (Blauel).  The  long  bones  are 
occasionally  the  seat  of  hard  fibroma  for  which  a  history  of  trauma  is  common. 
In  the  fasciae  especially  about  the  joints  are  encountered  hard  fibromas  which 
may  reach  a  considerable  size.  The  osteal  and  periosteal  fibromas  frequently 
exhibit  areas  of  calcification,  chondrification,  and  true  bone  formation,  in 


164 


N  EOF  LAST  1C  DISEASES 


which  processes  characteristic  osteoblasts  engage.  Bone  also  forms  in  fibromas 
apart  from  any  connection  with  periosteum.  In  the  large  fascial  fibromas 
hyalinosis,  calcification,  and  central  softening  may  occur  leading  to  arrest 
of  growth. 

Desmoid  Tumors. — This  term  was  given  by  J.  Muller  and  the  older 
writers  to  the  general  class  of  hard  fibromas.  It  is  now  used  chiefly  to  desig- 
nate a  group  of  tumors  arising  from  the  rectus  abdominis  muscle.  This  condi- 
tion is  of  rather  frequent  occurrence,  Ledderhose  having  analyzed  100  cases, 
and  Bodenstein,  21. 

The  tumors  occur  chiefly  in  women  after  gestation,  between  the  2oth 
and  35th  years.  Kramer  and  Greig  have  described  congenital  cases.  They 
appear  at  any  point  in  the  abdominal  wall  between  costal  border  and  pubes, 
and  grow  slowly  until  they  reach  variable  but  often  considerable  dimensions, 
Bodenstein's  tumor  measuring  24  x  27  cm.  Bouffleur's  tumor  filled  groin 


FIG.  34. — Structure  of  a  recurrent  bulky  desmoid  tumor  of  abdominal  wall. 

and  pelvis  and  was  attached  to  iliac  spine.  The  growth  usually  springs  from 
the  transverse  or  vertical  fibers  on  the  posterior  surface  of  the  muscle,  to 
which  it  is  attached  by  a  broad  base  or  narrow  pedicle.  It  frequently  involves 
a  considerable  area  of  peritoneum,  the  excision  of  which  forms  the  main 
difficulty  in  operation. 

The  structure  varies  from  a  hard  acellular  fibroma  to  a  rather  cellular 
fibrosarcoma,  the  latter  type  exhibiting  somewhat  active  growth.  The  prog- 
nosis is  good. 

The  origin  of  the  tumors  in  adults,  especially  after  gestation,  may  prob- 
ably be  referred  to  trauma  of  the  muscle  and  to  interference  with  the  healing 
process  by  constant  traction.  Yet  the  congenital  cases  and  those  following 
laparotomy  suggest  that  there  is  some  anatomical  predisposition  to  tumor 


FIBROMA  165 

growth  in  this  region.     The  possible  relation  to  neurofibroma  is  to  be  con- 
sidered. 

FIBROMA  OF  GLANDULAR  ORGANS 

Breast. — The  fibromas  of  the  breast  are  usually  complex  fibre-adenomas 
and  will  be  considered  under  epithelial  tumors. 

Kidney. — Small  fibromas  of  the  kidney  are  of  frequent  occurrence.  They 
are  single  or  multiple,  often  bilateral,  hard,  opaque,  homogeneous  nodules 
which  project  under  the  capsule,  or  appear  in  the  cortex  or  more  frequently 
in  the  medulla  at  the  bases  of  the  pyramids.  Many  of  them  contain  smooth 
muscle-fibers  and  in  the  cortex  they  usually  inclose  compressed  or  cystic 
renal  tubules.  These  small  tumors  arise  from  disturbances  of  development 
of  the  kidney.  According  to  Genewein  they  are  not  true  neoplasms,  but 
tumor-like  nodules  resulting  from  superfluous  tissue  (Albrecht's  hamartoma). 


FIG.  35. — Fibroma  of  ovary. 

Large  fibromas  occasionally  grow  from  the  capsule  or  in  the  hilus  of  the 
kidney,  but  they  are  generally  associated  with  fat  and  smooth  muscle-tissue, 
and  exhibit  myxomatous  changes.  Under  the  term  myxoma  fibromatosum 
Tillmann  described  a  large  tumor  weighing  10  pounds  which  he  extirpated 
from  a  woman  of  28  years  and  which  soon  recurred.  Glaus,  Wilks,  and  Busse 
and  Reinach  have  reported  large  tumors  of  capsule,  cortex,  or  hilus  of  the 
kidney  which  were  nearly  pure  fibroma  or  mixed  with  lipoma,  myxoma,  or 
myoma.  In  a  large  tumor  of  this  class  I  found  lobules  of  nearly  pure  fibroma, 
with  others  of  fat  and  myxomatous  tissue.  These  growths  must  owe  their 
origin  to  some  developmental  disturbances  of  the  kidney,  the  nature  of  which 
is  undetermined.  Small  fibromyomas  or  nearly  pure  multiple  leiomyomas  are 
not  infrequently  seen  and  have  been  described  by  Lartigau  and  Larkin. 

Testis.— Pure  fibroma  of  the  testis  is  very  rare  (Langhans),  but  I  find 
that  tumors  chiefly  fibromatous  have  been  described  as  occurring  in  the  tunica 
albuginea,  testis,  epididymis,  or  cord.  On  close  examination  most  of  these 
tumors  disclose  evidence  of  complex  composition,  as  in  Chevassu's  case. 


166  NEOPLASTIC  DISEASES 

They  have  sometimes  reached  a  large  size.  Their  origin  has  been  referred  to 
the  interstitial  tissue  of  the  affected  locality,  but  that  some  of  them  are  re- 
lated to  teratoma  is  very  probable. 

•  Fibroma  in  the  ovary  presents  several  features  of  interest,  (a)  The  dif- 
fuse tumors  arise  chiefly  at  the  lateral  pole  and  involve  much  or  all  of  the 
organ.  They  are  capable  of  reaching  enormous  dimensions.  A  frequent 
accident  is  strangulation  by  torsion  of  the  pedicle.  The  structure  varies 
greatly  in  richness  in  cells,  or  vessels;  from  admixture  with  myoma;  from 
secondary  changes  toward  myxoma,  osteoma,  chondroma;  and  from  necrosis, 
and  cystic  softening.  Adler  describes  an  ovarian  intracanalicular  adeno- 
fibroma.  Ovarian  hematoma  may  be  connected  with  their  origin  (Brothers), 
and  a  special  type  develops  about  corpora  lutea  (Rokitansky).  Others  may 
be  of  teratomatous  nature. 

(6)  Papillary  fibroma  appears  as  multiple  warty  outgrowths  of  one  or 
both  organs. 

(c)  Ovarium  gyratum  is  a  form  of  superficial  fibrosis  of  both  ovaries  which 
obliterates  the  cortical  structures  and  transforms  the  organ  into  an  enlarged, 
hard,  very  opaque  mass,  with  wart-like  surface.  The  condition  was  so  named 
by  Adler  and  is  not  infrequent. 

FIBROMA  OF  THE  NARES.     NASAL  POLYP 

Although  there  has  been  much  debate  over  the  relation  of  nasal  polyps 
to  true  neoplasms,  here  as  elsewhere  it  is  impossible  to  draw  a  sharp  line  be- 
tween the  products  of  chronic  inflammation  and  tumor  processes,  so  that 
there  is  some  justification  in  the  current  usage  by  rhinologists  of  the  term 
fibroma  for  these  common  growths  (Bosworth,  Lit.).  Nevertheless,  it  is 
quite  clear  that  in  the  nares  more  than  in  any  other  mucous  membrane  the 
polypoid  outgrowths  of  chronic  inflammation  lack  the  histological  features 
of  an  autonomous  new  growth.  In  fact,  as  Chiari  claimed  in  1887,  many  of 
them  consist  of  nothing  more  than  localized  edematous  areas  of  mucous 
membrane  rendered  protuberant  by  mechanical  means,  but  without  other 
changes.  Once  established,  however,  these  masses  are  subject  to  various 
grades  of  hyperplasia  of  their  elements  which  render  them  not  only  persistent, 
but  often  progressive,  and  in  such  cases  there  may  be  considerable  change 
in  the  appearance  and  proportions  of  various  cells.  Since  this  change  is 
seldom  pronounced,  the  groups  of  nasal  polyps  must  stand  among  the  purest 
examples  of  pseudoneoplasms  of  inflammatory  origin. 

Nasal  polyps  are  probably  always  preceded  by  chronic  rhinitis  and  Tissier 
traces  an  unbroken  series  of  cases  from  simple  chronic  rhinitis  through  hyper- 
plastic  rhinitis  to  polypoid  inflammatory  outgrowths.  The  tumors  appear 
chiefly  in  young  subjects  and  infants,  rarely  after  30  years,  generally  at  the 
ostia  of  the  mucous  sinuses  opening  into  the  nares.  Empyema  of  these  sinuses 
is  a  common  antecedent.  They  are  commonly  multiple,  sometimes  very 
numerous,  and  they  occasionally  reach  a  large  size,  pressing  on  adjacent 
structures,  and  widening  the  bridge  of  the  nose,  with  obstruction  of  passages 
and  various  anatomical  and  clinical  sequelae.  Heymann  pictures  a  very 
large  nasal  polyp  which  filled  the  nasopharynx.  They  are  soft  in  the  early 
stages,  firmer  if  old,  gorged  with  blood,  or  gray  and  translucent  from  edema, 
with  smooth  warty  or  papillary  surface.  They  may  begin  as  numerous  low 
elevations  of  the  mucosa,  but  soon  tend  to  become  pedunculated. 

Histologically  three  somewhat  different  varieties  are  described  by  Zarniko, 
fibroma  edematodes  simplex,  adenofibroma  edematodes,  and  fibroma  edematodes 
•cysticum. 


FIBROMA  167 

Fibroma  Edematodes  Simplex. — This  tumor  is  composed  of  loose  connec- 
tive tissue  with  few  or  many  spindle-  or  star-shaped  fibroblasts.  The  stroma 
contains  loose  collagen  and  some  elastic  fibers.  The  grade  of  edema  varies, 
but  is  usually  pronounced,  sometimes  leaving  wide  spaces,  or  if  slight,  as  in 
old  cases,  yielding  rather  firm  cellular  areas.  Lymphocytes  may  be  abundant, 
beneath  the  epithelium,  about  the  vessels  or  in  small  foci.  Eosinophile  cells, 
Charcot-Leyden  crystals,  and  even  extensive  pigmentation  may  form  the 
sequel  of  hemorrhages.  Nerve-fibers  losing  themselves  in  the  stroma  have 
been  demonstrated  by  Billroth  and  by  Kalischer.  Blood-vessels  are  abundant, 
especially  in  the  pedicle,  but  tend  to  disappear.  In  some  old  cases  they  are 
very  numerous  and  cellular,  suggesting  angioma.  Dilated  venous  sinuses 
add  to  the  bulk  of  many  cases.  Lymph  sinuses  are  less  numerous.  Areas 
of  calcification  and  islands  of  true  bone  suggest  an  influence  of  the  neighbor- 
ing periosteum.  The  lining  epithelium  is  hypertrophic,  ciliated  or  transi- 
tional, or  squamous  from  attrition.  The  edematous  fluid  is  an  albuminous 
transudate,  but  may  contain  considerable  traces  of  mucin.  Hyaline  globules 
may  also  be  present. 

Adenofibroma  Edematodes. — In  some  polyps  new  gland  formation  is  promi- 
nent and  much  of  the  tissue  is  composed  of  various  slightly  distended  alveoli 
lined  by  several  layers  of  hypertrophic  epithelium.  Goblet  cells  may  be  very 
numerous.  In  some  cases  the  epithelial  hyperplasia  is  pronounced,  but  it 
rarely  suggests  a  true  neoplasm. 

Fibroma  Edematodes  Cysticum. — Most  of  the  large  and  some  smaller 
polyps  owe  their  bulk  to  the  formation  of  cysts  which  arise  from  distended 
alveoli  lined  with  overgrowing  cells,  or  if  ducts  are  occluded,  with  flat  cells. 
The  contents  are  serous  fluid,  mucus,  pus,  degenerating  epithelium,  fatty 
detritus,  or  hyaline  or  calcine  deposits. 

The  derivation  of  all  these  features  and  many  other  details  in  the  structure 
of  nasal  polyps  have  been  fully  traced  by  Heymann,  Zuckerkandl,  Wright, 
Zarniko,  and  many  others. 

The  natural  history  of  nasal  polyps  is  that  of  a  persistent  and  slowly 
progressive  pseudoneoplasm.  They  seldom  spontaneously  disappear,  except 
through  accidental  expulsion.  They  are  frequently  found  as  a  complication 
of  malignant  tumors,  but  malignant  transformation  of  a  benign  polyp  is 
extremely  rare,  Heymann  finding  only  3  somewhat  doubtful  cases.  They 
do  not  recur  after  complete  removal,  which  is  sometimes  difficult,  but  new 
tumors  often  succeed  those  removed.  In  the  etiology  a  special  predisposition 
may  possibly  exist,  but  the  growths  are  adequately  explained  as  the  result 
of  chronic  inflammation  and  the  irritation  of  retained  secretion. 

Amyloid  Tumors. — In  an  interesting  and  rare  group  of  cases  extensive 
amyloid  degeneration  appears  to  overtake  fibromas,  chondromas,  occasionally 
sarcomas,  and  some  chronic  productive  inflammatory  processes,  so  that  the 
cellular  structure  is  almost  completely  replaced  by  bulky  masses  of  amyloid. 
This  condition  is  observed  most  frequently  in  the  larynx  and  nares,  but  also 
in  the  conjunctiva,  bladder,  and  intestine  (Herxheimer,  Lit.).  The  process 
is  usually  of  slow  and  benign  course,  but  the  formation  of  amyloid  may  be 
rather  persistent  in  otherwise  harmless  conditions. 

Choanal  Polyp.— Arising  from  the  posterior  nasal  orifice  very  cellular 
firm  tumors  occur  which  lack  the  edema  of  the  intranasal  growths,  but  yet 
attain  large  dimensions,  reaching  into  the  pharynx  or,  as  in  Storck's  case, 
to  the  larynx.  Zaufal  removed  such  a  tumor  weighing  122  gm.  Zarniko 
observed  extensive  bone  formation  in  one  case  with  marked  hyperplasia 
and  metaplasia  of  the  epithelium.  Some  of  these  growths  show  more  definite 
neoplastic  characters  than  the  intranasal  growths.  The  choanal  polyp  often 


168 


NEOPLASTIC  DISEASES 


originates  from  the  mucosa  of  the  accessory  sinuses,  maxillary  and  antral, 
ethmoidal,  or  sphenoidal.  These  tumors  are  characterized  by  a  tendency 
to  reach  a  large  size,  by  the  presence  of  a  long  pedicle,  and  by  recurrence 
after  removal  of  the  tumor  without  the  pedicle.  After  repeated  recurrence 
it  is  usually  found  necessary  to  open  the  sinus  and  attack  the  growth  at  the 
base,  and  many  rhinologists  employ  the  radical  method  at  once  in  dealing 
with  these  polyps  (Moore,  Syme). 

Juvenile  Nasopharyngeal  Fibroma. — This  rare  and  peculiar  tumor  occurs 
chiefly  in  males  and  almost  invariably  between  the  ages  of  10  and  25  years. 
It  is  a  very  firm  almost  cartilaginous  tumor  which  appears  in  the  vault  of 
the  pharynx  and  grows  in  several  definite  directions.  According  to  Bensch 
it  produces  an  intrapharyngeal  tumor  when  arising  from  the  basilar  fibro- 


FIG.  36. — Malignant  angiomyxoma  growing  from  superior  nares  in  a  child. 

cartilages,  the  upper  cervical  vertebrae,  or  the  internal  lamina  of  the  pterygoid 
process;  or  an  extrapharyngeal  growth  when  arising  from  the  cartilage  of 
the  foramen  lac.  ant.,  or  the  sphenopalatine  fossa.  The  intrapharyngeal 
tumor  extends  forward  into  the  nares  and  the  adjacent  sinuses,  causing  atrophy 
of  the  bony  structures.  From  the  sphenoidal  origin  the  growth  extends  down 
between  the  masseter  muscle  and  the  mucosa;  or  it  pushes  between  the  ptery- 
goid and  styloid  muscles  into  the  temporal  fossa  and  forward  into  the  malar 
region;  or  through  the  inferior  orbital  fissure  it  extends  into  the  orbit,  or  by 
way  of  the  superior  orbital  fissure  or  lamina  cribrosa  it  reaches  the  cranial 
cavity.  From  these  points  the  courses  from  the  two  seats  of  origin  overlap. 

In  structure  the  tumor  is  composed  of  dense  fibrous  and  elastic  tissue 
which  rarely  shows  calcification,  cartilage,  or  bone.  The  cells  are  round, 
spindle-  or  star-shaped  fibroblasts  which  are  rather  scanty  except  in  certain 


FIBROMA  169 

foci  of  young  connective  tissue,  where  they  may  be  so  numerous  as  to  suggest 
fibrosarcoma.  Mast  cells  and  plasma-cells  may  be  present.  The  vessels 
are  numerous  (pharyngeal  angiofibroma)  and  sometimes  cavernous.  Involu- 
tion changes  follow  thickening  and  hyalinosis  of  vessel  walls,  the  stroma 
becoming  hyaline  and  the  tumor  undergoing  necrosis  or  fatty  degeneration 
(Ballo). 

The  course  is  of  an  actively  growing  tumor  which  disturbs  various  func- 
tions by  pressure,  leads  to  anemia  from  hemorrhage,  suffers  ulceration  and 
local  infection,  and  may  prove  fatal  in  this  way,  or  from  cerebral  disturbance. 
Metastases  are  not  observed.  A  remarkable  feature  of  this  tumor  attested 
by  many  observers  is  its  complete  spontaneous  regression  after  partial  re- 
moval (Bensch,  Grunwald,  Konig,  Bruns,  Zarniko).  This  event  seems  to 
occur  chiefly  toward  the  end  of  the  period  when  the  tumor  may  develop, 
i.  e.,  the  2  5th  year.  There  is  thus  illustrated  a  form  of  natural  immunity, 
which  may  be  referred  to  natural  anatomical  changes  at  the  point  of  origin 
from  which  alone  the  nutrition  of  the  growth  is  maintained.  According  to 
Bensch  the  development  of  the  male  and  female  face  and  skull  at  puberty 
explains  the  predominance  of  the  tumor  in  males,  while  the  completion  of 
the  cranial  development  at  the  2$th  year  determines  the  spontaneous  dis- 
appearance of  the  tumor.  It  is  not  clear  that  this  tumor  is  always  of  fibro- 
matous  structure.  Naab  observes  that  chondroma  and  sarcoma  may  appear 
under  much  the  same  conditions.  I  have  seen  a  tumor  corresponding  in  many 
particulars  to  the  above  description,  but  showing  the  structure  of  a  sarcoma 
with  indistinct  chondromatous  qualities.  Confusion  with  chondroma  seems 
possible.  Many  of  the  tumors  are  myxomatous  or  myxosarcomatous  and 
these  recur  persistently  and  are  commonly  fatal. 


CHAPTER  XI 
MYXOMA 

Myxoma  is  a  tumor  composed  of  mucous  tissue. 

Primary  myxoma,  a  tumor  which  probably  arises  from  embryonal  mucous 
tissue,  is  rare,  but  mesoblastic  tumors,  such  as  fibroma,  lipoma,  and  chondroma, 
which  contain  myxomatous  portions  are  not  infrequent.  It  is  often  difficult 
to  determine  whether  the  myxomatous  portion  of  a  complex  tumor  is  origi- 
nally of  this  type  or  represents  a  degeneration  of  the  more  adult  tissue.  In 
the  former  case  one  employs  the  terms  myxofibroma  or  myxolipoma,  in  the 
latter  case  the  myomatous  degeneration  is  indicated  by  the  suffix  myxo- 
matodes,  as  chondroma  myxomatodes. 

When  mucous  tissue  is  present  in  a  neoplasm  three  possibilities  as  to  its 
significance  must  be  considered.  The  mucous  tissue  may  be  developed  directly 
from  embryonal  mucous  tissue  and  the  tumor  may  be  a  primary  myxoma. 
Or  the  tissue  may  represent  a  metaplastic  product  of  other  tissues  and  the 
tumor  is  a  secondary  myxoma.  Or  the  tissue  may  result  from  chronic  edema 
of  other  structures  and  represent  a  form  of  spurious  mucous  tissue,  such 
as  is  seen  in  edematous  nasal  polyps  and  in  atrophic  fat  tissue.  These  theo- 
retical deductions  cannot  always  be  established  in  the  practical  examination 
of  tumors. 

Since  mucous  tissue  does  not  exist  in  the  adult  body,  a  primary  myxoma, 
according  to  the  above  definition,  must  be  rare  and  always  embryonal.  Fully 
developed  mucous  tissue  exists  in  the  embryo  only  in  the  umbilical  cord, 
and  although  a  few  myxomas  of  the  navel  have  been  described  which  prob- 
ably arose  from  cord  tissue  the  chief  source  of  myxomas  must  be  sought 
elsewhere.  Such  a  source  may  be  found  in  the  early  undifferentiated  con- 
nective tissue  of  the  embryo  which  has  a  mucous  quality.  Such  mucous 
tissue  is  widely  distributed  in  the  embryo,  especially  in  the  subcutaneous 
areas.  It  is  genetically  related  to  fat  tissue  into  which  it  is  extensively  trans- 
formed during  normal  growth.  It  may  be  assumed  that  many  primary 
myxomas  arise  from  islands  of  such  embryonal  tissue.  Since  such  islands  of 
mucous  tissue  may  readily  be  associated  with  cartilage  and  fibrous  and  fat 
tissues,  which  are  normally  developed  from  the  embryonal  mesoblast,  it  is 
reasonable  to  explain  the  occurrence  of  many  myxolipomas,  fibromas,  and 
chondromas  by  assuming  their  origin  from  islands  of  tissue  which  are  partly 
differentiated,  or  which  become  so  during  the  progress  of  the  growth.  It 
does  not  appear  that  pure  myxomas  ever  tend  to  differentiate  into  fibroma 
or  lipoma.  It  is  not  so  easy  to  decide  to  what  extent  other  mesoblastic  tumors 
become  transformed  into  true  myxoma.  Fibroma,  lipoma,  and  chondroma 
undoubtedly  become  transformed  by  degeneration  or  imperfect  growth  into 
tumors  containing  areas  of  typical  mucous  tissue.  The  group  of  secondary 
myxoma  develops  in  this  way. 

Virchow  considered  myxoma  to  be  very  closely  related  to  lipoma  and  as 
occasionally  arising  from  embryonal  fat  tissue.  Certain  myxomas  of  bone 
he  believed  might  arise  from  cartilage.  Ribbert,  however,  regards  such  sec- 
ondary changes  as  spurious  myxomas,  on  the  ground  that  already  differen- 
tiated tissues  cannot  become  transformed  into  true  mucous  tissue.  This 
objection  seems  to  me  adequate  to  separate  the  primary  from  secondary 

170 


MYXOMA  171 

myxomas,  but  not  to  eliminate  the  latter  class  from  the  general  category  of 
myxoma. 

In  the  sense  that  primary  myxomas  are  foreign  to  the  type  of  tissue  in 
which  they  arise  they  may  be  regarded  as  always  heterologous.  Yet  this 
character  is  not  equivalent  to  that  of  many  other  heterologous  tumors  which 
arise  from  tissues  widely  displaced  and  genetically  unrelated  to  the  tissue  in 
which  the  tumor  occurs. 

Myxoma  is  to  be  sharply  distinguished  from  epithelial  tumors  undergoing 
mucous  degeneration.  Here  the  mucus  is  a  form  of  hypersecretion,  while  in 
myxoma  it  is  an  integral  part  of  the  living  tissue. 

Anatomical  Characters. — Myxomas  are  soft,  lobulated,  polypoid,  or 
papillary  tumors,  which  on  section  are  smooth,  translucent,  and  gelatinous. 
The  loculation  is  determined  by  the  growth  about  blood-vessels  which  v. 
Rindfleisch  finds  on  injection  are  of  relatively  large  caliber  with  few  capil- 
laries. The  encapsulation  of  myxomas  is  seldom  complete,  the  mucinous 
material  tending  to  infiltrate  surrounding  tissues.  On  this  account  complete 
extirpation  is  sometimes  difficult  and  recurrence  follows  from  persistence  of 
widely  disseminated  mucous  material  and  cells.  In  some  cases  the  condi- 
tions suggest  a  transformation  of  normal  tissues  into  myxoma  under  the  in- 
fluence of  the  mucinous  material.  Virchow  observed  the  gradual  extension 
of  the  myxomatous  tendency  from  a  recurrent  tumor  of  the  ulnar  nerve  over 
the  greater  part  of  the  brachial  plexus. 

On  extraction  with  weak  alkali  myxomas  yield  a  solution  of  mucus  which 
is  precipitable  by  acetic  acid.  Alcohol  precipitates  mucus  in  membranous 
or  reticulated  form  resembling  fibrin. 

The  structure  of  myxoma  presents  typical  features  of  spindle-  and  star- 
shaped  cells  with  processes  anastomosing  or  disappearing  in  the  matrix,  and 
cytoplasm  usually  containing  fatty  and  watery  droplets.  Hydropic  degenera- 
tion may  be  extreme  in  edematous  tumors. 

The  cells  may  be  grouped  chiefly  about  blood-vessels  which  when  abun- 
dant may  call  for  the  designation  "telangiectatic"  or  "cavernous."  Or 
they  may  be  more  numerous  in  the  capsule  in  cases  showing  peripheral  growth. 
Various  admixtures  of  connective  tissue,  fat,  cartilage,  or  bone  occur  and 
may  deserve  suitable  recognition  in  the  terminology.  Cystic  myxoma  re- 
sults from  local  edema,  or  hemorrhage,  and  in  one  definite  group  of  cases 
dilated  lymph  spaces  or  vessels  yield  cysts.  Very  cellular  myxomas,  pure 
or  combined  with  other  tissues,  and  primary  or  secondary,  constitute  the 
important  group  of  myxosarcomas. 

The  matrix  of  myxomas  varies  greatly  in  bulk  and  in  structure.  It  may 
be  very  abundant,  widely  separating  the  cells,  and  appearing  as  nearly  homo- 
geneous or  faintly  fibrillated  or  granular,  but  always  basophilic  material. 
In  rapidly  growing  tumors  and  in  cellular  areas  it  may  be  very  scanty.  The 
bulk  of  the  matrix  depends  much  on  the  capacity  of  the  mucinous  material 
to  absorb  water.  In  the  secondary  myxomas  the  gradual  transformation  of 
fibrous  tissue,  fat,  cartilage,  and  bone  may  often  be  traced,  the  matrix  of  these 
tissues  becoming  transformed  into  mucous  tissue  and  the  cells  assuming 
spindle  and  star  shapes.  Similar  changes  may  sometimes  be  observed  on 
the  edges  of  infiltrating  myxomas,  but  the  invaded  tissue  is  usually  passively 
displaced  by  the  tumor. 

Epithelial  and  endothelial  cells  may  become  incorporated  in  the  advancing 
myxoma  and  rendered  indistinguishable  from  the  tumor-cells.  In  some  endo- 
theliomas  myxomatous  changes  may  be  so  complete  as  to  greatly  obscure 
the  true  nature  of  the  growth.  The  myxosarcomas  exhibit  many  more  cells, 
usually  more  vessels,  and  less  matrix  than  the  simple  myxomas.  As  a  rule 


172 


N  EOF  LA  STIC  DISEASES 


the  mucous  tissue  is  associated  with  areas  of  fine  spindle-cells  often  grouped 
about  blood-vessels.  In  a  bulky  myxoma  of  the  fascia  of  the  thigh  I  found 
that  all  the  spindle-cells  could  be  traced  to  the  walls  of  very  numerous  capil- 
laries. This  tumor  was  strictly  a  myxo-endothelioma.  Myxomatous  tissue 
is  often  combined  with  fat  tissue,  cartilage,  bone,  or  other  neoplastic  elements. 
When  the  formation  of  mucous  tissue  in  such  a  tumor  is  the  predominating 
feature  the  growth  may  be  designated  as  myxosarcoma,  but  when  mucous 
degeneration  affects  only  small  areas  the  term  sarcoma  myxomatodes  is 
employed.  The  former  group  constitutes  a  numerous  class  of  tumors,  among 
which  the  lipomatous  and  chondromatous  varieties  are  most  numerous. 
The  malignancy  of  myxosarcoma  depends  chiefly  on  its  local  effects,  metastases 


FIG.  37. — Recurrent  myxosarcoma  of  nares  in  a  child. 

not  being  very  common.  According  to  Malherbe,  myxoma  of  striated  muscle, 
fasciae,  and  of  certain  viscera  is  usually  malignant  and  equivalent  to  sarcoma, 
while  in  the  nares,  breast,  bone,  and  nervous  system  it  is  almost  always  benign. 
The  clinical  course  of  myxoma  is  of  a  slowly  growing  tumor  which  pro- 
duces no  symptoms  except  local  swelling  and  pressure.  After  complete  extir- 
pation they  do  not  recur,  but  thorough  removal  is  not  always  readily  accom- 
plished and  local  recurrence  of  this  benign  tumor  is  not  uncommon.  In  the 
skin  and  nerve-trunks  they  are  frequently  multiple  and  new  tumors  develop 
after  extirpation  of  the  old.  Yet  Virchow  refers  to  2  cases  of  myxoma  of 
cheek,  and  of  labium,  which  recurred  after  operation  and  eventually  pro- 
duced many  myxomatous  metastases.  As  a  rule,  malignant  myxomas  fall 
readily  in  the  class  of  myxosarcoma. 


MYXOMA  173 

Simple  myxoma  rarely  attains  a  large  size  and  the  onset  of  myxomatous 
changes  usually  marks  a  partial  limitation  of  the  growth  capacities  of  a  tumor. 
Yet  the  myxolipomas  grow  to  very  large  size  and  for  some  of  the  diffuse  forms 
of  this  tumor  Virchow  suggested  a  relation  to  elephantiasis.  Such  a  case 
affecting  the  leg  and  thigh  is  reported  by  Barling.  In  certain  situations  the 
pressure  symptoms  of  myxomas  become  serious  (nares,  brain,  cord). 

The  location  of  myxomas  is  chiefly  the  subcutaneous  and  intermuscular 
tissue  of  localities  where  the  structure  is  loose  and  much  fat  is  commonly 
present.  The  regions  most  affected  are  the  thigh,  neck,  cheek,  leg,  and  peri- 
toneum, and  less  frequently,  the  bones,  meninges,  nerve-trunks,  mucous  and 
serous  membranes,  and  hilus  of  the  kidney.  I  have  seen  a  myxoma  as  large 
as  an  orange  involving  three  lobes  of  the  placenta. 


FlG.  38. — A  vascular  myxoma  of  superior  nares. 

Certain  clinical  forms  of  myxoma  are  rather  well  denned.  Myxoma  of 
the  nervous  system  affects  the  peripheral  nerves,  meninges,  and  brain  tissue. 
In  the  nerve-trunks  single  and  multiple  primary  myxoma  occurs  under  much 
the  same  conditions  as  multiple  fibroma  and  probably  represents  a  more 
embryonal  form  of  this  tumor.  Some  of  the  cutaneous  myxomas  are  prob- 
ably of  neural  origin.  They  arise  in  the  endoneurium  and  perineurium  prob- 
ably from  foci  of  embryonal  tissue,  and  produce  rounded  or  elongated,  soft, 
but  often  painful  tumors.  After  extirpation  new  tumors  may  develop.  Wilms 
observed  a  large  cystic  myxoma  of  the  ulnar  nerve. 

The  optic  nerve  is  especially  susceptible  to  myxoma,  which  here  tends  to 
pursue  a  characteristic  clinical  course  (Sattler,  Parsons,  Salzmann).  The 
tumor  occurs  chiefly  in  young  subjects,  produces  a  fusiform  swelling  of  the 
whole  nerve-trunk,  blindness  results,  but  the  eyeball  is  usually  not  invaded, 
and  extirpation  of  the  tumor  is  usually  successful.  In  a  case  studied  in  this 


174 


N EOF LA  STIC  DISEASES 


laboratory  with  Knapp  the  central  portions  of  the  tumor  were  softened  and 
cystic,  the  nerve-fibers  were  nearly  all  destroyed,  while  the  capsule  presented 
the  structure  of  an  angiosarcoma.  In  the  meninges  several  soft  myxomas 
have  been  described,  especially  by  the  older  authors,  of  which  Virchow  col- 
lected a  series.  In  the  brain  tissue  Virchow  described  as  myxoma  certain 
tumors  which  were  probably  gelatinous  gliomas. 

In  the  mucous  membranes  polypoid  outgrowths  in  many  regions  present 
some  of  the  features  of  myxoma.  They  are  chiefly  edematous  fibro-adenomas 
or  inflammatory  hyperplasias  and  contain  little  or  no  mucin. 

In  the  bones  Virchow  described  both  primary  and  secondary  myxoma. 
The  primary  myxoma  he  believed  might  arise  from  mucous  connective  tissue 
in  the  marrow,  but  he  was  not  sure  that  it  did  not  develop  from  some  trace 


FIG.  39. — Myxoma  of  portion  of  placenta. 

of  cartilage.  This  tumor  absorbs  the  shaft  while  the  periosteum  lays  down 
an  enlarging  shell  of  bone,  but  it  may  perforate  the  shaft  and  periosteum  and 
invade  the  soft  tissues. 

The  misplaced  islands  of  cartilage  found  in  the  marrow  cavity  in  rickets 
and  other  diseases  of  bone  form  a  ready  source  of  secondary  myxoma,  and 
fragments  of  cartilage  or  bone  have  often  been  found  in  central  myxomas. 
Portions  of  benign  giant-cell  tumors  of  bone-marrow  may  present  a  myxoma- 
tous  structure,  but  it  is  associated  with  other  features  of  the  benign  process. 

The  majority  if  not  all  of  the  extramedullary  myxomas  of  bone  must 
be  interpreted  as  degenerating  chondromas  or  osteomas. 

Whatever  the  origin,  a  myxomatous  structure  indicates  a  tendency  to 
local  recurrence.  These  tumors  behave  much  as  do  recurring  chondromas. 


MYXOMA 


175 


Without  much  increase  in  cellular  content  they  may  produce  local  or  distant 
metastases,  especially  after  operation.  Pseudomyxomatous  changes  in 
bone-marrow  are  not  infrequent  and  should  not  be  confused  with  true  myxoma. 
Virchow  warns  against  including  spongy  osteomas  with  mucoid  marrow  tissue 
in  the  category  of  myxoma. 

Myxoma  of  bone  is  of  rare  occurrence,  but  rather  wide  distribution.  A 
common  seat  is  in  the  phalanges  of  the  fingers,  in  which  locality  Bloodgood 
has  collected  a  series  of  cases.  Other  locations  are  the  tibia,  femur,  shoulder, 
and  spine.  The  rather  unsatisfactory  results  of  surgical  treatment,  and  the 
uncertainties  of  diagnosis,  suggest  that  they  should  first  be  subjected  to 
treatment  by  physical  agents. 

Congenital  myxoma  or  myxosarcoma  of  the  navel  is  described  by  Kauf- 
mann  with  the  report  of  a  case  and  review  of  the  literature.  I  have  observed 
a  cystic  myxoma  of  the  umbilical  cord  and  navel  measuring  10  cm.  in  diam- 
eter, and  associated  with  congenital  malformation  of  the  kidneys. 


FIG.  40.— Lobulated  myxoma  of  right  auricle:  A  and  B,  Main  lobes  of  tumor;  D,  elon- 
gated portion;   V,  vena  cava  superior;  T,  tricuspid.     (After  Ribbert.) 

Myxoma  of  the  Heart. — The  endocardium  is  the  seat  of  a  series  of  tumors 
which  include  small  fibromas,  larger  soft  myxomas,  and  more  cellular  myxo- 
sarcomas.  The  interpretation  of  any  one  of  these  tumors  should  be  influenced 
by  our  knowledge  of  the  entire  group. 

Brenner  collected  33  reports  of  cardiac  myxomas,  of  which  20  were  located 
in  the  left  auricle,  chiefly  on  the  septum,  10  on  the  heart  valves,  2  in  the  right 
ventricle,  and  i  on  the  apex  epicardium.  The  smaller  tumors  offer  little 
difficulty  of  recognition,  since  they  usually  take  the  form  of  typical  fibro- 
myxoma.  With  increasing  growth  they  assume  a  lobate,  papillary,  polypoid, 
or  even  villous  form  and  the  structure  is  greatly  altered  by  edema,  hemor- 
rhage, and  progressive  thrombosis  of  blood  with  organization  on  the  surface. 
In  this  form  they  are  difficult  to  distinguish  from  organized  thrombi.  In 
fact,  Czapek,  Thorel,  and  others  regard  most  of  the  reported  cardiac  myxomas 


176  NEOPLASTIC  DISEASES 

as  organized  thrombi.  The  tumors  are  as  small  as  a  pea  or  as  large  as  a  hen's 
egg,  and  while  they  usually  produce  no  symptoms,  some  seriously  obstruct 
the  circulation.  They  are  usually  covered  with  blood-clot,  organized  por- 
tions of  which  are  fused  with  the  tumor.  Fibrin  emboli  may  be  detached, 
and  Marchand  found  a  growing  tumor  embolus  hi  a  cerebral  vessel. 

The  structure  of  the  tumors  is  rather  uniform,  but  varies  as  the  original 
myxomatous  tissue  is  altered  or  replaced  by  edema,  hemorrhage,  perivascular 
infiltration  with  round  cells,  and  organization  of  secondary  thrombi.  The 
framework  consists  of  a  system  of  blood-vessels  radiating  from  the  pedicle 
which  support  the  overabundant  mucinous  material  composing  the  bulk 
of  the  tumor.  The  vessels  are  usually  thin  arterioles  or  venules  or  capil- 
laries surrounded  by  lymphocytes  or  large  mononuclear  cells.  Muscle-fibers 
may  be  drawn  into  the  pedicle  from  the  myocardium.  An  abundance  of 
elastic  fibers  is  a  common  element  which  Brenner  attributes  to  the  mechan- 
ical influence  of  cardiac  contraction  upon  the  tumor  stroma.  In  one  of 
Czapek's  cases  the  stroma  was  nearly  cartilaginous.  The  separation  from 
organized  thrombi  may  be  based  on  the  highly  mucinous  character  of  the 
stroma,  on  the  presence  of  orderly  radiating  blood-vessels  and  elastic  fibers, 
and  on  the  absence  of  masses  of  blood  detritus  undergoing  organization. 
While  many  of  the  larger  tumors  may  be  difficult  to  identify  (as  in  Oppen- 
heimer's  case)  it  seems  unlikely  that  a  simple  organizing  blood-clot  can  re- 
produce the  positive  features  of  the  true  myxoma.  Hence  the  great  majority 
of  the  reported  cases  of  cardiac  myxoma  are  probably  genuine. 

The  origin  of  the  tumors  has  been  referred  to  superfluous  embryonal 
tissue  in  the  region  of  the  foramen  ovale  where  many  of  the  growths  are 
attached.  Curtis  expressed  the  view  that  the  process  is  not  a  genuine  neo- 
plasm, but  a  result  of  chronic  inflammation  of  rheumatic  nature  producing 
nodular  outgrowths  of  the  endocardium  which  continued  to  grow  because  of 
the  mechanical  influences  to  which  they  are  exposed. 

Primary  sarcomas  of  the  heart  are  probably  connected  in  origin  with  the 
myxomas.  Binder  collected  15  cases,  of  which  8  were  located  in  the  right 
auricle.  They  reach  large  dimensions,  grow  into  the  veins,  occlude  the  heart, 
but  rarely  give  metastases.  The  composition  is  chiefly  of  spindle-cells,  but 
giant-cell  and  round-cell  tumors  also  occur. 

Apparently  pure  myxomas  have  been  observed  in  the  mesentery  (Borst) 
and  in  the  thymus  (Winogradow). 

Chondromyxoma  may  make  up  the  bulk  of  the  mixed  tumor  of  the 
parotid,  and  in  the  fourth  recurrence  of  an  original  cartilaginous  tumor  of 
the  parotid  I  have  found  pure  myxoma.  Certain  of  the  nasopharyngeal 
polyps  which  are  of  cartilaginous  origin  may  appear,  especially  in  recur- 
rences, as  pure  myxosarcoma.  In  other  organs  also,  as  testis,  mammae,  and 
bones,  it  seems  probable  that  certain  myxomas  represent  imperfect  growth 
of  cartilage  in  embryonal  chondromas. 

In  several  notable  cases  the  intramuscular  metastases  of  cartilaginous  or 
choriomatous  teratoma  testis  have  appeared  in  the  form  of  myxoma.  In 
fact,  there  is  reason  to  believe  that  the  condition  of  nutrition  of  intravascular 
tumors  strongly  favors  the  myxomatous  type  of  growth  in  many  tumors. 

The  combination  of  myxoma  and  lipoma  occurs  in  certain  tumors  of 
clinical  importance  and  many  of  these  growths  reach  a  large  size  and  prove 
malignant.  In  the  retroperitoneal  region,  in  the  hilus  of  the  left  kidney,  and 
in  the  spermatic  cord  are  encountered  locally  malignant  myxolipomas.  In 
the  eleventh  recurrence  of  an  original  lipoma  of  the  spermatic  cord  which 
I  was  able  to  follow  over  a  period  of  15  years  some  lobules  were  pure  myxoma. 
Robertson,  in  an  analysis  of  51  cases  of  lipoma  myxomatodes,  found  that 


MYXOMA  177 

43  per  cent,  developed  in  the  muscles  of  the  lower  extremities,  33  per  cent, 
in  the  retroperitoneal  region;  i  reached  a  weight  of  65  pounds,  and  33  per 
cent,  were  malignant. 

In  the  etiology  of  myxomas  special  factors  must  be  considered  for  different 
groups  and  an  etiological  classification  becomes  of  interest. 

A  congenital  origin  has  been  established  for  myxomas  of  the  navel  which 
probably  arise  from  foci  of  umbilical  cord  tissue,  and  for  the  mesenteric  tumor 
described  by  Borst.  The  general  source  of  myxomas  must  be  sought  in  super- 
fluous or  aberrant  foci  of  embryonal  connective  tissue,  fat,  and  cartilage. 
Virchow  regarded  myxoma  as  arising  indifferently  from  several  embryonal 
mesoblastic  tissues  and  from  glia-tissue.  Ribbert  would  limit  their  origin 
rather  strictly  to  embryonal  connective  tissue.  The  conditions  which  give 
rise  to  secondary  myxoma  may  apparently  represent  an  embryonal  reversion 
of  connective  tissue,  fat,  or  cartilage,  or  it  may  result  from  chronic  edema 
and  a  true  mucous  degeneration. 

Special  embryonic  disturbances  do  not  seem  to  be  connected  with  myxomas, 
although  Marchand  suggested  that  abnormalities  in  the  construction  of  the 
cardiac  septa  might  be  responsible  for  myxoma  of  the  endocardium.  As 
already  stated,  an  intravascular  position  favors  the  appearance  of  myxomatous 
changes  in  a  tumor.  Chronic  inflammation  and  edema  lead  to  the  growth 
of  myxomatoid  polyps  of  mucous  membranes.  Finally,  in  the  testis,  spermatic 
cord,  and  possibly  in  the  kidney  myxomas  are  probably  of  teratoid  origin, 
and  in  some  other  regions,  as  parotid,  breast,  they  represent  mixed  tumors. 

Sanarelli  and  Splendore  have  studied  a  filterable  virus  which  on  inocula- 
tion produces  multiple  tumors  resembling  myxoma  in  the  skin  and  organs 
of  rabbits.    Rous'  tumor  of  chickens  which  he  was  able  to  reproduce  by  the 
inoculation  of  filtered  extracts  has  a  myxomatous  character. 
12 


CHAPTER  XII 

LIPOMA 

A  lipoma  is  a  tumor  composed  of  fat  tissue. 

The  gross  appearance  of  most  of  these  tumors  is  characteristic.  They 
form  firm,  elastic,  rounded,  usually  multilobulated  growths,  which,  without 
encapsulation,  are  sharply  circumscribed  from  the  surrounding  tissue.  Their 
size  varies  from  that  of  a  pea  to  masses  weighing  many  pounds  which  pro- 
duce serious  results  from  weight  and  pressure.  The  consistence  is  usually 
that  of  normal  fat  tissue,  lipoma  molle,  but  this  density  may  be  reduced  by 


FIG.  41. — Lipoma  of  forearm  in  adult,  containing  fetal  fat  tissue. 

secondary  changes,  or,  more  often  increased,  by  admixture  with  fibrous  tissue 
or  by  forms  of  metaplasia.  In  many  situations  they  become  pendulous  and 
by  constriction  of  the  pedicle  spontaneous  atrophy  may  result.  The  color 
is  usually  that  of  normal  fat  tissue,  but  xanthomatous  changes  may  yield 
an  orange  yellow  tint,  or  various  secondary  processes  may  give  corresponding 
alterations.  Very  cellular  areas  with  imperfect  fat  formation  are  recogniz- 
able by  a  lighter  opaque  color,  while  the  fully  developed  tumor  tissue  is  yellow 
and  translucent. 

178 


LIPOMA 


179 


Lipomas  exhibit  a  striking  connection  with  the  nutrient  blood-vessels, 
each  of  the  multiple  lobules  growing  about  a  branch  of  the  main  vessel. 
Lateral  anastomoses  of  these  vessels  are  scanty,  so  that  the  tumor  grows 
expansively  and  is  readily  shelled  out  of  its  position.  With  pure  lipomas 
appositional  growth  is  not  observed,  but  this  rule  is  less  rigid  for  mixed  lipoma 
and  liposarcoma. 

The  microscopical  structure  resembles  normal  fat  tissue,  but  the  lobules 
vary  greatly  in  size  and  the  supporting  stroma  is  irregular  in  distribution. 
The  cells  may  be  overdistended  with  fat,  or  may  produce  the  smaller  type 
of  embryonal  fat  tissue,  and  often  there  are  areas  of  polyhedral  cells  in  which 
the  fatty  deposits  are  incomplete.  It  is  from  such  cells  lying  in  isolated  foci 
or  along  the  vessels  that  the  growth  of  lipomas  chiefly  occurs.  In  some  of 


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r*s 

,-\— *        T^ 

•  \         '  * 

oH 

FIG.  42. — Subcutaneous  lipoma.    Gross  texture  of  orange  tint.    Lipoid  material  appears 
in  granular  form  as  in  xanthoma. 

these  foci  an  alveolar  structure  may  be  produced  by  polyhedral  cells  with 
incomplete  fat  deposits.  Occasionally  the  young  cells  contain  granular  lipoid 
pigment  and  strongly  resemble  xanthoma  cells,  and  this  character  may  be 
diffuse  throughout  rather  large  lipomas,  especially  about  the  kidney.  The 
blood-vessels  are  usually  overabundant  and  many  cellular  arterioles  are 
found  in  the  stroma  running  out  into  the  lobules  and  dividing  into  capil- 
laries. Extensive  overgrowth  of  blood-vessels  leads  to  the  formation  of  vas- 
cular fatty  tumors,  lipoma  telangiectaticum  or  cavernosum,  so  that  it  is  some- 
times difficult  to  distinguish  between  vascular  lipoma  and  angioma.  Lymph- 
vessels  also  may  be  overdeveloped,  and  Borst  observed  the  transformation 
of  a  lipoma  into  a  fibrous  lymphangioma. 

Secondary  changes  in  lipomas  are  common  in  advanced  stages  ot  growth. 
One  of  the  more  frequent  is  a  mucinous  degeneration  which  occurs  in  atro- 


180  NEOPLASTIC  DISEASES 

phic  or  edematous  areas  and  may  reach  extensive  proportions  without  con- 
stituting a  true  myxolipoma.  Diffuse  mucinous  degeneration  produces  a 
peculiar  tumor- tissue  designated  by  Miiller  as  collonema.  Mucinous  changes 
are  more  common  in  liposarcomas,  where  they  usually  represent  a  true  myxo- 
lipoma. Borst  has  observed  the  transformation  of  the  fat  in  portions  of 
lipomas  into  a  waxy  material.  Beriel  and  Delachanal  followed  the  myxo- 
matous  and  sarcomatous  transformation  of  a  lipoma  of  the  sciatic  sheath 
which  eventually  produced  lipomatous  and  sarcomatous  metastases  in  lymph- 
nodes  and  lung.  Calcification  either  of  isolated  foci  or  of  the  entire  capsule 
may  occur  and  is  rarely  followed  by  ossification  (Lipoma  petrificum  ossificans, 
Virchow). 

Cysts  form  in  lipomas  from  the  fluidification  of  the  central  portions  of 
large  lobules  producing  areas  of  fluid  fat  (oil  cysts)  which  are  said  to  result 
chiefly  from  trauma.  In  mucinous  and  edematous  lipomas  irregular  cystic 
areas  may  form  containing  mucous  or  serous  fluid,  fatty  crystals  and  cal- 
cific  deposits.  Lymph-cysts  with  clear  fluid  are  occasionally  observed. 

Lipomas  may  exhibit  an  excess  of  fibrous  tissue  resulting  from  atrophy 
of  fat  and  fibrous  replacement  or  from  admixture  with  true  fibroma  (fibro- 
lipoma).  More  frequently  true  myxoma  is  combined  with  lipoma,  and  occa- 
sionally chondrolipomas  are  observed.  In  a  considerable  class  of  tumors  all 
the  cells  are  abundant  and  one  has  to  deal  with  various  types  of  liposarcoma. 
In  the  abdominal  cavity  of  a  dog  I  have  observed  a  large  tumor  composed  of 
adult  fat,  embryonal  fat,  myxoma,  chondroma,  and  large  areas  of  osteoma. 

Many  interesting  features  are  occasionally  observed  in  the  clinical  course 
of  lipomas.  Some  internal  growths,  as  in  the  thorax,  abdomen,  or  cranium, 
reach  such  a  size  and  exert  such  pressure  as  to  cause  serious  symptoms  or 
even  death,  with  symptoms  referable  to  the  affected  organs.  Very  large 
lipomas  seem  to  be  capable  of  diverting  the  nutrition  of  the  body  and  inducing 
emaciation.  This  feature  is  prominent  in  many  of  the  retroperitoneal  tumors 
collected  by  Voeckler.  The  limit  of  growth  of  simple  lipoma  is  often  con- 
siderable, but  in  many  of  the  very  large  tumors  portions  of  the  growth  become 
more  cellular  and  exhibit  sarcomatous  structure.  The  occurrence  of  multiple 
lipomas,  even  hundreds  (Virchow),  is  evidence  of  a  peculiar  dyscrasia  of  the 
fat  tissues  of  these  subjects,  in  whom  the  tumors  may  appear  in  the  lungs 
and  liver  where  fat  is  normally  absent.  A  remarkable  case  is  that  of  Broca, 
in  which,  in  a  man  of  31  years,  after  extirpation  of  a  large  lipoma  of  thigh, 
hundreds  of  small  tumors  appeared  over  the  body  and  persisted  for  40  years. 
The  patient  finally  suffered  from  dysphagia,  with  regression  of  most  of  the 
tumors,  but  at  autopsy  a  large  fatty  tumor  surrounded  and  compressed  most 
of  the  esophagus.  Persistent  local  recurrence  of  lipomas  is  rare  and  usually 
associated  with  a  cellular  and  vascular  or  sarcomatous  structure.  Yet  in  a 
case  of  recurrent  lipoma  of  the  spermatic  cord  extirpated  many  times  in  the 
course  of  15  years,  the  structure  was  never  very  cellular  and  varied  little 
throughout  the  course. 

The  capacity  of  the  organism  to  appropriate  the  fat  of  lipomas  has  been 
investigated  by  Wells,  who  found  no  peculiarity  in  the  chemical  composition 
of  the  fat  of  lipomas,  no  deficiency  of  lipase,  and  no  ground  for  the  common 
assumption  that  the  fat  of  these  tumors  is  beyond  the  reach  of  the  fat-mo- 
bilizing factors  of  the  body.  Since  many  lipomas  have  continued  to  grow 
while  the  body  was  emaciating,  and  not  a  few  remain  unaffected  during  the 
loss  of  body  fat  in  phthisis  (Madelung)  or  gastritis  (Kuster),  it  is  necessary 
to  assume  that  local  conditions,  possibly  the  character  of  the  circulation, 
prevented  the  absorption  of  the  lipoma. 

Into  the  etiology  of  lipoma  many  factors  seem  to  enter.    An  hereditary 


LI  POM  A  181 

influence  was  recognized  in  a  family  observed  by  Murchison  in  which  the 
father  and  3  daughters  had  multiple  symmetrical  lipomas  while  9  sons  were 
free.  In  Blaschko's  case  only  the  male  members  were  affected  and  the  tumors 
appeared  at  puberty.  Other  hereditary  cases  are  recorded  by  Meerbeck  and 
Petren. 

The  occurrence  of  multiple  symmetrical  lipomas  has  suggested  to  many 
a  connection  with  the  peripheral  nerves  (Payer,  Kottnitz).  In  a  group  of 
cases  the  tumors  have  been  painful  and  associated  with  other  lesions  of  the 
nervous  system.  Alsberg  found  several  neurofibromas  with  many  lipomas 
in  the  same  case  and  he  traced  nerve-fibers  into  certain  lipomas.  Both 
xanthoma  and  multiple  lipoma  have  also  been  observed  with  multiple  neuro- 
fibroma.  Yet  the  occurrence  of  lipomas  with  multiple  neurofibroma  is  ex- 
tremely rare  and  it  has  not  been  possible  to  establish  for  lipoma  such  a  rela- 
tion to  the  peripheral  nerves  as  exists  with  fibroma.  Grosch  and  others  have 
argued  that  multiple  lipomas  may  originate  in  connection  with  the  sebaceous 
glands,  as  the  result  of  a  trophoneurosis,  but  later  observers  have  been  unable 
to  find  support  for  this  theory  (Lit.  Goebel). 

Virchow  described  as  capsular  lipoma  certain  limited  but  sometimes  bulky 
growths  occurring  in  atrophying  organs  as  the  kidney  and  breast.  A  similar 
growth  of  fat  tissue  replaces  the  atrophic  thymus  and  bone-marrow  and  is 
very  often  seen  in  the  atrophic  lymph-nodes  of  cachectic  or  emaciated  sub- 
jects and  with  chronic  mastitis.  Askanazy  was  able  to  show  that  in  several 
cases  of  small  multiple  lipomas  the  tumors  were  located  in  atrophic  lymph- 
nodes,  and  he  suggested  that  this  was  a  common  origin  of  lipomas.  The  term 
''replacement  lipomatosis"  seems  more  applicable  to  this  process,  which  may 
produce  fatty  growths  of  moderate  dimensions,  but  not  true  lipomas. 

Multiple  lipomas  have  been  observed  in  many  cases  of  disease  or  atrophy 
of  the  thyroid  gland  in  cases  of  obesity  and  in  alcoholism,  but  it  does  not 
appear  that  these  constitutional  conditions  have  any  direct  bearing  on  the 
etiology  of  true  lipoma  (Curling,  Madelung,  Kottnitz).  They  seem  more 
clearly  connected  with  the  forms  of  diffuse  or  regional  overgrowth  of  fat  tissue 
which  bear  the  same  relation  to  lipoma  as  diffuse  fibromatosis  holds  to  fibroma. 
In  such  conditions  disturbances  of  the  thyroid  and  pituitary  glands  seem  to 
be  an  important  factor. 

A  congenital  tissue  predisposition  seems  to  be  an  essential  factor  in  the 
origin  of  most  lipomas.  This  predisposition  may  take  the  form  of  a  disturb- 
ance of  development  of  the  fat  tissue.  It  has  been  shown  by  Kolliker  and 
Toldt  that  the  fat  lobules  have  a  certain  independence  in  development  which 
constitute  them  a  sort  of  primitive  organ.  The  comparative  isolation  of 
the  blood-supply  of  these  lobules  reappearing  in  lipomas  suggests  that  the 
anomaly  predisposing  to  lipoma  is  connected  with  the  distribution  of  blood- 
vessels in  the  fatty  tissues.  . 

A  more  definite  embryonic  disturbance  is  probably  responsible  for  the 
origin  of  many  lipomas  of  the  internal  organs,  as  in  the  kidney,  where  mis- 
placed islands  of  capsular  fat  are  held  to  give  rise  to  tumors  (Selter,  Lu- 
barsch,  Manasse,  Miiller). 

More  complex  embryogenic  anomalies  are  concerned  with  those  lipomas 
which  arise  in  the  cranial  cavity  with  cholesteatoma,  where  complex  epidermal 
tissues  are  involved  (Bostroem) ;  with  spina  bifida  (v.  Recklinghausen,  Arnold) ; 
with  a  rudimentary  cervical  rib  (Volcker);  in  the  uterus  (Merckel). 

Certain  lipomas  result  from  predominance  of  fat  tissues  in  mixed  tumors. 
Such  is  probably  the  nature  of  the  recurrent  lipoma  of  the  spermatic  cord. 
(Sazarin.  Ehrendorfer,  Porges). 

Trauma  of  many  types  has  acted  as  an  exciting  factor  with  many  soli- 


182  NEOPLASTIC  DISEASES 

tary  superficial  lipomas  in  subjects  in  which  a  local  or  general  predisposition 
must  be  assumed  to  exist. 

In  the  general  etiological  classification  of  lipoma  and  lipomatoid  processes 
one  must  recognize  many  different  forms  of  hypertrophy  of  fat  tissue  as  fol- 
lows: (i)  Obesity;  (2)  localized  overgrowth  of  fat  tissue,  lipoma  annulare  colli; 
(3)  replacement  lipomatosis,  as  in  atrophic  organs,  marrow,  kidney,  capsular 
lipoma,  lymph-nodes;  (4)  homologous  lipoma,  a  group  including  the  ma- 
jority of  solitary  subcutaneous  lipomas;  (5)  heterologous  lipoma  from  mis- 
placed groups  of  embryonal  tissue  cells;  (6)  overgrowth  of  lipoma  in  mixed 
tumors  and  teratomas. 

Clinical  Types  of  Lipoma. — Subcutaneous. — The  subcutaneous  tissue  is  the 
commonest  seat  of  lipoma,  and  the  back,  neck,  shoulders,  axilla,  and  abdom- 
inal wall  are  most  frequently  affected.  According  to  Grosch,  who  has  plated 
a  large  number  of  subcutaneous  lipomas,  these  tumors  occur  in  inverse  pro- 
portion to  the  number  of  glandular  structures  in  the  skin.  The  cutaneous 
lipomas  are  single  or  multiple,  unilateral  or  bilateral  and  symmetrical,  small 
or  large,  and  polypoid,  or  pendulated.  They  arise  in  the  derma,  beneath  the 
superficial  fascia,  and  in  the  deeper  fascias. 

Small  congenital  lipomas  occur  beneath  the  skin  on  the  volar  side  of  the 
fingers  and  hands.  They  arise  from  the  deep  fascia  and  may  be  connected 
with  the  tendon  sheaths. 

Lipoma  annulare  colli  is  a  diffuse  form  of  lipomatosis  occurring  in  the  neck, 
producing  great  enlargement  of  this  region,  and  involving  the  fat  tissues  of 
the  skin  and  subcutaneous  and  intramuscular  structures  (Madelung).  It 
is  not  a  true  lipoma,  but  a  localized  overgrowth  of  the  abundant  fat  tissues 
of  this  region.  Somewhat  similar  overgrowths  of  fat  tissue  may  occur  in  the 
hips  and  thighs  (Shattock).  More  general  hypertrophy  of  fat  tissues  is  seen 
in  adiposis  dolorosa  (Dercum).  Subcutaneous  lipomas  often  reaching  con- 
siderable size  occur  in  the  scrotum  and  labia. 

Synovial. — Lipoma  and  lipomatous  processes  affect  the  joints.  Solitary 
lipoma  may  arise  within  the  joint  cavity  through  rupture  of  the  synovial 
membrane  and  protrusion  of  the  subcapsular  fat  which  then  goes  on  to  con- 
tinuous hyperplasia  (Konig).  Solitary  lipomas  may  also  arise  in  the  joint 
from  overgrowth  of  fat  in  synovial  fringes  (Otterbeck,  Filter).  Extra-articular 
lipomas  arising  from  the  subcapsular  fat  occur  about  the  knee  and  hip.  Lipoma 
arborescens  is  a  characteristic  extensive  papillary  outgrowth  from  the  fat 
tissues  of  the  synovial  membrane  and  joint  capsule  of  the  knee  which  fills 
the  joint  spaces  and  interferes  with  function.  It  occurs  with  simple  chronic 
and  with  tuberculous  arthritis  in  which  case  it  is  probably  of  inflammatory 
origin  with  overgrowth  of  synovial  fat  (Kaufmann),  but  it  occurs  apart  from 
any  inflammatory  processes  as  a  true  tumor  of  pure  fat  tissue  in  which  the 
characteristic  relation  of  lobules  to  branching  subcapsular  blood-vessels  is 
observed  (Borst,  Ribbert). 

Intermuscular. — In  the  cheek  a  congenital  lipoma  arises  from  a  mass  of 
fat  in  the  canine  fossa,  on  inner  surface  of  masseter  muscle,  long  known  as 
corpus  adiposum  mala  (Bichat),  pushes  its  way  beneath  the  skin  and  appears 
as  a  subcutaneous  tumor  of  moderate  dimensions.  Several  tumors  of  this 
origin  have  been  collected  by  Bruns  and  Ransohoff.  They  may  readily  be 
mistaken  for  tumors  of  the  parotid  with  which  they  are  in  intimate  connection. 

Beneath  the  pectoralis  lipomas  arise  probably  from  extensions  of  the 
axillary  fat  which  cause  protrusion  of  the  breast  (Billroth).  Deep  lipomas 
are  also  observed  in  the  orbit,  at  the  base  of  the  tongue,  and  in  the  larynx. 
Grosch  has  collected  many  lipomas  occurring  about  the  cranium. 

Cranial. — In  the  cranial  cavity  lipomas  have  been  observed  in  various 


LI  POM  A  183 

situations  in  most  of  which  small  collections  of  fat  tissue  are  normally  pres- 
ent. The  chief  locations  include  the  surface  of  the  corpus  callosum,  the  base 
of  the  cerebrum,  the  brain  stem  and  cerebellum,  the  ventricles,  and' the  roots 
of  the  cranial  nerves  (v.  Sury,  Lit.).  They  invariably  arise  from  the  pia, 
although  many  appear  to  be  embedded  in  the  brain  tissue.  Taubner  argued 
that  they  may  arise  from  the  glia-tissue. 

Virchow  mentions  6  lipomas  of  the  pia,  i  of  the  raphe  of  the  corpus  cal- 
losum, and  4  at  the  base.  In  the  choroid  plexus  and  nourished  by  its  vessels 
they  have  been  observed  by  Virchow,  Wallmann,  and  Hackel.  Rindfleisch 
saw  small  multiple  lipomas  of  dura  and  ventricular  ependyma.  Fere  and 
Francillon  report  symmetrical  lipomas.  Garnier's  lipoma  was  attached  to 
the  crus  cerebri.  Small  lipomas  of  the  corpora  quadrigemina  are  reported 
by  Bernhard  and  Taubner.  The  most  characteristic  type  is  the  lipoma  which 
is  nourished  by  the  vessels  of  the  corpus  callosum,  grows  along  this  structure, 
and  largely  replaces  the  nerve  tissue  (Virchow,  Benjamin,  Coats).  Peri- 
neural  lipomas  inclose  the  roots  of  the  cranial  nerves  or  olfactory  bulbs 
(Shouppe).  A  central  nucleus  of  bone  has  been  found  by  Benjamin,  Chiari, 
Ernst,  and  v.  Sury. 

Many  of  the  tumors  are  small  and  fail  to  produce  symptoms,  while  not 
a  few  reach  sufficient  bulk  to  cause  atrophy  of  adjacent  nerve  tissue.  Weil 
removed  at  operation  a  lipoma,  10  X  10  X  4  cm.  from  the  temporal  fossa. 
Wurth's  lipoma  of  the  basal  pia  extended  into  the  left  hemisphere  and  caused 
epilepsy  and  hemiplegia.  From  the  studies  of  Bostroem,  who  collected  28 
cases,  it  appears  probable  that  most  intracranial  lipomas  originate  from  epi- 
dermal inclusions,  although  no  dermal  elements  have  been  found  in  them. 
Nippe  found  a  lipoma  of  the  parietal  lobe  surrounded  by  gliosarcoma  which 
he  attributed  to  trauma. 

Lipomas  may  develop  in  connection  with  defective  development  of  the 
spinal  canal  and  meninges.  A  series  of  tumors,  some  of  which  were  pure 
lipoma,  others  composed  of  fat,  fibrous  tissue  or  cartilage,  have  t>een  observed 
in  connection  with  spina  bifida  and  with  scantily  developed  meningocele 
(v.  Recklinghausen) .  Arnold's  hairy  fibrolipoma  of  the  scalp  appears  to 
have  originated  from  imperfect  closure  of  a  cranial  suture. 

Renal. — In  the  kidney  small  circumscribed  multiple  lipomas  occur  be- 
neath the  capsule  or  replacing  a  portion  of  cortex,  or  reaching  to  the  medulla. 
The  structure  of  these  tumors  varies.  Some  of  them  are  composed  of  pure 
fat  tissue;  others  contain  considerable  fibromatous  tissue,  so  that  Virchow 
and  others  have  spoken  of  them  as  fibrolipoma.  In  either  case  the  light 
yellow  translucent  color  seems  to  distinguish  them  from  the  more  common 
struma  suprarenalis  of  Grawitz,  which  is  opaque  and  of  an  orange  tint.  In 
not  a  few  cases  smooth  muscle-tissue  has  been  found  in  such  tumors  and 
Selter,  Lubarsch,  and  Manasse  have  described  them  as  myofibroma;  while 
in  other  cases  sarcomatous  features  are  observed  as  in  the  case  of  Miiller's 
(myoliposarcoma).  I  have  observed  a  very  large  liposarcoma  of  this  type, 
in  one  lobe  of  which  xanthomatous  changes  were  pronounced.  Borst  and 
Selter  describe  symmetrical  lipomas  of  the  kidneys  chiefly  of  the  upper  half 
of  the  organ.  In  Borst's  case  double  myolipoma  was  associated  with  fibro- 
muscular  tumors  of  the  same  portions  of  both  kidneys.  All  these  features 
point  to  a  congenital  and  embryonal  origin  of  these  tumors,  but  the  exact 
nature  of  the  embryogenic  disturbance  is  undetermined.  That  they  may 
be  connected  in  some  way  with  Grawitz's  struma  suprarenalis  is  indicated 
by  the  presence  of  adrenal  tissue  in  Muller's  case,  and  by  the  occurrence  of 
curious,  complex,  chiefly  liposarcomatous  tumors  of  the  kidney,  in  one  of 
which  I  have  observed  areas  of  perithelioma  mingled  with  liposarcomatous 


184  NEOPLASTIC  DISEASES 

tissue.  Somewhat  similar  myolipomatous  growths  occur  along  the  spermatic 
cord. 

Partial  or  complete  replacement  lipomatosis  of  the  kidney  has  been  ob- 
served in  a  series  of  cases  reported  by  Lacrampe-Loustan.  Rayer  and  Epstein 
have  described  such  cases  in  which  no  trace  of  renal  tissue  remained,  while 
the  intact  capsule  of  the  organ  inclosed  pure  fat  tissue.  Selter  called  atten- 
tion to  the  fact  that  in  most  of  these  cases  a  single  large  calculus  occupies 
the  renal  pelvis.  The  proliferation  of  fat  begins  in  the  pelvic  adipose  tissue, 
and  follows  atrophy  of  the  renal  parenchyma. 

True  pelvic  lipomas  probably  develop  from  such  capsular  tumors  which 
early  project  into  the  cavity.  Warthin  described  a  very  large  pedunculated 
intrapelvic  growth  over  which  the  mucosa  and  atrophic  kidney  tissue  was 
widely  stretched,  while  a  tongue-like  mass  extended  several  inches  into  the 
ureter. 

Perirenal  lipomas  containing  connective  tissue,  mucoid  areas,  and  often 
sarcomatous  areas  occur  in  infants  and  adults  and  may  reach  very  large 
dimensions.  In  advanced  stages  they  pass  as  retroperitoneal  lipomas.  Lau- 
wers  describes  a  tumor  arising  at  birth  and  reaching  a  weight  of  6  pounds 
at  7  years.  Windle's  liposarcoma  weighed  50  pounds.  Adami  described  2 
very  large  tumors  composed  of  adult  fat  tissue  with  cellular  stroma.  The 
growth  is  usually  slow,  but  with  sarcomatous  structure  the  progress  may  be 
rapid  and  recurrence  is  frequent. 

Gastro-intestinal. — In  the  gastro-intestinal  tract  lipomas  are  of  rare  occur- 
rence. They  arise  from  the  submucosa  and  from  the  appendices  epiploicae 
of  the  colon.  Dewis  collected  44  cases  in  9  of  which  the  tumor  was  expelled 
spontaneously,  while  intussusception  occurred  in  21.  The  subserous  lipomas 
may  be  worked  loose  in  the  peritoneum.  Ehrlich  has  collected  52  cases  of 
intestinal  lipomas.  In  the  gastric  submucosa  small  fatty  tumors  may  occur. 
I  have  observed  a  large  fatty  tumor  4  X  10  cm.  surrounding  the  appendix 
which  was  the  seat  of  chronic  suppuration.  Very  large  retroperitoneal  lipomas 
have  been  observed.  (Madelung,  Waldeyer,  Adami). 

Mediastinal. — In  the  mediastinum  localized  overgrowth  of  fat  tissue  is 
not  unknown,  especially  in  alcoholic  and  obese  subjects.  True  lipomas  of 
the  mediastinum  may  reach  large  dimensions  and  cause  pressure  symptoms 
from  the  thoracic  organs.  Arising  from  many  different  points  in  the  sub- 
pleural  fat,  mediastinal  lipomas  may  project  into  the  pleural  cavity  or  along 
the  intercostal  spaces  (Rokitansky).  Or  the  growth  may  perforate  the  chest 
wall  and  appear  externally  in  the  back  (Czerny),  beneath  the  breast  (Gussen- 
bauer)  or  on  the  front  of  the  chest  (Cruveilhier,  Conner).  In  the  writer's 
case  the  tumor  encircled  nearly  all  the  structures  in  the  thorax.  In  Fitz's 
case  there  was  congenital  hypoplasia  of  the  left  lung.  Carless  observed  a 
large  lipoma  of  the  thyroid  region  of  which  the  pedicle  was  traced  into  the 
mediastinum  and  which  was  associated  with  other  multiple  symmetrical 
lipomas.  I  have  seen  one  mediastinal  liposarcoma  with  tumor  fragments 
in  sputum  and  metastasis  in  deltoid  muscle. 

Cardiac. — In  the  heart  lipomas  have  been  described  by  Ribbert,  Orth, 
Petrocchi,  Spalty,  Hagedorn,  and  others.  They  may  originate  in  misplaced 
islands  of  epicardial  fat  tissue.  Dittrich's  tumor  was  congenital. 

Uterine. — In  the  uterus  Orth  has  observed  a  polypoid  lipoma  and  Wer- 
kel  2  intramural  lipomas,  while  lipoma tous  areas  of  mixed  tumors  of  the 
uterus  are  described  by  Gebhart.  Pollak  thought  his  intrauterine  lipoma 
originated  from  a  portion  of  omentum  protruding  into  a  wound  of  the  uterus. 

Myelogenous. — A  true  lipoma  of  the  marrow  of  the  fibula  in  a  young  girl 
has  been  recorded  by  Wehrsig. 


CHAPTER  XIII 
CHONDROMA 

Localized  overgrowth  of  cartilage  occurs  in  several  forms  between  which 
it  is  sometimes  difficult  to  draw  sharp  distinctions.  Limited  outgrowths 
of  preexisting  cartilage  occur  on  the  ribs,  in  the  larynx,  and  about  joints, 
which  exhibit  the  characters  of  a  simple  hyperplastic  process,  and  are  called 
ecchondroses.  True  progressive  neoplasms  composed  of  cartilage  appear 
in  the  same  situations  and  also  in  tissues  not  normally  containing  cartilage, 
and  these  are  called  chondromas  or  enchrondromas.  That  many  ecchondroses 
possess  some  of  the  properties  of  tumors  is  indicated  by  the  occasional  occur- 
rence of  large  chondromas  as  a  sequel  of  ecchondrosis.  Thus  chondromas 
as  large  as  an  apple  occur  at  the  chondrosternal  junction.  In  a  case  of  Weber's 
there  was  striking  symmetry  in  the  location  of  multiple  chondromas  and 
ecchondroses. 

Virchow  classed  as  ecchondroses  the  smooth  diffuse  outgrowths  of  per- 
manent cartilage,  and  as  enchondromas  the  large  circumscribed  lobulated 
tumors  of  transitory  cartilage.  Between  these  main  classes  are  many  inter- 
mediate forms  which  display  more  or  less  clearly  the  neoplastic  qualities. 

The  ecchondroses  are  usually  small,  multiple,  smooth  and  nodular,  or 
diffuse  outgrowths  of  preeexisting  cartilage.  After  reaching  a  certain  stage 
their  growth  tends  to  culminate,  often  with  the  natural  growth  of  cartilage 
in  the  body,  after  which  they  may  remain  quiescent  or  undergo  secondary 
changes,  chiefly  calcification  or  ossification.  Amyloid  deposits  may  also  occur. 

In  structure  the  ecchondroses  copy  normal  hyaline  and  fibrocartilage 
according  to  their  points  of  origin,  and  show  few  of  the  atypical  features 
of  true  chondroma.  They  are  usually  surrounded  by  normal  perichondrium, 
from  a  portion  of  which,  according  to  v.  Rindfleisch,  they  originate. 

Ecchondroses  are  not  extremely  common,  but  rather  widely  distributed. 
The  most  familiar  examples  occur  at  the  costochondral  junctions,  where  they 
appear  as  smooth  multiple  nodular  swellings  which  tend  to  calcify  or  ossify. 
Virchow  and  others  believed  that  these  and  most  other  ecchondroses  were  a 
sequel  of  rickets  and  this  origin  probably  applies  to  the  ecchondroses  arising 
in  early  life  and  soon  tending  to  calcify. 

A  well-known  form  of  ecchondrosis  appears  on  the  inner  surface  of  the 
symphysis  pubis,  and  may  reach  such  dimensions  as  to  obstruct  labor  (pelvis 
spinosd).  About  the  epiphyses  of  any  of  the  long  bones  small  nodular  out- 
growths of  cartilage  may  appear. 

Localized  cartilaginous  outgrowths  of  the  cricoid  and  thyroid  cartilages 
have  been  described  by  Virchow  and  many  later  writers.  They  project  in- 
ward with  deformation  of  the  larynx,  but  with  rare  exceptions  do  not  obstruct 
breathing.  The  entire  cricoid  cartilage  may  be  diffusely  thickened  by  multiple 
ecchondroses.  From  the  upper  and  lower  surfaces  of  the  tracheal  rings  multiple 
cartilaginous  nodules  may  develop.  They  are  connected  with  the  rings  by 
strands  of  fibrous  tissue  of  perichondrium,  and  they  may  become  so  numer- 
ous as  to  cause  fusion  of  many  adjacent  rings  (Virchow,  Recklinghausen, 
Mischaikoff).  Ecchondroses  usually  of  small  size  develop  from  the  inter- 
vertebral  discs  and  project  outward  or  into  the  spinal  canal. 

185 


186  NEOPLASTIC  DISEASES 

In  the  joint  cavities  multiple  ecchondroses  are  a  frequent  result  of  chronic 
arthritis  with  osteochondritis.  The  modes  of  origin  of  these  growths  and 
the  manner  in  which  they  become  detached,  forming  joint  mice,  have  been 
exhaustively  discussed  by  Virchow. 

Enchondroma. — The  true  chondroma  is  a  rather  common  tumor,  the 
varied  features  of  which,  perhaps  more  than  any  other  benign  tumor,  illus- 
trate the  peculiarities  of  neoplasms.  This  result  is  perhaps  dependent  upon 
the  facts  that  cartilage  is  essentially  an  embryonal  and  transitory  tissue, 
and  that  cartilage  cells  although  encased  in  a  firm  matrix  have  rather  active 
proliferative  powers,  possess  ameboid  properties,  and  are  readily  subject  to 
metaplastic  changes.  For  the  most  striking  display  of  these  characters  one 
must  pass  to  the  tumors  of  lower  animals  with  which  chondromas  are  more 
common  than  with  man. 

The  chondroma  produces  a  hard,  rounded,  lobulated  tumor  which  often 
reaches  large  dimensions.  The  lobulated  structure  is  referred  to  the  expan- 
sive growth  from  multiple  centers,  as  a  result  of  which  the  surrounding  tissues 
are  pressed  aside.  In  this  way  large  tumors  may  form,  composed  of  con- 
voluted masses  resembling  the  convolutions  of  the  brain.  Such  growths  are 
commonly  encapsulated  by  perichondrium  and  are  cartilaginous  throughout 
at  all  stages.  Other  chondromas  are  imperfectly  encapsulated,  encroach 
upon  surrounding  tissues  as  a  malignant  tumor,  and  invade  blood-vessels. 
In  such  cases  one  finds  many  stages  of  the  formation  of  the  perfected  cartilage 
from  more  cellular  tissue,  the  nature  of  which  is  not  always  clear.  The  nutri- 
tion of  the  solid  chondromas  is  maintained  by  a  system  of  lymph  spaces  from 
the  periphery.  Rindfleish  and  Borst  have  traced  a  rich  system  of  lymphatics 
from  the  periphery  of  a  submaxillary  chondroma  and  communicating  with 
the  pericellular  spaces.  Through  most  of  these  growths  there  are  irregular 
bands  of  connective  tissue  carrying  blood-vessels  and  this  feature  becomes 
pronounced  as  the  tumors  tend  to  calcify  or  ossify.  About  many  chondromas 
there  is  an  excessive  development  of  blood-vessels  to  which  Virchow  and  v. 
Recklinghausen  ascribe  an  important  and  primary  influence  in  the  develop- 
ment of  the  tumors.  Such  growths  have  been  termed  angiochondroma  and  a 
few  of  them  have  been  deeply  pigmented  by  diffusion  of  extravasated  blood 
pigment  (Siegert). 

The  capsule  of  subperiosteal  chondromas  may  consist  chiefly  of  the 
thickened  periosteum  which  may  go  on  to  produce  bone,  and  a  bony  capsule 
may  surround  chondromas  developing  in  the  marrow  cavities. 

While  most  chondromas  are  solid,  many  become  softened  by  mucinous 
degeneration,  and  cysts  filled  with  mucinous,  serous,  or  fatty  material  may 
form.  The  skin  over  a  chondroma  may  atrophy,  and  ulceration,  excavation 
of  portions  of  the  tumor,  and  suppuration  may  be  established.  Although 
the  chondromas  are  usually  localized  and  benign  they  sometimes  grow  ex- 
tensively in  the  blood-vessels,  filling  the  lumen  with  nodular  or  solid  masses 
and  extending  over  wide  areas.  In  a  case  reported  by  Ernst  a  chondroma 
of  the  lumbar  spine  invaded  many  of  the  abdominal  and  pelvic  veins,  traveled 
up  the  vena  azygos  and  vena  cava,  filled  the  right  ventricle  and  continued 
into  the  pulmonary  artery.  Discontinuous  metastases  also  occur  especially 
in  the  lungs,  occasionally  in  the  lymph-nodes. 

The  multiple  character  of  certain  chondromas  has  been  a  striking  feature, 
and  in  some  cases  nearly  every  bone  in  the  body  has  been  affected.  In  the 
notable  case  reported  by  Recklinghausen  the  hands,  feet,  knee,  elbow,  and 
ribs  were  the  seat  of  very  numerous  chondromas. 

The  location  of  skeletal  chondromas  is  usually  in  the  diaphyses  of  the 
bones  near  the  epiphyses.  They  may  project  externally,  pushing  outward 


CHONDROMA  187 

the  periosteum,  or  growing  in  the  medullary  cavity  they  distend  the  cavity 
and  are  surrounded  by  the  thin  bony  shaft. 

The  structure  of  chondromas  reproduces  that  of  the  various  normal  types 
of  cartilage,  chiefly  the  hyaline  variety.  Ranvier  classified  chondromas, 
according  to  their  structure,  in  four  groups,  (i)  A  single  lobe  of  hyaline 
cartilage.  (2)  Several  lobules  of  hyaline  cartilage  separated  by  fibrocartilage. 
(3)  Fetal  cartilage.  (4)  Cartilage  with  stellate  cells.  The  cells  may  be  more 
or  less  numerous  than  in  normal  cartilage.  They  vary  greatly  in  size  and 
usually  lack  the  orderly  arrangement  into  groups  of  cells  with  opposed  sur- 
faces flattened.  Peculiar  vacuoles  are  common  in  these  cells  and  were  described 
by  Virchow  under  the  term  "physaliden."  The  cells  are  usually  rounded 
and  lie  in  distinct  spaces,  but  with  imperfect  formation  of  chondrin  matrix 
they  become  stellate  with  mucinous  degeneration,  fusiform  as  they  approach 
the  connective-tissue  type,  calcific  granules  may  be  deposited  in  them,  and 
in  some  cases  they  show  all  transitions  up  to  the  bone  cell  in  osteoid  and 
osseous  areas.  The  cells  usually  contain  glycogen  and  fat  granules  and  well- 
marked  fatty  degeneration  may  occur. 

The  growing  cells  of  a  chondroma  are  not,  as  a  rule,  those  inclosed  in  the 
matrix,  but  rather  those  on  the  periphery  of  the  tumor.  The  matrix  of  the 
chondroma  is  usually  hyaline,  but  may  be  fibrillated  or  may  contain  elastic 
fibrils.  Ernst  noted  very  active  production  of  the  elastic  fibrils  in  a  rapidly 
growing  tumor.  The  matrix  is  not  an  integral  part  of  the  cells,  but  a  product 
which  is  deposited  under  cellular  influence  (Ribbert).  The  chondrin  is  usually 
deficient  and  irregularly  distributed  and  various  types  of  secondary  change 
are  frequent. 

Calcification  with  the  deposit  of  phosphate  and  carbonate  of  lime  affects 
first  the  matrix,  producing  an  irregular  network  of  densely  basic  staining 
material  which  is  composed  of  granules  compacted  together  and  becoming 
homogeneous.  The  borders  of  the  cell  spaces  may  be  first  affected  and  from 
this  point  the  deposit  appears  in  the  cells,  so  that  in  advanced  stages  both 
matrix  and  cells  may  become  heavily  incrusted.  In  such  areas  the  cells 
assume  a  stellate  form  approaching  the  character  of  bone  cells. 

Ossification  of  chondromas  occurs  under  several  conditions.  An  imper- 
fect formation  of  islands  of  bone  may  take  place  at  different  points  through- 
out chondroma,  this  change  being  preceded  by  increased  vascularity  of  the 
septa,  and  by  calcification  and  final  ossification. 

More  often  the  connective  tissue  in  and  about  the  chondroma  having 
first  laid  down  cartilage  goes  on  to  replace  it  by  trabeculae  of  well-formed 
bone  surrounded  by  typical  osteoblasts.  In  this  process  the  normal  events 
in  the  production  of  bone  in  cartilaginous  matrix  take  place. 

About  central  chondromas  which  invade  the  shaft  of  a  bone  the  peri- 
osteum may  be  incited  to  the  production  of  a  bony  capsule  which  is  of  inflam- 
matory origin  and  not  a  part  of  the  tumor. 

In  many  chondromas  the  formation  of  cartilaginous  matrix  is  imperfect 
and  a  simple  hyaline  or  partly  fibrillated  or  mucinous  material  takes  its  place. 
This  imperfect  chondrification  is  much  more  common  than  any  form  of  soften- 
ing of  chondrified  matrix.  In  the  soft  matrix  the  cells  may  attain  large  size 
and  lie  in  very  large  round  spaces,  or,  in  myxochondroma  they  become  stellate 
and  the  matrix  fibrillated.  Some  of  the  soft  chondromas  are  composed  of  a 
shell  of  perichondrium  from  which  spring  papillary  fringes  of  poorly  chondrified 
cartilage,  while  the  central  portions  are  filled  with  mucinous  fluid  (cystic, 
papillary  chondroma). 

Distinctly  malignant  cartilaginous  tumors,  chondrosarcomas,  occur  in 
several  forms.  Medullary  chondromas  may  perforate  the  shafts  of  long 


188 


NEOPLASTIC  DISEASES 


bones  and  destroy  the  epiphyses,  proving  malignant  from  mechanical  fac- 
tors. Infiltrating  chondromas  in  which  very  cellular  peripheral  portions 
invade  surrounding  tissues  and  produce  nodules  of  cartilage  are  properly 
called  chondrosarcoma.  There  is  a  considerable  group  of  chondromas  occur- 
ring in  mixed  tumors  and  teratomas,  which  are  usually  very  cellular,  con- 
taining other  tissues  besides  cartilage,  and  which  invade  tissues,  lymph- 
nodes,  and  blood-  and  lymph-vessels.  Invasion  of  veins  is  not  confined  to 
the  embryonal  or  teratoid  chondromas,  for  in  Virchow's  case  of  tumor  of 
fibula  and  in  Ernst's  case  of  fibrochondroma  of  spine  there  were  extensive 
intravascular  growths,  while  the  pelvic  chondromas  in  several  cases  have  in- 
vaded blood-vessels  and  lymphatics  (Foerster,  Weber,  Biesiadecki).  In 
this  group  the  malignant  properties  are  often  out  of  proportion  to  the  cel- 


FIG.  43. — Structure  of  the  wall  of  a  cystic  chondroma. 

lular  quality.  In  a  group  of  sarcomas  of  long  bones  composed  of  cartilage, 
bone,  and  cellular  tissue,  the  local  destructive  effects  and  recurrence  after 
operation  lead  to  their  designation  as  osteochondrosarcoma. 

While  in  general  the  more  cellular  and  softer  tumors,  as  myxochondroma, 
are  the  more  malignant,  both  clinical  and  histological  features  should  be 
regarded  in  applying  the  term  "chondrosarcoma."  The  metastases  of  chon- 
dromas exhibit  most  of  the  characters  observed  with  other  malignant  tumors 
and  a  special  capacity  to  invade  the  large  veins  must  be  ascribed  to  them. 
Invasion  of  the  lymphatics  also  occurs.  The  structure  of  these  invasive 
chondromas  does  not  always  suggest  malignancy.  In  Ernst's  case  the  intra- 
vascular cartilage  was  provided  with  firm  hyaline  matrix,  but  this  tumor 
did  not  produce  embolic  nodules.  To  account  for  the  invasive  properties 


CHONDROMA 


189 


one  must  assume  that  the  active  growth  and  infiltrative  properties  reside 
in  t,he  undifferentiated  cells  of  the  periphery  of  the  cartilaginous  nodules 
and  in  some  cases  extensive  continuous  growths  in  vessels  and  embolic  met- 
astases  have  consisted  almost  exclusively  of  such  undifferentiated  cells.  By 
such  changes  a  chondrosarcoma  may  lose  much  or  possibly  all  of  its  chon- 
dromatous  character.  This  possibility  also  suggests  that  certain  tumors 
originating  from  the  mother  tissue  of  cartilage  may  never  show  pronounced 
chondromatous  features,  but  appear  as  simple  sarcoma  or  myxosarcoma. 
Certain  nasopharyngeal  sarcomas  (polyps)  are  probably  of  this  character. 

Etiology. — The  majority  of  chondromas  occur  in  early  life  and  about 
puberty.  Some  are  congenital,  and  multiple  chondroma  of  the  spine  is  heredi- 
tary and  congenital.  Many  of  them  are  located  at  the  growing  ends  of  bones 
and  in  not  a  few  there  is  a  distinct  tendency  toward  standstill  and  regres- 
sion at  the  period  when  the  development  of  the  skeleton  is  complete.  All 
of  these  facts  point  to  an  origin  from  disturbances  in  development  of  the 
cartilaginous  elements  in  the  formation  of  bones  and  joints.  An  inherited 
predisposition  has  been  emphasized  by  Weber,  who  observed  many  chon- 
dromas and  ecchondroses  in  several  members  and  three  generations  of  the 


- 


FlG.  44. — Island  of  superfluous  cartilage  in  periosteum  of  rib.     (E.  Miiller.} 

same  family.  In  the  French  family  of  Pellerin  members  of  three  generations 
were  affected  with  multiple  chondromas  of  tibia,  ribs,  and  humerus  (Ernst). 

Virchow,  Recklinghausen,  and  many  others  have  shown  that  rickets  is  an 
important  factor  in  the  disturbance  of  the  growth  of  bones  that  leads  to 
chondroma.  Borst  has  found  widely  misplaced  islands  of  cartilage  in  ra- 
chitic  bones  and  believes  that  these  may  give  origin  to  chondroma  of  limited 
growth,  but  doubts  the  general  applicability  of  the  rachitic  theory  of  skele- 
tal chondroma.  Ribbert  also  fails  to  find  in  this  theory  a  sufficient  explana- 
tion of  any  large  group  of  chondromas  and  thinks  the  disturbance  must  result 
from  some  unknown  fetal  disorder  of  the  bones.  E.  Miiller  has  described 
islands  of  superfluous  cartilage  in  the  periosteum  of  the  ribs  and  suggested 
that  these  structures  may  be  the  source  of  chondromas. 

In  the  remarkable  case  of  Recklinghausen 's  in  which  multiple  chondromas 
of  feet  and  hands  were  associated  with  angioma,  the  author  assumed  that 
congenital  aplasia  of  the  blood-vessels  subsequently  leading  to  passive  dila- 
tation and  angioma,  prevented  the  normal  progress  of  replacement  of  car- 
tilage by  bone  and  resulted  in  overgrowth  of  cellular  cartilage.  The  tumors 
ceased  to  grow  at  22  years. 


190  NEOPLASTIC  DISEASES 

For  the  large  group  of  distinctly  heterologous  chondromas  of  breast, 
parotid,  neck,  uterus,  etc.,  various  embryonic  disturbances  must  be  assumed 
to  exist,  in  most  of  which  complex  masses  of  tissue  are  involved.  Chondroma 
of  the  sex  glands  results  from  the  one-sided  development  of  teratomas  and 
it  is  probable  that  in  other  localities  certain  chondromas  have  a  similar  origin. 

Trauma  and  inflammation  are  frequent  causes  of  ecchondroses,  and  trauma 
is  not  infrequently  reported  as  preceding  chondroma  and  chondrosarcoma 
(50  per  cent.  Weber),  especially  of  the  long  bones,  in  which  cases  it  must  be 
assumed  that  there  is  also  a  local  or  general  predisposition. 

Clinical  Types  of  Chondroma. — The  skeletal  chondromas  are  the  most 
frequent  forms  of  this  tumor.  They  occur  most  often  as  single  or  multiple 
tumors  of  the  hands  and  feet,  but  may  affect  any  of  the  bones  (Nasse,  Lit.). 
They  arise  from  periosteum  or  in  the  medulla,  usually  near  the  diaphysis 
and  regularly  before  puberty,  tending  to  become  stationary  at  that  period. 
They  deform  the  shafts  of  the  bones  and  the  joints.  From  the  pelvic  syn- 
chondroses  they  may  grow  to  very  large  size,  a  case  of  Weber's  having  reached 
a  diameter  of  2  feet.  These  tumors  as  well  as  the  pubic  ecchondroses  may 
obstruct  labor.  In  a  girl  of  15  years  Pfeiffer  observed  a  pelvic  chondroma 
which  measured  i  meter  in  circumference  and  weighed  27  pounds.  Most 
of  these  large  pelvic  tumors  have  shown  rapid  growth  (Ernst). 

Pronounced  cases  of  multiple  osteochondroma  represent  a  somewhat 
specific  malady  which  is  probably  related  to  chondrodysplasia  and  other 
disturbances  in  the  growth  of  bone  (Ashurst,  Lit.).  It  is  responsible  for  a 
variety  of  skeletal  deformities,  as  depicted  by  Hagen.  The  disease  some- 
times exhibits  hereditary  tendencies,  being  transmitted  by  affected  males 
and  females  and  by  unaffected  females.  Honeij  finds  that  subjects  in  the 
progressive  stage  of  the  disease,  when  placed  on  a  diet  poor  in  calcium,  show 
excessive  calcium  elimination.  The  tumors  may  appear  at  birth,  or  be  de- 
layed until  the  5oth  year,  and  one  tumor  may  be  growing  while  another  is 
regressing.  There  is  generally  a  limit  of  growth  about  puberty.  The  growth 
of  the  long  bones  may  be  so  inhibited  that  the  subject  is  dwarfed.  Growth 
of  radius  over  that  of  ulna  may  produce  a  deformity  resembling  dislocation 
of  the  radius,  and  growth  of  tibia  over  fibula  results  in  pes  valgus.  The  x-ray 
shows  osteoporosis  of  the  ends  of  the  bones,  and  often  a  cystic  appearance, 
while  the  compact  bone  of  the  ends  of  shafts  may  be  very  deficient.  At  vari- 
ous points,  usually  about  the  joints,  the  multiple  out  growths  appear.  The 
structure  shows  a  persistence  and  overgrowth  of  poorly  ossified  or  calcified 
cartilage,  in  which  the  cells  are  irregular  in  size  and  form  (Carman,  Fisher). 
The  ordinary  epiphyseal  line  is  irregular  or  obliterated.  Late  ossification 
leaves  the  bone  deformed  and  covered  with  osteophytes.  Lenormant  col- 
lected a  series  of  cases  in  which  osteosarcoma  appeared  to  develop  on  the 
basis  of  the  early  lesions. 

Chondroma  of  the  scapula  arises  from  various  portions  of  the  bone,  and 
exhibits  the  structure  of  the  benign  chondroma  or  that  of  chondrosarcoma, 
often  myxomatous.  The  great  variations  in  the  structure  and  course  of  these 
tumors  is  fully  presented  by  Deganello  in  a  study  of  39  cases.  Osteoid  chon- 
droma is  a  peculiar  form  of  skeletal  chondroma  arising  beneath  the  perios- 
teum of  the  long  bones.  As  the  growth  enlarges  the  bone  assumes  a  thickened 
spindle  form.  The  structure  is  that  of  hyaline  acidophilic  osteoid  tissue  in 
which  the  cells  approach  the  form  of  bone-cells,  and  true  bone  may  form  in 
them.  Many  of  the  osteosarcomas  correspond  to  this  description.  Virchow 
describes  an  extensive  case,  largely  ossified,  arising  in  the  soft  intercostal 
tissues  and  producing  metastases  in  the  lung  and  pleura. 

Branchiogenic  chondromas  occur  in  the  neck  from  misplaced  islands  of 


CHONDROMA 


191 


cartilage  derived  from  the  branchial  clefts.  They  are  located  in  and  about 
the  sternomastoid  ligament  and  muscle  with  branchiogenic  cysts  and  fistulas, 
and  near  the  parotid  gland.  Zahn  has  collected  12  cases  in  which  misplaced 
islands  of  cartilage  were  discovered  in  this  region,  and  Bidder  observed  a 
congenital  tumor  arising  from  such  an  island.  Recklinghausen's  chondroma 

of  the  thyroid  may  have  arisen  from 
such  a  tissue  rest.  Symmetrical  islands 
of  cartilage  and  bone  have  been  found  in 
the  tonsil,  but  do  not  seem  to  have  given 
rise  to  tumors  (Deichert). 


(After 


FIG.  45.  FIG.  46. 

FIG.  45. — Multiple  congenital  ecchondroses  in  a  negro  girl  of   11   years. 
Ashhurst,  A.  S.,  63.)  , , 

FIG.  46.— Multiple  congenital  osteochondroma.    x-Ray  photograph  of  bones  ot 
arm.     (After  Carman  and  Fisher,  A.  S.,  61.) 


An  auricular  chondroma  is  described  by  Virchow  as  springing  from  a 
misplaced  portion  of  the  fibre-elastic  cartilage  of  the  ear. 

The  chondromas  of  the  hyoid  region  described  by  Boeckel  and  Spishamy 
seem  to  have  been  connected  entirely  with  abnormalities  of  the  hyoid  bone. 


192  N EOF  LAS  TIC  DISEASES 

The  various  embryological  disturbances  giving  rise  to  cysts,  rests,  and  tumors 
in  this  region  will  be  discussed  elsewhere. 

Chondroma  of  the  respiratory  tract  occurs  in  the  trachea,  bronchi,  and 
lungs,  apparently  arising  from  the  same  structures  that  lead  to  ecchondroses. 
Virchow  has  described  multiple  chondromas  of  the  lung,  located  at  the  root, 
in  the  parenchyma  and  on  the  pleura.  While  often  purely  cartilaginous,  they 
may  become  calcified  or  ossified.  In  the  lung  rare  tumors  occur  as  multi- 
lobed  growths  of  hyaline  cartilage,  subpleural  or  deep  within  the  lobe,  and 
their  association  with  connective  and  fat  tissue  points  to  an  origin  for  some 
of  them  from  a  complex  mass  of  tissue.  In  Siegert's  case  the  chondroma 
projected  from  the  bronchial  wall  into  a  dilated  bronchus.  Chronic  thicken- 
ing of  the  pleura  may  yield  flat  plates  resembling  cartilage,  but  composed  of 
hyaline  or  calcified  connective  tissue.  Yet  Kramer  has  described  a  lobulated 
chondroma  of  the  pleural  surface  of  the  diaphragm. 


FIG.  47. — Structure  of  multiple  osteochondroma.  Section  through  outer  bony  shell: 
A,  Hyaline  cartilage  with  atypical  cells  and  calcium  deposit;  B,  bone  trabeculae;  C, 
mucoid  connective  and  fat  tissue.  (After  Carman  and  Fisher.) 

In  the  breast  pure  chondroma  is  occasionally  observed,  but  more  often  the 
cartilaginous  growth  is  a  portion  of  a  mixed  tumor  usually  of  epithelial  type. 

It  is  commonly  assumed  that  in  all  instances  these  tumors  arise  from 
isolated  masses  of  tissue  which  include  a  skeletal  portion  giving  rise  to  the 
chondroma,  but  the  correctness  of  this  view  is  not  demonstrated.  It  is  pos- 
sible that  some  of  the  cartilaginous  tumors  arise  by  metaplasia  of  other  tissues. 
In  the  dog  a  large  proportion  of  mammary  cancers  contain  cartilage  and 
the  histological  structure  strongly  suggests  its  formation  by  metaplasia  from 
other  tissues.  Williams  has  collected  many  reports  of  cartilaginous  and  bony 
tumors  of  the  breast  and  argues  in  favor  of  the  origin  from  misplaced  masses 
of  complex  tissue. 

In  the  uterus,  especially  in  the  cervix,  cartilaginous  and  bony  tumors 
are  occasionally  observed  (Williams,  Lit.).  It  seems  probable  that  they  arise 


CHONDROMA 


193 


from  misplaced  islands  containing  skeletal  tissue.  Thus  Meyer  found  a 
bony  nodule  in  the  cervix  associated  with  a  remnant  of  the  Wolffian  duct. 
Miller  found  an  osseous  tumor  replacing  the  corpus  in  a  subject  in  whom 
the  vagina  was  absent.  In  several  uterine  myomas  cartilage  has  been  found 
(Williams). 

In  the  mixed  tumors  of  the  salivary  glands  cartilaginous  areas  are  very 
common,  and  especially  in  the  submaxillary  the  tumor  may  be  nearly  pure 
chondroma.  Here  the  cartilage  is  of  imperfect  hyaline  variety  and  often 
of  myxomatous  type.  In  recurrences  of  these  tumors  there  may  be  a  tend- 
ency toward  elimination  of  all  but  the  cartilaginous  elements.  The  various 
questions  that  concern  these  tumors  will  be  discussed  elsewhere. 

Teratoid  chondroma.  A  considerable  group  of  chondromas,  including 
many  of  those  which  invade  the  vessels  and  prove  malignant,  represent  one- 
sided development  of  the  cartilaginous  portions  of  teratomas.  Most  of  these 


pIG    4g. — Metastasis  from  malignant  chordoma  in  the  cavernous  sinus  of  a  pelvic 

lymph-node.     (Lewis'  case.) 

chondromas  arise  in  the  sex  glands,  ovary,  and  more  especially  the  testis, 
but  with  the  extensions  of  the  limits  of  occurrence  of  teratomas  it  seems 
probable  that  chondromas  of  this  origin  may  be  more  numerous  than  now 
appears.  In  the  testis  these  tumors  are  solid  or  cystic,  and  other  elements 
besides  cartilage  are  usually  present  in  abundance.  The  cartilage  may  be 
reduced  to  very  minute  traces  which  escape  detection  in  many  tumors  or 
tridermal  type  (Ewing).  In  several  notable  cases  extensive  intravascular 
growths  and  metastases  occurred  (Paget,  Ohkubo,  Lit.). 

Chordoma.— A  remnant  of  the  chorda  dorsalis^  a  specific  entodermal 
embryonal  tissue  about  which  the  spinal  column  develops,  regularly  persists 
in  infants  in  the  centers  of  the  intervertebral  discs  (Kolliker).  It  was  shown 
by  H.  Miiller  that  portions  of  chorda  tissue  commonly  persist  at  the  base 
of  the  skull  and  in  the  coccyx,  and  that  this  tissue  probably  gives  origin  to 
.certain  peculiar  tumors  which  Virchow  first  described  as  ecchondrosis  spheno- 
13 


194 


NEOPLASTIC  DISEASES 


occipitalis.  Ribbert  found  chorda  remnants  in  the  bony  tissue  and  flat  plates 
beneath  the  dura  mater  of  the  Clivus  Blumenbachii,  and  held  that  they  pro- 
duced tumors  only  when  misplaced  and  lying  outside  the  bony  encasement. 
He  found  the  tumors  in  about  2  per  cent,  of  a  series  of  subjects,  in  the  form 
of  bean-shaped  masses  which  perforate  the  dura  and  become  adherent  to 
the  basilar  artery  with  which  they  may  be  torn  away  in  removing  the  brain. 
By  careful  sectioning  he  was  able  to  show  that  the  small  intradural  tumors 
are  connected  by  a  pedicle  with  the  underlying  bone  in  which  their  roots 
are  embedded.  They  seldom  reach  a  large  size  and  being  soft  do  not  produce 
pressure  or  other  symptoms.  Yet  Grahl  observed  a  lobulated  extradural 
chordoma  of  the  sella  turcica  which  produced  fatal  pressure  symptoms.  A 
large  chordoma  lying  in  front  of  the  upper  cervical  vertebrae  has  been  observed 
by  Klebs.  Hassner's  tumor  measured  5.5  X  6.5  cm.  and  had  produced  pres- 
sure symptoms  for  four  years. 


FIG.  49. — Malignant  chordoma  infiltrating  the  pelvic  fat  tissues.     (From  a  case  of  Dr. 

N.  D.  C.  Lewis.) 


In  structure  chorda  tissue  is  composed  of  groups  of  large  vacuolated  cells 
lying  in  soft  homogeneous  basic  staining  matrix,  and  the  tumors  accurately 
produce  this  structure.  Virchow  described  the  peculiar  vacuolated  cells  of 
these  growths  under  the  term  "ecchondrosis  physalifora,"  and  since  somewhat 
similar  vacuolation  occurs  in  chondroma,  he  was  inclined  to  regard  all  of 
them  as  chondromas.  Although  chorda  tissue  does  not  produce  cartilage 
and  there  can  be  no  transition  forms  between  chondroma  and  chordoma, 
yet  it  may  at  times  be  difficult  to  distinguish  between  them. 

Malignant  Chordoma. — The  exact  limits  of  the  occurrence  and  possible 
variations  in  structure  and  course  of  chordoma  have  not  been  determined. 
It  would  seem  likely  that  a  tissue  as  extensive  as  the  chorda  dorsalis  might 
persist  at  various  points  along  its  normal  location,  and  that  it  might  give 
origin  to  structures  varying  from  that  of  the  simple  chordoma. 

Nebelthau  has  shown  that  remnants  of  chorda  tissue  may  occur  at  several 
points  along  the  base  of  the  skull.  Fischer  has  described  a  malignant  chor- 
doma arising  beneath  the  dura  of  the  clivus  B.,  invading  the  spinal  canal  and 


CHONDROMA  195 

compressing  the  cord.  A  small  vein  was  invaded  by  polyhedral  tumor-cells 
The  structure  corresponded  to  that  of  chordoma,  but  some  areas  resembled 
cartilage. 

Link  obtained  portions  of  a  tumor  in  the  pharyngeal  vault,  which  affected 
the  internal  ear  and  compressed  several  cranial  nerves  and  which  he  believed 
arose  from  the  clivus  B.  Besides  the  usual  chorda-like  tissue  it  contained 
groups  of  polyhedral  tumor-cells  so  that  Linck  recalls  the  entodermal  origin 
of  the  chorda  and  discusses  the  question  whether  the  malignant  chordoma 
should  be  called  sarcoma  or  carcinoma.  Coccygeal  chordomas  are  described 
by  Feldmann  and  Vecchi,  and  in  the  latter  case  the  growth  recurred  after 
operation.  Albert  describes  a  coccygeal  chordoma  which  involved  the  rectal 
wall  and  recurred  promptly  after  operation. 


1. 1  -  .•  .•  ;  -     ' 

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FIG.  50. — Sacral  chordoma.     (From  a  section  received  from  Dr.  Mallory.) 

The  positive  identification  of  chordoma  is  not  readily  accomplished.  Two 
common  tumors  closely  simulate  or  even  duplicate  the  structure  attributed 
to  chordoma — viz.,  myxochondroma  and  colloid  carcinoma  of  the  intestinal 
canal.  The  gross  relations  of  the  tumor'  should  be  given  first  consideration  in 
the  diagnosis.  Especially  in  the  sacral  region  chordoma  is  difficult  to  separate 
satisfactorily  from  chondroma  or  colloid  carcinoma.  Feldman  analyzes  in 
detail  the  features  which  distinguished  his  tumor  which  eroded  the  sacrum, 
from  colloid  carcinoma,  but  I  have  seen  all  these  features,  except  the  broad 
attachment  to  the  sacrum,  in  colloid  carcinoma  of  the  rectum.  In  the  pharyn- 
geal region  atypical  chondromas  are  rather  common  and  must  be  considered 
a  more  probable  occurrence  than  chordoma. 


CHAPTER   XIV 

OSTEOMA 

Circumscribed  overgrowth  of  bone  occurs  under  such  a  wide  variety  of 
conditions  and  the  distinctions  between  inflammatory  and  neoplastic  hyper- 
plasia  of  the  tissue  are  so  often  obscure  that  it  has  never  been  possible  to 
exactly  define  the  limits  of  osteoma.  True  progressive  neoplasms  which 
adhere  to  Virchow's  criteria  and  in  which  bone  is  the  essential  and  not  the 
secondary  or  accidental  product,  are  not  common,  but  chronic  processes 
which  result  in  bone  formation  from  trauma,  inflammation,  and  disturbances 
of  nutrition  are  numerous.  Volkmann  concluded  that  all  exostoses  that 
arise  from  cartilage  are  true  tumors,  others  not.  Borst,  who  separates  from 
the  tumors  all  the  bone-producing  processes  which  are  self-limiting  or  clearly 
associated  with  trauma  and  inflammation  has  little  to  say  about  true  osteoma. 
Virchow  and  Ribbert  largely  agree  in  recognizing  neoplastic  qualities  in  many 
processes  in  which  trauma  and  inflammation  are  originally  concerned,  and 
which,  whether  true  tumors  or  not,  illustrate  the  complex  etiology  of  neo- 
plasms. 

Bone  formation  in  necrotic  tissue  (brain,  eye,  kidney,  aorta) ;  in  the  floors 
of  ulcers;  in  the  course  of  syphilis,  tuberculosis,  and  chronic  suppuration  in 
and  about  bones;  after  fractures,  in  chronic  arthritis;  at  the  insertion  of  the 
overused  tendons;  in  bursae;  in  the  muscles  of  riders — are  some  of  the  proc- 
esses in  which  neoplastic  qualities  are  least  prominent.  Yet  in  all  of  them 
the  size  of  the  resulting  bony  mass,  the  long  duration  of  the  process,  and  its 
eventual  independence  of  the  original  exciting  factor  occasionally  reveal 
definite  neoplastic  characters.  Hence  in  discussions  of  osteoma  it  is  custo- 
mary to  include  all  forms  of  overgrowth  of  bone,  thus  securing  an  effective 
comparison  of  true  and  partial  bony  neoplasms. 

Histological  study  fails  as  a  rule  to  distinguish  simple  hyperplastic  growth 
of  bone  from  true  osteomas.  When  originating  in  bone  both  processes  show 
a  participation  of  some  or  many  osteoblasts  which  surround  the  edges  of  the 
new  growth  and  add  to  its  substance  from  one  or  many  sides.  Both  processes 
yield  dense  lamellated  bone  with  few  Haversian  canals  or  spongy  bone  with 
many  vessels  and  abundant  marrow  spaces  and  cells.  Bone  forms  in  con- 
nective tissue  without  the  appearance  of  many  osteoblasts,  the  fixed  cells 
being  passively  incorporated  in  osseous  matrix,  but  this  character  does  not 
always  distinguish  self-limiting  from  extensively  progressive  osteosis. 

The  gross  and  clinical  features  seem  to  form  the  best  criteria  by  which  to 
separate  osteoma  from  simple  hyperostosis. 

Spontaneous  or  traumatic  but  non-inflammatory  origin,  progressive 
course,  circumscribed  form,  active  participation  of  osteoblasts,  and  derivation 
from  cartilage,  are  features  which  are  more  prominent  in  true  osteoma,  while 
an  inflammatory  origin,  self-limitation,  multiplicity,  diffuse  form,  reduced 
numbers  or  absence  of  osteoblasts,  and  origin  from  connective  or  other  soft 
tissues,  belong  to  the  less  definite  or  spurious  bony  neoplasms. 

Terminology. — "Osteoma"  is  the  term  applied  to  tumors  composed  of 
bone.  Strictly  speaking,  it  should  be  limited  to  true  neoplasms. 

Exostoses  are  circumscribed  masses  which  project  above  the  bony  surface. 

Enostoses  lie  within  compact  or  cancellous  bone. 

196 


OSTEOMA  197 

Hyperostoses  are  more  diffuse  enlargements  of  bone.  "Osteophyte"  is  the 
general  term  applied  to  inflammatory  periosteal  bony  deposits. 

The  new  tissue  may  be  ivory-like  with  solid  lamellae  with  few  or  no 
Haversian  canals  (exostosis  eburnea);  or  spongy  with  cancellous  tissue  (ex- 
ostosis  spongiosa);  or  it  may  contain  wide  marrow  cavities  or  spaces  (ex- 
ostosis medullaris).  The  growth  may  affect  bony  structures  or  other  tissues, 
and  is  thus  hyperplastic  or  hetero plastic. 

The  osteophyte  is  an  inflammatory  cortical  or  supracortical  deposit  of 
bone  from  the  periosteum.  It  appears  as  a  flat,  often  extensive  plate  or  more 
circumscribed  mass  deposited  on  preexisting  bone  from  which  it  may  usually 
be  detached.  Microscopically  it  consists  of  many  small  islands  and  thin 
traveculae  of  bone  lying  in  the  cellular  and  vascular  connective  tissue  of  the 
thickened  periosteum  and  continuous  with  the  preformed  bone  from  which 
it  springs.  Many  stages  of  the  process  of  ossification  are  visible  in  early 
cases. 

Any  area  of  periosteum  which  is  affected  by  chronic  inflammation  may 
produce  osteophytes.  They  are  most  frequently  observed  on  the  shafts  of 
long  bones;  in  the  neighborhood  of  chronic  sinuses  or  ulcers;  as  a  prominent 
feature  in  the  course  of  chronic  arthritis;  on  the  maxillae  about  inflamed  teeth; 
and  beneath  the  dura  of  the  frontal  or  occipital  bones  in  gestation. 

The  course  -of  inflammatory  peiiosteal  bony  deposits  varies  with  their 
etiology.  Most  cases  reach  a  standstill  as  the  inflammation  subsides,  leaving  , 
deformities  and  interference  with  function.  Ankylosis  of  joints  may  result. 
In  not  a  few  cases  osteophytic  growth  seems  to  have  led  to  progressive  over- 
growth and  the  production  of  extensive  tumor-like  processes.  In  the  case 
of  Forcade's  son,  cited  by  Virchow,  suppuration  in  the  lacrimal  region  led 
to  progressive  enlargement  of  many  bones  of  the  face  and  skull  continuing 
for  33  years,  and  resulting  in  extensive  leontiasis  ossea. 

Hyperostosis.— Diffuse  hypertrophy  of  large  portions  of  bones,  or  whole 
bones,  or  several  bones,  occurs  under  many  conditions.  The- most  familiar 
form  of  hyperostosis  results  from  osteomyelitis,  periostitis,  and  arthritis. 
While  the  hypertrophies  of  this  class  may  be  extensive  they  are  readily  sepa- 
rated from  neoplastic  growths.  In  acromegaly  there  is  diffuse  overgrowth 
of  bones  of  skull  and  extremities  resulting  from  disturbance  of  function  of 
the  hypophysis  (leontiasis  ossea).  The  old  and  frequently  cited  case  of  San- 
cerotte  of  general  leontiasis  ossea  is  unique  but  of  uncertain  nature.  The 
bones  of  the  face  and  skull  are  specially  prone  to  diffuse  enlargement  from 
local  factors,  trauma,  inflammation,  and  rickets,  and  not  all  cases  of  cranio- 
sclerosis  can  be  referred  to  acromegaly.  Virchow  collected  many  cases  of 
diffuse  enlargements  of  temporal,  sphenoid,  maxillary  and  malar  bones,  and 
head  of  femur,  apparently  resulting  from  varied  causes,  not  distinctly  inflam- 
matory. He  considered  these  overgrowths  of  bone  as  comparable  to  ele- 
phantiasis of  the  skin  and  lipomatosis. 

Exostoses. — The  circumscribed  tumor-like  masses  projecting  from  the 
surface  of  bones  and  intimately  connected  with  the  shaft,  present  a  varied 
form,  course,  and  etiology.  They  are  flat  or  tuberous,  nodular,  globular,  or 
pointed  or  ragged  growths,  which  appear  in  many  striations,  at  epiphyseal 
junctions  or  on  the  shafts  of  long  bones,  and  at  the  insertions  'of  tendons  and 
fascia.  They  are  flat,  smooth  and  ivory-like  as  is  usually  the  case  with 
exostoses  of  the  skull  (ex.  clavata),  or  spongy  with  cancellous  spaces  com- 
municating with  those  of  the  shaft.  The  porous  exostoses  may  later  become 
solid.  They  are  usually  multiple,  often  symmetrical,  and  some  notable  cases 
are  recorded  in  which  there  was  a  prominent  hereditary  tendency  transmitted 
through  the  males  (Heymann,  Reinecke).  In  a  case  of  hereditary  multiple 


198  NEOPLASTIC  DISEASES 

exostoses  E.  Miiller  found  very  numerous  islands  of  cartilage  in  the  perios- 
teum of  long  and  flat  bones. 

In  advanced  forms  the  general  development  of  the  bones  has  been  retarded 
and  even  dwarfism  has  occurred  (Virchow).  As  a  rule  exostoses  occur  in 
young  subjects  before  puberty  during  the  period  of  active  growth  of  the 
bones  (exostoses  de  croissance). 

Exostoses  usually  arise  from  overgrowth  of  subperiosteal  bone  and  these 
must  be  attributed  to  an  irritation  affecting  the  periosteum.  Yet  the  entire 
thickness  of  the  shaft  may  be  involved  and  new  cancellous  spaces  of  the 
exostosis  communicate  with  the  old.  Or  the  new  growth  may  lie  within  the 
bone  shaft  or  marrow  cavity  (enostosis).  In  other  cases  the  process  is  en- 
tirely superficial  and  periosteal  and  some  of  these  may  lie  within  the  perios- 
teum and  apart  from  the  shaft  (parosteal  exostosis).  Trauma,  with  or  without 
misplacement  of  a  fragment  of  periosteum,  or  fracture,  is  often  the  exciting 
cause  of  such  growths.  About  the  ends  of  long  bones  portions  of  cartilage 
may  be  found  in  exostoses  (ex.  cartilaginea).  An  origin  from  a  misplaced 
island  of  cartilage  is  probable,  and  may  be  referred  to  trauma,  rickets,  or 
preexisting  ecchondrosis.  Microscopically  exostoses  usually  begin  with  pro- 
liferation of  the  inner  vascular  layer  of  the  periosteum  and  the  formation 
of  a  network  of  osteoid  tissue.  This  matrix  may  at  once  become  eburnated, 
or  vascular  channels  may  persist  and  the  tissue  remain  spongy.  The  under- 
lying bone  becomes  sclerosed  and  fused  with  the  new  growth,  or  it  becomes 
rarefied  and  the  adjacent  marrow  spaces  communicate  with  those  of  the 
exostosis.  According  to  Virchow  the  former  process  may  be  called  histioid, 
the  latter  organoid. 

Clinical  Groups  of  Exostoses. — The  largest  class  of  exostoses  are  those 
which  form  at  the  ends  of  long  bones  and  are  connected  with  disturbances  of 
growth.  They  are  multiple,  tend  to  grow  less  rapidly  as  the  subject  reaches 
puberty  and  rarely  they  may  spontaneously  disappear  (Hartmann).  The 
long  bones,  the  vertebrae,  pelvis,  scapula,  and  the  skull  are  the  chief  sites 
affected.  Partly  cartilaginous  exostoses  occur  about  joints  and  may  possess 
a  synovial  covering  which  is  derived  from  and  may  communicate  with  the 
joint  (exostoses  bursata) .  Some  of  these  are  probably  originally  intra-articular 
and  gradually  become  separated  from  the  joint  cavity  (Bergmann,  Volkmann). 

Multiple  exostoses  occur  on  the  bodies  of  the  vertebrae  and  involving  the 
intervertebral  discs.  In  the  cervical  region  they  may  produce  palpable  tumors. 

Traumatic  exostoses  constitute  a  well-defined  class.  They  occur  at  the 
seat  of  fractures  when  excessive  callus,  forms  and  after  single  or  repeated 
trauma  of  the  periosteum  or  bone  and  along  the  alveolar  borders  after  extrac- 
tion of  teeth.  Virchow  cites  2  cases  where  broken  splinters  of  bone  hyper- 
trophied,  forming  exostoses  of  moderate  size.  The  great  toe  is  the  seat  of  a 
subungual  exostosis  which  may  occasionally  develop  into  a  true  osteoma  or 
osteochondroma.  Continuous  mild  trauma  is  also  responsible  for  the  dis- 
continuous exostoses  which  form  in  the  deltoid  in  soldiers  where  the  gun 
rests  on  the  shoulder,  and  in  the  adductor  muscles  of  riders. 

In  nearlv  all  these  situations  occur  larger  growths  with  more  distinct 
neoplastic  characters,  suggesting  that  the  small  exostoses  may  occasionally 
give  origin  to  true  osteomas. 

In  the  trachea  Ribbert  and  Mischaikoff  have  fully  described  the  multiple, 
round,  flat  or  ragged  nodules  and  plates  of  bone  which  grow  in  the  submucosa, 
and  have  found  that  most  of  them,  like  the  tracheal  ecchondroses,  are  con- 
nected with  the  perichondrium  of  the  tracheal  rings.  In  a  very  advanced 
case  described  by  Heyman,  with  extensive  ossification  in  the  larynx,  there 
were  many  bony  masses  with  marrow  spaces  throughout  the  trachea. 


OSTEOMA 


TRUE  OSTEOMA 


199 


Osteoma  of  Facial  Bones  and  Antra. — The  bones  of  the  face  are  the  seat 
of  a  variety  of  bony  overgrowths  which  are  difficult  to  classify. 

In  the  maxilla  osteosclerosis  and  hyperplastic  bone  formation  occurs  in 
connection  with  dislocated  and  inflamed  teeth,  producing  exostoses  or  enos- 
toses,  or  hyperplastic  masses  some  of  which  project  externally  or  into  the 
antrum  of  Highmore.  Many  of  these  must  be  regarded  as  inflammatory, 
while  others  are  true  osteomas. 

In  the  orbit  bony  growths  arise  from  any  of  the  bones  of  this  cavity,  usu- 
ally from  the  upper  and  inner  segment. 

They  not  infrequently  appear  as  congenital  tumors  in  young  girls.  Vir- 
chow  concluded  that  they  arose  as  enostoses  of  the  orbital  wall  and  grew 


FIG.  51. — Growing  osteoma  of  antrum. 

either  into  the  orbit  or  nares  or  into  the  cranial  cavity.  He  described  4  cases, 
in  some  of  which  cysts  were  found  lined  by  ciliated  epithelium.  Many  bony 
tumors  have  been  described  as  arising  from  the  ethmoid,  frontal,  and  superior 
maxillary  bones,  projecting  into  the  cranium,  nares,  frontal  sinus,  or  antrum 
of  Highmore. 

LaGrange  has  collected  148  cases.  Their  origin  appeared  to  be  from  the 
periosteum  or,  as  Lesser  states,  from  embryonal  cartilaginous  portions  of  the 
ethmoid.  Projecting  into  the  sinuses  they  present  a  covering  of  inflamed 
and  often  cystic  mucosa  (Panas).  The  chief  site  is  the  upper  inner  wall  of 
the  orbit.  They  may  penetrate  the  skull,  but  seldom  cause  grave  cerebral 
symptoms,  while  only  2  such  cases  were  fatal.  Knapp  has  reported  2  enuclea- 
tions,  in  i  of  which  the  growth  was  broadly  attached  over  the  upper  wall  of 
the  orbit. 


200 


NEOPLASTIC  DISEASES 


Osteoma  of  the  frontal  sinus  is  believed  to  arise  from  fragments  of  carti- 
lage connected  with  the  ethmoid.  It  produces  a  characteristic  swelling  over 
the  orbit  and  progresses  steadily  until  extirpated.  Its  structure  is  usually 
solid  and  lamellated.  Most  of  the  osteomas  of  the  nares  and  antrum  of  High- 
more  also  arise  from  the  ethmoid  (Bornhaupt).  Tillmanns  collected  several 
cases  in  which  these  tumors  were  found  loose  in  the  nasal  cavity  or  antrum 
(dead  osteoma). 

Secondary  Osteoma. — Osteoma  occurs  as  an  element  in  many  other 
tumors  where  it  appears  as  a  result  of  secondary  ossification  of  the  connec- 
tive tissue.  Here  it  may  signify  a  terminal  product  in  a  series  of  transforma- 
tions of  the  tissues  of  fibroma,  lipoma,  sarcoma  (Borst).  In  periosteal  fibroma 
bone  is  a  natural  end  product  of  the  growth  (fibro-osteoma). 

In  certain  cases  it  represents  an  integral  part  of  a  mixed  tumor.  In  the 
common  breast  tumors  of  dogs,  bone  formation  may  be  very  active  and  exten- 


FIG.  52. — Osteoma  of  orbit.     (After  Knapp. 


sive,  producing  complex  osteo-chondro-carcino-sarcomas.  In  the  ovary  os- 
teoma occurs  in  several  forms  (Kroemer,  Lit.).  True  bone  with  periosteum 
and  marrow  spaces  is  observed  in  connection  with  dermoids  and  teratomas. 
Ovarian  stones  composed  of  a  thick  shell  of  bone  about  a  central  cavity  arise 
from  ossification  of  cysts,  some  of  which  are  from  corpora  lutea.  They  are 
usually  preceded  by  active  inflammation.  Metaplastic  bone  formation  occurs 
in  ovarian  fibromas  and  chondromas,  either  in  small  foci  or  throughout  the 
tumor. 

Osteoma  in  the  Nervous  System. — In  a  considerable  portion  of  cachectic 
subjects,  especially  of  the  insane  and  epileptic,  there  are  multiple  nodules  of 
bone  in  the  cerebral  or  spinal  arachnoid.  Zanda  finds  that  these  nodules 
form  about  small  vessels  through  degeneration,  exfoliation,  and  sclerosis  of 
endothelial  cells  and  connective  tissue,  which  form  hyaline,  then  osteoid,  and 
finally  bone  tissue.  From  these  nodules  or  over  large  areas,  especially  in  the 


OSTEOMA  201 

falx  cerebri  and  cerebral  and  spinal  dura,  larger  masses  of  bone  may  form 
with^cellular  and  fatty  marrow  spaces,  yielding  bony  plates  which  are  smooth 
and  incorporated  in  the  dura  externally,  and  rough  internally  where  growth 
progresses  (Zanda,  Ziegler,  Borst). 

Larger  tumors  compressing  the  brain  or  cord  and  lying  within  the  brain 
tissue  or  arising  from  the  membranes  have  been  described  by  several  authors 
(Virchow,  Meschede,  Ebstein,  Bidder,  DeVecchi). 

The  intracerebral  growths  were  referred  by  Virchow  to  osteogenesis  by 
the  glia-tissue.  Some  are  associated  with  encephalitis  with  softening.  Others 
doubtless  originate  from  misplaced  islands  of  the  bone-forming  matrix  of  the 
dura. 

Heteroplastic  Bone  Formation. — In  heteroplastic  bone  formation  the 
process  begins  either  in  a  cartilaginous  or  a  fibrous  matrix.  The  cartilage 
becomes  more  vascular  and  ossification  occurs  about  the  small  vessels  through 
the  activities  of  osteoblasts.  In  connective  tissue  the  stroma  becomes  hyaline, 
calcification  occurs  under  the  influence  of  osteoblasts  with  the  appearance 
of  osteoid  and  finally  osseous  tissue.  Here  one  must  conclude  that  the  process 
is  metaplastic,  the  fibroblasts  acquiring  the  function  of  osteoblasts. 

Several  factors  may  be  regarded  as  tending  to  call  forth  osteoblastic 
properties  in  fibroblasts. 

1.  Proximity  to  Bone. — Some  authors  have  assumed  that  bone  formation 
always  results  from  osteoblasts  that  have  wandered  out  from  periosteum 
(Busch).     In  myositis  ossificans  this  theory  finds  a  certain  support  as  the 
process  begins  in  the  periosteum. 

2.  The  presence  of  calcific  deposits  figures  in  many  instances  of  ossification 
of  necrotic  tissue. 

3.  An  active  productive  inflammation  with  organization  of  dead  tissue  and 
blood-clot  is  probably  essential  in  the  ossification  of   muscle-tissue  after 
trauma  (Busse,  Berndt,  Rapke,  Lit.). 

4.  A  special  predisposition  to  calcification  and  ossification,  possibly  con- 
nected with  disturbance  of  calcium  metabolism,  must  be  assumed  to  exist 
in  certain  cases,  notably  in  those  of  reticulated  osteoma  of  the  lung. 

In  many  cases  heteroplastic  bone  formation  occurs  without  the  appear- 
ance of  many  osteoblasts,  the  fixed  cells  being  passively  incorporated  in 
osteoid  and  osseous  matrix. 

Clinical  Forms. — The  lung  is  subject  to  an  interesting  and  rare  type  of 
bone  deposit  through  the  progressive  ossification  of  inflammatory  connective 
tissue.  This  condition  was  first  described  by  Luschka  and  may  be  termed 
reticulated  osteoma. 

The  condition  appears  in  three  forms  which  are  probably  stages  of  the  same 
process.  It  first  produces  multiple  nodules  or  tuberosities  in  the  connective 
tissue  of  one  or  several  lobes. 

In  early  cases  in  young  subjects  both  lungs  throughout  presented  about 
fifty  pea-  to  bean-sized  nodules  with  much  new  connective  tissue  (Wagner, 
Heschl).  In  later  stages  one  or  more  lobes  are  the  seat  of  extensive  reticu- 
lated bony  deposits  radiating  in  stalactite  form  from  the  root  of  the  lung 
(Forster,  Bostrom,  Picchini,  Triboulet,  Arnsperger).  In  a  few  cases  one 
lobe  is  transformed  into  a  nearly  diffuse  mass  of  bone  while  nodules  appear  in 
other  lobes  (Port,  Cohn). 

Bone  masses  in  the  wall  of  a  cavity  with  nodules  in  other  portions  of  the 
lung  were  observed  by  Rullier,  Browning,  and  LeDiberder. 

Microscopically  the  process  begins  as  an  interstitial  growth  of  connective 
tissue,  in  the  septa,  walls  of  bronchi  and  alveoli,  and  about  the  large  vessels, 
all  of  which  are  inclosed  and  eventually  occluded  by  ossifying  connective 


202  NEOPLASTIC  DISEASES 

tissue.  The  vessels  may  show  endarteritis  obliterans  (Picchini).  The  islands 
of  bone  are  surrounded  by  numerous  osteoblasts  and  marrow  spaces  filled 
with  fat  and  marrow-cells  may  appear. 

The  majority  of  observers  have  concluded  that  the  process,  at  least  at  its 
inception,  is  an  ossifying  interstitial  pneumonia.  In  advanced  stages  it  seems 
to  acquire  certain  neoplastic  characters,  and  Virchow  regarded  the  diffuse 
form  as  a  true  osteoma.  The  reticulated  osteoma  is  to  be  distinguished  from 
ossifying  chondroma  of  the  lung,  but  in  advanced  cases  this  may  be  difficult 
to  accomplish. 

Simple  calcification  may  occur  in  the  walls  of  cavities  (Krauss,  Nusser) 
and  the  lung  is  a  frequent  seat  of  metastatic  osteosarcoma  (Gross). 

In  the  penis  of  a  subject  42  years  old,  Lenhossek  has  described  the  for- 
mation of  bony  and  cartilaginous  plates  which  probably  resulted  from  the 
changes  in  inflammatory  tissue  in  the  fibrous  septum  and  sheath.  Konig 
refers  to  similar  cases. 

In  the  skin  multiple  nodules  of  compact  bone  appear  in  the  epidermis  or 
derma,  sometimes  about  cartilaginous  matrix  (Virchow). 

Coleman  has  described  osseous  plates  in  the  sole  of  the  foot. 

In  the  eye,  the  sclera  and  choroid,  are  occasionally  seen  bone  plates  which 
result  from  metaplastic  changes  in  inflammatory  connective  tissues. 

Bone  formation  in  necrotic  tissue  occurs  in  many  situations,  as  in  phthisis 
bulbi  (Virchow),  in  the  wall  of  the  sclerotic  aorta  (Cohn,  Klotz),  in  the  walls 
of  abscesses  and  in  chronic  pleurisy,  and  in  advanced  stages  marrow  spaces 
and  cells  may  appear.  After  ligation  of  the  main  vessels  of  the  kidney  there 
may  be  extensive  formation  of  bone  and  cellular  marrow  in  the  necrotic  organ 
of  the  rabbit. 

Myositis  Ossificans. — Spongy  bone  may  form  as  a  result  of  trauma  in 
the  muscles  of  working  people  and  has  been  observed  in  the  biceps,  digastric, 
vastus  externus,  adductor  magnus,  and  diaphragm  (Virchow).  In  these 
cases  the  ossification  is  self-limiting,  but  in  not  a  few  cases  of  traumatic  origin 
there  is  a  certain  progressive  tendency  suggesting  a  relation  to  myositis 
ossificans. 

The  progressive  ossification  of  one  or  many  muscles,  first  fully  described  by 
Munchmayer  and  called  progressive  myositis  ossificans,  arises  spontaneously, 
chiefly  in  young  subjects  and  pursues  a  chronic  intermittent  course.  It  affects 
the  shoulder,  face,  trunk  and  limbs,  and  may  become  quite  extensive.  In 
the  early  exacerbations  there  may  be  local  congestion  and  pain. 

Once  established,  it  tends  to  progress  until  the  affected  muscle  is  com- 
pletely ossified  and  immobile.  Yet  Elliott  observed  complete  resolution  of 
the  preliminary  myositis.  According  to  Ribbert  the  ossification  emanates 
from  the  periosteum,  spreading  along  the  fascia,  tendons  and  the  perimysium 
and  endymysium,  with  atrophy  of  the  muscle-fibers. 

Lexer  finds  first,  increase  of  connective  tissue,  then  chondrification,  and 
finally  ossification,  constituting  three  stages  in  the  process. 

Since  the  disease  occurs  at  an  early  age  in  subjects  with  deformities  of 
fingers  and  toes,  is  associated  with  multiple  exostoses,  and  progresses  inde- 
pendently of  any  originating  trauma  or  other  known  factor,  Ribbert  regards 
the  process  as  blastomatous.  Since  the  intermuscular  connective  tissue  may 
be  regarded  as  a  part  of  the  skeletal  system  and  intimately  connected  with 
the  periosteum  (Koester),  it  may  be  supposed  that  in  these  cases  the  former 
tissue  retains  more  of  the  periosteal  character  than  is  normal,  thus  constitut- 
ing a  tissue  predisposition  toward  bone  formation  (Mays).  The  occurrence 
of  very  similar  lesions  in  tabes  and  syringomyelia  suggests  that  a  spinal  trophic 
influence  may  be  concerned  in  some  cases  (Kaufmann). 


CHAPTER  XV 

MYOMA 

Myoma,  a  tumor  of  muscle-tissue,  occurs  in  two  types:  leiomyoma,  con- 
taining smooth  muscle-tissue,  and  rhabdomyoma,  composed  of  striated  muscle- 
tissue.  In  both  cases  supporting  connective  tissue  and  blood-vessels  usually 
accompany  the  muscle-cells  and  the  structure  is  organoid.  Yet  pure  leio- 
myoma occurs  in  the  gastro-intestinal  wall  and  the  early  stages  of  many 
myomas  contain  little  or  no  connective  tissue.  According  to  the  rule  with 


Jr    *  #^ 

WM. 


FlG.  53. — Structure  of  simple  benign  myoma  uteri. 

benign  tumors,  myomas  are  easily  recognizable  as  such,  and  metaplasia  and 
inflammatory  factors  play  a  very  subordinate  role  in  their  history. 

LEIOMYOMA 

Leiomyoma  occurs  in  the  form  of  single  or  more  often  multiple,  miliary 
or  voluminous,  firm  and  opaque,  or  cystic  tumors  chiefly  in  preexisting  smooth 
muscle-tissues.  Some  contain  much  connective  tissue  and  are  quite  hard, 
leiomyoma  durum;  others  are  succulent  and  edematous,  leiomyoma  molle; 
rarely  dilated  blood-vessels  are  prominent,  leiomyoma  cavernosum;  and  occa- 

203 


204 


NEOPLASTIC  DISEASES 


sionally  cysts  of  dilated  lymph-vessels,  glandular  structures,  or  softened 
edematous  areas  may  form.  Extreme  congestion  may  render  them  dark 
and  mottled,  and  after  strangulation  of  vessels  they  become  black.  Fatty 
degeneration  may  produce  yellowish  soft  areas,  and  calcification  may  trans- 
form entire  tumors  into  stony  masses. 

On  section  leiomyoma  presents  characteristic  striated  or  convoluted  mark- 
ings from  intertwining  bands  of  muscle-cells.  The  tumor  is  more  opaque 
than  normal  muscle-tissue  and  is  usually  sharply  circumscribed,  often  shelling 
readily  out  of  its  bed.  The  curved  markings  often  center  about  blood-vessels 


FIG.  54. — Multiple  myomas  of  uterus,  one  cystic. 

from  which  the  growth  appears  to  originate.  In  injected  specimens  Ribbert 
finds  the  blood-vessels  small  and  scanty  as  compared  with  surrounding  tissue, 
and  the  nutrition  is  maintained  largely  by  lymph-vessels.  Hence  myomas 
grow  slowly  and  are  very  subject  to  standstill  and  regression. 

The  structure  of  leiomyoma  presents  a  system  of  intertwining  bundles 
of  muscle-cells  supported  by  septa  and  fibrils  of  connective  tissue.  In  some 
cases  the  muscle  bundles  are  definitely  related  to  small  blood-vessels  or  glandu- 
lar structures,  but  more  often  no  such  relation  is  apparent.  The  edges  of  the 
tumor  are  usually  sharply  defined,  but  may  grade  insensibly  into  the  surround- 


MYOMA  205 

ing  tissues.  The  tumor-cells  are  thicker  and  shorter  than  normal  smooth 
muscle-cells,  the  cytoplasm  grows  less  acidophile,  and  the  nuclei  are  larger 
and  richer  in  chromatin.  In  actively  growing  tumors  there  is  increase  in  the 
neoplastic  characters  of  the  cells,  especially  in  their  size,  and  in  malignant 
leiomyomas  very  large  spindle-cells  appear,  giant-cells  form  of  enormous 
dimensions,  and  the  connective-tissue  stroma  disappears. 

The  diagnosis  between  leiomyoma  and  spindle-cell  sarcoma  is  often  difficult 
and  may  be  based  on  the  clinical  history,  the  acidophile  character  of  muscle 
cytoplasm,  the  long  oval  nuclei,  the  arrangement  of  the  cells  and  the  presence 
of  many  adult  collagenous  fibrils  running  between  the  cells.  Both  cells  and 
nuclei  are  more  uniform  in  size  and  exhibit  more  evenly  rounded  ends  than 
fibroblasts.  Special  stains  facilitate  the  diagnosis.  The  appearance  of  cross- 
sections  of  muscle  bundles  with  nuclei  embedded  in  acidophile  fibers,  alter- 
nating with  longitudinal  sections,  is  usually  quite  characteristic. 

The  connective- tissue  stroma  is  acellular,  often  edema tous  or  infiltrated 
with  round-cells.  Two  types  of  blood-vessels  are  found  in  most  myomas. 
In  one  the  walls  are  normal,  while  the  others  participate  in  the  neoplastic 
process,  the  walls  are  composed  chiefly  of  hypertrophic  muscle-cells  and 
the  adventitia  is  deficient  or  absent. 

Regressive  changes  are  frequently  present.  Fatty  degeneration  affects 
individual  cells  in  moderate  degree,  and  extreme  fatty  and  hydropic  degenera- 
tion or  necrosis  with  edema  produce  softened  areas.  Hyaline  degeneration 
may  overtake  small  areas  or  an  entire  tumor.  Calcification  follows  fatty 
degeneration  or  hyaline  change  and  may  become  universal.  Inflammatory 
changes  in  myomas  are  usually  slight.  Round-cell  infiltration  of  the  stroma 
is  associated  with '  edema,  and  about  the  included  glandular  structures  of 
some  myomas  there  is  adenoid  tissue,  or  lymph-follicles  may  develop.  Mast 
cells  may  be  very  numerous  (Reich,  Gottschalk).  Occasionally  myomas 
become  infected  and  infiltrated  with  polynuclear  leukocytes,  and  cystic 
myomas  may  be  found  distended  with  pus. 

The  course  of  leiomyoma  is  slowly  progressive  over  a  period  of  years 
and  the  symptoms  are  mainly  of  mechanical  origin,  or  referable  to  associated 
conditions.  There  is  a  natural  tendency  for  many  leiomyomas  to  reach  a 
standstill  after  a  long  period  of  growth  or  to  regress  with  atrophy  of  muscle- 
fibers,  replacement  fibrosis,  hyaline  degeneration,  and  calcification.  In  the 
uterus  this  tendency  reveals  itself  especially  at  the  menopause,  but  it  is  not 
constant.  On  the  contrary,  very  rapid  growth  or  sarcomatous  transforma- 
tion may  begin  at  the  menopause.  Gibson  observed  the  appearance  of  a 
uterine  myoma  and  growth  to  the  size  of  a  child's  head  within  7. months 
after  removal  of  both  tubes  and  ovaries.  Regressive  changes  may  be  hastened 
by  pedunculation,  by  hyaline  changes  in  stroma,  by  closure  of  vessels,  by 
separation  from  attachments,  and  by  inflammatory  processes.  Acceleration 
of  growth  may  result  from  abnormal  adhesions. 

Myoma  Malignum.— In  a  group  of  cases,  now  rather  numerous,  leio- 
myoma has  proved  malignant,  breaking  its  natural  boundaries,  and  produc- 
ing metastases  in  liver,  lungs,  kidney,  peritoneum,  and  lymph-nodes,  and 
thereby  acquiring  the  designation  myoma  malignum.  From  the  uterus,  stomach, 
esophagus,  and  intestine  this  usually  benign  tumor  has  developed  extensive 
local  and  general  secondary  growths  and  proved  fatal.  This  event  has  occurred 
in  the  later  periods  of  the  growth  or  after  extirpation  of  tumors  which  had 
long  remained  benign,  so  that  it  would  appear  that  a  malignant  change  had 
taken  place  in  the  character  of  the  tumor.  The  symptoms  observed  are  a 
rapid  increase  in  the  size  of  a  long  quiescent  growth,  signs  of  secondary  growths, 
ascites  in  the  uterine  cases,  and  cachexia.  The  main  tumor  has  usually  been 


206 


NEOPLASTIC  DISEASES 


adherent,  with  cavernous,  softened,  or  cystic  areas.  In  one  of  my  cases  the 
softening  spread  from  a  crater-like  ulcer  in  the  adherent  endometrium.  In 
Schlagenhaufer's  case  it  was  limited  to  an  angiomatous  area. 

In  most  of  the  cases  the  structure  of  the  soft  pultaceous  areas  and  of 
the  metastatic  growths  which  probably  emanate  from  these  areas,  differed 
from  that  of  ordinary  leiomyoma.  The  cells  were  larger,  the  nuclei  more 
massive  and  hyperchromatic,  mitoses  were  present,  the  fusiform  cells  became 
shorter  or  rounded,  giant-cells  formed,  intercellular  connective  tissue  was 
scanty  or  absent,  and  the  walls  of  vessels  were  defective  (Krische,  Langer- 
hans,  Williams,  Beeston,  Moser,  Basso).  Evans  finds  that  the  presence  of 
many  mitotic  figures  (estimated  at  2200  to  12,000  per  cubic  millimeter  of 
tissue)  is  a  reliable  sign  of  clinical  malignancy  in  uterine  myomas.  With 


FIG.  55. — Miliary  myoma  in  a  uterine  vein.     The  tumor  is  benign. 

fewer  mitotic  figures  or  when  they  are  absent  the  tumors  do  not  recur.  In 
Hansemann's  malignant  myoma  of  the  stomach  the  cells  were  uniform,  but 
short  or  rounded,  and  the  nuclei  very  rich  in  chromatin.  In  Eising's  esophageal 
myoma  islands  of  adenocarcinoma  were  present  and  the  muscle-cells  much 
increased  in  size.  In  i  of  Evelt's  cases  the  sarcoma  was  apparently  melanotic. 
In  3  uterine  cases  I  found  the  structural  changes  very  marked.  In  i  (3461) 
there  was  extensive  mucoid  degeneration.  In  another  (2287)  the  spindle- 
cells  and  giant-cells  reached  enormous  dimensions.  In  all  the  derivation 
from  muscle-cells  was  clear.  So  far  as  I  have  been  able  to  learn  no  case  has 
been  fully  studied  in  which  definite  variation  from  the  usual  structure  of 
leiomyoma  were  wanting,  although  in  several  instances  these  variations  have 
not  been  very  pronounced. 


MYOMA  207 

In  one  case  of  large  uterine  myoma  I  found  the  peritoneum  of  the  uterus 
thickly  beset  with  miliary  myomas  identical  in  structure  with  ordinary  myoma, 
and  in  a  case  of  recurrent  multiple  nodular  myomas  of  the  broad  ligament 
the  cells  varied  little  from  the  usual  type,  although  they  were  shorter  and 
looser  and  the  tissue  was  very  vascular.  In  neither  case  were  there  distant 
metastases.  Accordingly,  it  may  be  said  that  the  structure  of  malignant 
myoma  varies  from  that  of  the  benign  type. 

It  is  not  to  be  assumed  without  adequate  proof  that  a  malignant  myoma 
represents  the  transformation  of  a  previously  benign  tumor.  Many  and 
probably  the  majority  of  these  tumors  are  malignant  from  the  first.  Malignant 
myoma  usually  occurs  after  the  menopause,  at  an  average  age  of  about  50 
years  (Evans),  but  polypoid  myomas  of  the  cervix  are  usually  malignant  at 
all  ages;  adenomyomas  are  often  cellular  and  adherent;  while  extra-uterine 
myomas,  especially  if  multiple,  frequently  recur. 

Ribbert  has  protested  against  the  term  "myosarcoma,"  employed  by  many 
for  the  malignant  tumors,  on  the  ground  that  sarcoma  implies  a  tumor  of 
connective  tissues.  Yet  in  a  morphological  sense  this  term  seems  admissible. 
Objection  has  also  been  made  to  the  interpretation  of  the  above  changes  as 
genuine  sarcomatous  degeneration  of  myomas.  There  has  been  a  tendency 
on  the  part  of  gynecologists  to  multiply  the  cases  of  this  sort,  and  to  search 
for  suspicious  foci  over  wide  areas  of  perfectly  benign  tumors.  Some  esti- 
mates place  the  frequency  of  the  change  at  10  per  cent,  of  all  uterine  myomas. 
From  the  reports  of  Winter,  Henkel,  Hofmeier,  and  Flautau,  in  1880  cases 
of  fibroids  48,  or  2.5  per  cent.,  were  found  to  show  sarcomatous  changes.  The 
manner  in  which  these  statistics  were  obtained  is  perhaps  fairly  indicated  in 
the  study  of  Winter.  In  his  first  series  of  500  cases  he  examined  only  suspi- 
cious-looking areas  and  found  16  (3.2  per  cent.)  to  contain  sarcomatous  foci. 
In  253  later  cases  he  examined  all  parts  of  the  tumor  and  succeeded  in  rais- 
ing the  number  of  sarcomas  to  n  (4.3  per  cent.).  There  were  sometimes 
present  general  signs  of  malignancy,  as  rapid  growth,  polypoid  masses  on  the 
main  tumor,  and  changes  in  consistence,  but  local  metastases  occurred  only 
once  and  cachexia  resulted  chiefly  from  hemorrhage.  In  the  same  manner 
Cullen  has  reported  17  cases  of  sarcomatous  degeneration  of  uterine  myomas. 

These  observations  show  that  ordinary  myomas  vary  in  structure  in 
different  portions  and  probably  at  different  periods,  and  they  seem  to  justify 
the  suspicion  with  which  the  gynecologist  regards  the  entire  group.  But  it 
must  be  considered  that  these  suspicious  changes  may  not  always  be  pro- 
gressive, but  may  signify  merely  a  temporary  or  local  acceleration  of  growth 
which  may  subside  and  even  regress.  They  do  not  seem  to  justify  their  desig- 
nation as  sarcomatous  transformations,  for  which  much  more  extensively 
altered  areas  or  even  general  metastases  might  well  be  demanded.  Sarcoma- 
tous tendencies  and  precancerous  changes  do  not  constitute  real  sarcoma  or 
cancer.  I  have  encountered  3  malignant  uterine  myomas  with  general 
metastases  and  2  with  local  recurrence  in  20  years,  and  Winter  found  no  case 
among  753,  so  that  malignant  degeneration  of  myoma  must  be  rare. 

It  has'been  claimed  that  certain  myosarcomas  arise  through  a  malignant 
transformation  of  the  connective  tissue  of  leiomyoma.  (Ricker,  v.  Franque, 
and  Hauser).  In  Ricker's  case  the  change  occurred  in  numerous  foci  sharply 
separated  from  the  muscle-tissue  which  was  either  infiltrated  with  the  sarcoma- 
cells  or  underwent  atrophy.  Yet  the  descriptions  of  these  authors  are  not 
entirely  convincing  that  they  were  not  dealing  with  the  ordinary  type  of 
malignant  change  in  muscle-cells. 

Clinical  Types  of  Leiomyoma. — Uterine  Fibromyoma.—The  uterus  is 
the  commonest  seat  of  leiomyoma.  The  tumors  are  usually  multiple,  in 


208 


NEOPLASTIC  DISEASES 


fact,  in  several  cases  the  entire  uterus  has  been  found  to  consist  of  a  congeries 
of  discrete  myomatoid  masses  (Cruveilhier,  Williams,  Stone).  The  location 
is  widely  distributed,  the  posterior  wall,  anterior  wall,  sides,  and  cervix  appear- 
ing in  the  order  named.  From  5  to  8  per  cent,  of  these  tumors  are  cervical 
(Fehling).  Extra-uterine  tumors  of  the  same  type  and  significance  occur 
also  in  the  broad  ligaments,  vagina,  tubal  junction,  in  the  pelvic  fasciae,  and 
in  the  round  ligament  as  far  down  as  the  groin  or  labium  majus  (Cullen, 
Aschoff).  The  position  of  the  uterine  tumor  may  be  subserous,  interstitial, 
or  submucous.  Both  subserous  and  submucous  tumors  tend  to  become  pedun- 
culated  or  even  separated  from  the  uterus,  being  rarely  discharged  per  vaginam 
(Simpson),  or  lying  free  in  the  peritoneum  (Turner),  or  becoming  attached  to 
surrounding  organs.  Submucous  tumors  may  gradually  separate  from  their 


FIG.  56. — Structure  of  a  multiple  nodular  recurrent  myoma  of  broad  ligament. 


original  site  and  become  implanted  on  the  opposed  mucous  surface  (Leyden, 
Kustner).  Diffuse  myomatosis  may  cause  thickening  of  a  small  focus  or 
of  a  large  area,  or  of  almost  the  whole  organ.  Miliary  myomas  appear  in  the 
peritoneum  during  the  course  of  larger  tumors,  while  Hunter  found  at  autopsy 
a  single  tumor  weighing  140  pounds. 

The  form  of  uterine  myoma  is  usually  a  rounded,  sharply  circumscribed 
solid  and  elastic  mass  which  projects  prominently  from  the  cut  surface.  Many 
very  early  myomas  and  many  adenomyomas  are  without  definite  demarca- 
tion, and  the  diffuse  forms  remain  so,  but  with  increasing  age  most  tumors 
show  more  and  more  isolation  and  some  become  encapsulated.  Cysts,  multiple 
and  superficial  or  large  and  central,  form  in  many  myomas  from  dilated  gland 
alveoli,  or  from  chronic  edema  and  mucinous  softening.  Their  contents  are 
serous  or  mucinous  fluid  with  cholesterin,  or  after  infection  they  may  become 


MYOMA  209 

distended  with  pus.  Some  of  the  cystic  myomas  reach  a  very  large  size  (Mar- 
tin), that  removed  by  Severanu  of  Bucharest  being  one  of  the  largest  tumors 
ever  observed.  They  may  contain  pus  or  chocolate-brown  or  bloody  fluid. 
The  uterus,  which  is  the  seat  of  myoma,  especially  of  the  submucous  or  inter- 
stitial varieties,  enlarges  with  the  growth  of  the  tumor  and  becomes  extensively 
deformed.  There  is  hypertrophy  and  hyperplasia  of  the  muscle-cells  as  a 
result  of  contractions  caused  by  irritation  from  the  tumor  (Bertelsman),  but 
Tillaux  saw  the  uterus  greatly  enlarged  with  a  small  tumor  of  the  lower  seg- 


•^^•^•i^^^^^^^^^"^^^^™*^^^^^"^™ 

pIG    57 — Myoma  of  uterus,  confined  under  pressure  with  edema,  small   cysts,  and 

polypoid  growths  into  cysts. 


ment.  The  vessels  about  the  tumor  are  enlarged  and  the  whole  organ  is 
hyperemic.  Endometritis,  interstitial  or  glandular,  commonly  results,  espe- 
cially with  submucous  varieties,  and  mucous  and  bloody  discharge  becomes 
a  prominent  symptom.  Inflammatory  hyperplasia  may  be  limited  to  the 
mucosa  overlying  the  tumor  (Wyder),  or  it  may  extend  also  to  the  tubes 
(Fabricius)  and  ovaries  (Bulius).  Profuse  hemorrhage  between  or  prolong- 
ing the  mentrual  periods  marks  the  course  of  many  forms  of  myomas,  and 
sometimes  proves  fatal.  According  to  the  position  of  the  tumors  the  uterine 
cavity  becomes  elongated,  irregular,  or  occluded.  The  stretching  c 
14 


210 


NEOPLASTIC  DISEASES 


myometrium  may  produce  peculiar  rhombic  spaces  in  the  stroma  and  the 
stretching  has  even  led  to  rupture  of  fundus  from  the  cervix  (Lennander, 
Hedren).  Mural  myomas  may  cause  extensive  torsion  of  the  uterus,  and 
submucous  tumors  may  lead  to  prolapse  or  inversion  (Kuster,  Kotschau). 
The  gross  section  reveals  the  usual  convoluted  markings  of  myoma,  or  a 
congeries  of  multiple  tumors.  Islands  of  adenoid  tissue  and  the  sections 
of  glands  may  be  revealed  by  the  hand  glass.  Multiple  minute  cysts  appear 
when  the  alveoli  are  moderately  dilated.  The  tumor  vessels  are  usually 
scanty,  while  the  surrounding  tissue  supports  numerous  dilated  veins,  but 
small  areas  (Cullen)  or  the  entire  tumor  (Virchow,  Martin)  may  be  telan- 
giectatic.  Dilated  lymph-vessels  were  prominent  in  two  myosarcomas  de- 


FIG.  58. — Structure  of  a  locally  infiltrating  myoma  uteri. 

scribed  by  Menge.     Submucous  myomas  are  often  traversed  by  glandular 
tracts,  the  openings  of  which  may  be  seen  on  the  mucous  surface. 

Extensive  degenerative  changes  frequently  alter  the  appearance  of  uterine 
myomas.  Marked  edema  produces  softening  and  cystic  areas.  Chronic 
edema  leads  to  extensive  mucinous  degeneration  with  increase  in  the  size  of 
the  tumor  and  formation  of  cysts.  With  increasing  age  there  is  a  tendency 
toward  atrophy  and  fib  ro  sis  which  may  greatly  reduce  the  size  of  large  tu- 
mors and  render  others  very  hard.  Fatty  degeneration  of  muscle-cells  is 
associated  with  their  atrophy  and  probably  precedes  calcification.  Fatty 
changes  may  become  very  active  during  gestation,  and  Martin  saw  a  large 
myoma  almost  wholly  transformed  into  fatty  semifluid  material  during  ges- 


MYOMA  211 

tation  and  the  puerperium.  Large  tumors  undergo  fatty  degeneration  and 
may  be  reduced  to  small  nodules  or  entirely  disappear  (Duncan,  Hewitt, 
Gusserow).  Hyaline  degeneration  may  affect  the  blood-vessels,  stroma,  or 
muscle-tissue,  in  small  foci  or  in  considerable  areas.  According  to  Ribbert 
this  change  may  precede  calcification,  the  salts  being  deposited  in  the  hyaline 
material.  Stratz  saw  amyloid  degeneration  about  the  vessels  of  a  polypoid 
myoma.  Calcification  overtakes  fatty  and  atrophying  myomas  and  com- 
pletely transforms  them  into  stony  masses.  Uterine  stones  of  large  dimen- 
sions are  thus  found  in  the  cavity,  wall,  or  on  the  peritoneal  surface  of  the 
uterus  (Henocque),  and  they  have  been  discharged  through  the  vagina  or 
intestine,  or  into  the  bladder  (Payr).  Everett  found  the  composition  to  be 
calcium  carbonate  49  per  cent.,  phosphate  29  per  cent.,  sulphate  13  per  cent., 
with  traces  of  lithates  and  organic  material.  Turner  and  Wylie  found  a  com- 
plete separation  from  the  uterus  of  calcified  subperitoneal  myomas.  Throm- 
bosis of  vessels  is  not  an  uncommon  event,  especially  with  pedunculated  myo- 
mas, and  leads  to  hemorrhagic  infarction,  necrosis,  softening,  and  even  to 
excavation  and  discharge  of  large  portions  of  submucous  tumors. 

Sarcomatous  changes,  previously  considered,  occur  in  a  small  proportion 
of  uterine  myomas.  Carcinoma  is  sometimes  observed  with  uterine  myoma 
and  may  result  from  several  conditions.  In  adenomyoma,  carcinoma  may 
develop  from  the  epithelial  elements  in  the  tumor.  A  submucous  myoma 
may  be  complicated  by  carcinoma  of  the  overlying  and  long  inflamed  mu- 
cosa,  and  the  carcinoma  may  penetrate  the  myoma.  Or  the  carcinoma  may 
arise  in  a  distant  portion  of  the  mucosa.  Carcinoma  of  other  organs  has 
been  known  to  produce  metastases  in  uterine  myomas  (Liebmann,  Schafer, 
Rolley). 

The  microscopical  structure  of  uterine  myomas  reveals  two  forms  of  this 
tumor — fibromyoma  and  adenomyoma.  The  great  majority  of  the  tumors 
are  of  the  former  class  and  present  the  usual  characteristic  structure  of  fibro- 
myoma. At  their  inception  these  tumors  are  nearly  pure  myomas  and  some 
remain  so  throughout  most  of  their  course,  but  with  increasing  age  there  is 
a  tendency  toward  increasing  development  of  connective  tissue  which  in 
atrophying  tumors  may  exceed  the  muscular  tissue.  The  connective  tissue 
is  distributed  in  septa  supporting  vessels  and  as  finer  fibrils  ramifying  be- 
tween the  muscle-cells.  Gebhard  observed  a  large,  purely  fibrous  nodule 
in  the  center  of  a  solid  myoma.  The  connective  tissue  does  not  participate 
in  the  tumor  process,  although  some  observers  have  claimed  that  it  might 
give  rise  to  sarcomatous  changes  in  myomas.  The  tumor-cells  are  larger, 
thicker,  and  more  granular  than  normal  uterine  muscle-cells,  and  the  nuclei 
are  larger,  more  rounded,  and  richer  in  chromatin.  During  gestation  the 
cells  of  myomas  increase  in  size.  Their  arrangement  is  in  intertwining  bundles 
running  in  all  directions  and  without  definite  relation  to  any  structural  unit. 
Certain  large  tumors  are  composed  of  a  congeries  of  somewhat  discrete  nodules 
in  the  centers  of  which  are  blood-vessels,  and  in  some  early  myomas  the 
growth  centers  chiefly  about  blood-vessels  from  the  walls  of  which  the  tumor 
seems  to  spring.  In  such  cases  the  adventitia  of  the  vessel  walls  may  be 
deficient  (Rosger).  It  has  been  claimed  that  nerves  have  been  demonstrated 
in  uterine  myoma  (Hertz),  but  they  are  insensitive,  and  their  existence  has  been 
denied. 

In  rare  cases  islands  of  bone  have  been  found  in  uterine  myoma  (Lebert, 
Freund);  a  nodule  of  cartilage  has  been  encountered  by  Bennet;  and  in  one 
malignant  case  of  adenomyosarcoma  Kaufmann  found  both  bone  and  car- 
tilage. A  fibrochondro-osteoma  described  by  Kworostansky  was  possibly 
an  atypical  myoma  suffering  extensive  metaplasia. 


212 


NEOPLASTIC  DISEASES 


Adenomyoma  presents  the  usual  structure  of  the  muscle-tissue,  but  it 
contains  glandular  alveoli  which  appear  in  various  forms.  They  usually 
form  small  groups  of  acini  lined  by  cubical  or  cylindrical  and  sometimes  cili- 
ated epithelium  supported  by  lymphoid  stroma.  These  acini  are  identical 
in  appearance  with  fragments  of  uterine  mucosa  with  which  they  are  often 
directly  connected.  Or  the  cells  are  more  embryonal  in  type,  with  relatively 
large  nuclei,  with  or  without  cilia,  and  the  lymphoid  stroma  may  be  present 
or  absent.  Most  observers  have  been  unable  to  establish  any  constant  dis- 
tinctions between  the  epithelial  structures  in  adenomyomas  in  different  lo- 
cations, but  the  development  of  the  glands  varies  widely  from  a  few  scanty 
acini  to  large  cystic  tumors  composed  largely  of  epithelial  lined  cysts.  Pap- 
illary projections  may  grow  into  the  cysts,  and  Cullen  saw  adenocarcinoma 
developing  from  the  papillae.  During  menstruation  there  is  congestion  and 
•hemorrhage  into  the  glands  (Cullen),  and  Amos  has  described  decidual  changes 
during  gestation. 


FIG.  59. — Structure  of  adenomyoma  of  broad  ligament. 

The  occurrence  of  adenomyoma  is  relatively  infrequent,  but  its  distri- 
bution is  wide-spread.  They  may  be  submucous,  interstitial,  or  subperito- 
neal,  and  they  have  been  found  in  the  broad  ligament,  round  ligament,  and 
groin  (Cullen),  cervix,  vaginal  wall,  Fallopian  tube,  and  rectum. 

Etiology. — Uterine  myoma  is  the  most  frequent  of  all  tumors,  its  occur- 
rence being  estimated  at  50  per  cent,  of  all  women  over  50  years  of  age  (Klob), 
and  at  20  per  cent,  for  those  over  35  years.  The  incidence  reaches  its  acme, 
38.8  per  cent.,  between  the  ages  of  30  and  40  years  (Gusserow).  The  negress 
is  especially  susceptible.  Before  puberty  it  is  extremely  rare,  but  Tillaux 
reported  in  a  girl  of  19  a  cervical  myoma  which  had  given  symptoms  for  6 
years.  Leopold's  statement  that  the  rudiments  of  myomas  may  be  found 
in  the  uterus  in  children  has  not  been  verified.  An  hereditary  influence  seems 
to  have  existed  in  certain  families  in  which  several  members  suffered  from 
myoma  at  an  early  age  (Veit,  Gusserow). 

Sterility  has  long  been  held  to  be  a  factor  in  the  etiology  of  myoma  and 
Veit  concludes  that  abnormal  excitation  and  congestion  of  the  organ  without 
conception  may  excite  tumor  growth.  It  is  highly  probable  that  myoma 
favors  sterility  from  the  mechanical  and  inflammatory  effects  of  the  tumor. 
Both  sterility  and  myoma  are  favored  by  the  infantile  type  of  uterus  and  by 


MYOMA 


213 


misplacements  and  other  defects  in  the  organ  which  go  with  each  of  these 
conditions.  Virchow  held  that  myoma  is  caused  by  local  irritation.  Many 
authors  have  pointed  out  sources  of  such  irritation  and  shown  that  these 
act  as  secondary  and  exciting  factors,  which  are  not  constant  or  essential. 


FIG.  60. — Diagrammatic  representation  of  development  of  genito-urinary  tract.  (After 

Heisler.) 

The  Miillerian  duct  and  derivatives  are  jet  black.  The  Wolffian  body  and  deriva- 
tives include  all  other  structures  except  the  sex  glands,  bladder,  prostate,  and  rectum. 

i,  Indifferent  type.  2,  Indifferent  type,  later  stage,  the  Wolffian  and  Mxillerian 
ducts  and  primitive  ureter  now  opening  into  the  urogenital  sinus.  3,  Male  type,  lower 
ends  of  Mtillerian  ducts  fused  to  form  the  sinus  pocularis.  4,  Female  type. 

The  essential  factor  in  the  etiology  of  myoma  is  an  embryogenic  dis- 
turbance in  the  structure  of  the  uterus.  The  remarkable  degree  of  isolation 
of  many  myomas,  their  wide-spread  occurrence  apart  from  the  uterine  body, 
and  the  presence  in  many  cases  of  heterotopic  inclusions,  epithelial,  carti- 
aginous,  osseous,  fatty,  and  rhabdomyomatous,  clearly  point  to  an  embry- 


214  NEOPLASTIC  DISEASES 

onal  origin.  Moreover,  as  Williams  has  emphasized,  uterine  myomas  are 
often  associated  with  a  large  number  of  abnormalities  in  the  genito-urinary 
system. 

The  nature  of  the  embryogenic  disturbance  varies  with  different  tumors. 

(a)  It  is  generally  agreed  that  the  common  pure  fibromyoma  results  from 
a  disturbance  in  the  formation  of  the  tubes,  uterus,  and  vagina  from  the  Miil- 
lerian  ducts,  which  split  off  from  the  Wolffian  ducts  at  an  early  period  and 
fuse  to  form  the  genital  canal. 

The  relation  of  certain  early  myomas  to  the  blood-vessels  of  the  uterus  has 
long  impressed  many  observers  and  suggested  that  uterine  myomas  arise 
from  disturbances  in  the  growth  of  the  blood-vessels  from  the  walls  of  which 
the  uterus  and  vagina  originally  receive  their  muscular  tissue.  Rosger,  Klein- 
wachter,  Sobotta,  and  others  have  traced  the  development  of  early  myomas 
from  the  vessel  walls  and  concluded  that  the  blood-vessels  control  the  origin 
and  growth  of  uterine  myomas.  This  view  has  much  evidence  to  commend 
it,  although  it  is  seldom  possible  to  demonstrate  such  a  relation  in  advanced 
stages  of  the  tumors.  Yet  in  many  pure,  in  adenomatous  and  in  telangiectatic 
myomas,  the  blood-vessels  are  composed  of  neoplastic  muscular  tissue.  In  a 
case  of  multiple  recurrent  telangiectatic  myoma  of  the  broad  ligament  I  found 
striking  evidence  of  the  origin  of  the  tumor  masses  from  blood-vessels. 

The  cases  in  which  the  whole  uterus  is  composed  of  a  congeries  of  myomas, 
or  where  a  myoma  replaces  the  cervix  (Landau)  or  causes  uterus  didelphys 
(Pick),  strongly  suggest  an  origin  from  misfitting  vascular  units  which  go 
to  make  up  the  uterine  muscle.  Likewise  single  isolated  myomas  seem  to 
represent  overgrowth  of  muscle  from  single  vascular  units  which  have  not 
fitted  the  general  texture  of  the  myometrium.  Into  many  such  tumors  the 
invasion  of  gland-  has  been  traced  from  the  mucosa.  There  are  many  who 
believe  that  the  great  majority  of  myomas  of  all  types  originate  in  this  way. 

(6)  Regarding  the  origin  of  adenomyomas  opinions  are  at  variance  and 
it  is  probable  that  no  single  mode  of  origin  can  apply  to  all  these  tumors. 

1.  A  Miillerian  origin  accounts  most  satisfactorily  for  the  majority  of 
uterine  adenomyomas,  especially  for  the  submucous,  interstitial,  and  diffuse 
varieties.     Duplication  of  the  duct,  fetal  budding  of  the  epithelium,  mis- 
placements of  islands  of  fetal  mucosa,  postembryonal  misplacement  of  gland 
tissue,  and  invasion  of  the  myometrium  by  gland  alveoli  during  inflammation 
have  been  observed  or  suggested  as  accounting  for  the  origin  of  these  tumors 
(Meyer,  Pick,  Hauser,  Schroeder,  Ruge). 

In  many  submucous  or  deeper  adenomyomas  the  epithelial  structures 
have  been  traced  to  the  uterine  mucosa,  on  the  surface  of  which  they  some- 
times open  by  patent  canals  (Ribbert,  Cullen).  The  invasion  of  a  tubal 
myoma  by  glands  of  the  tubal  mucosa  has  been  traced  in  serial  sections  by  v. 
Franque.  The  structure  of  the  glands  in  most  adenomyomas  is  an  exact 
duplicate  of  the  uterine  glands  and  they  seem  to  functionate  as  does  the 
uterine  mucosa. 

2.  Mesonephric  Adenomyoma. — The  epithelial  structures  in  certain  adeno- 
myomas were  interpreted  by  Babes  and  by  Recklinghausen  as  remnants  of 
the  Wolffian  body  or  mesonephros,  and  many  have  supported  this  view 
(Ricker,   Schroeder,   Pick,   Schickele,   Ernst).     Recklinghausen  believed  the 
glandular  structures  in  certain  cases  presented  the  characteristics  of  the  meso- 
nephros which  forms  a  closed  system  consisting  of  a  chief  canal  or  ampulla 
into  which  many  parallel  smaller  canals  open.    The  smaller  canals,  starting 
in  wide  ampullae,  advance  in  the  form  of  convoluted  secreting  tubules  lined  by 
cubical  epithelium  and  empty  into  the  chief  canal  while  lined  by  high  or  cili- 
ated epithelium.     Vascular  polypoid  projections  of  cellular  tissue  along  the 


MYOMA  215 

canals  in  certain  tumors  he  interpreted  as  pseudoglomeruli.  Occasional 
deposits  of  pigment  he  compared  with  the  pigment  of  Giralde's  organ  (rem- 
nant of  lower  Wolffian  tubules). 

Recklinghausen  and  Pick  have  attempted  to  divide  adenomyomas  into  submucous 
(central  and  ventral)  and  paroophoral  (dorsal  and  peripheral),  the  former  deriving  its 
glands  from  the  endometrium,  the  latter  from  the  paroophoron,  the  remnant  of  the 
Wolffian  body  (lower  tubules).  Pick  holds  strongly  to  the  dual  origin  of  adenomyoma 
uteri,  claiming  that  the  tumors  located  in  the  broad  ligament  are  of  Wolffian  origin  and 
may  be  designated  as  parpvarian  and  paroophoral  adenomyomas.  Under  the  term 
"adenomyoma  psammopapillare"  he  describes  a  remarkable  multiple  papillary  tumor 
arising  in  the  broad  ligament  which  well  illustrates  Recklinghausen's  voluminous  paro- 
ophoral adenomyoma.  As  the  chief  histological  distinction  he  states  that  lymphoid 
stroma  usually  but  not  always  accompanies  uterine  glands  in  adenomyoma,  while  the 
alveoli  of  Wolffian  origin  lie  in  immediate  contact  with  muscle  tissue  and  lack  the 
lymphoid  stroma.  Yet  Cullen  finds  such  lymphoid  stroma  in  tumors  of  the  round 
ligament. 

While  it  is  probable  that  certain  extra-uterine  adenomyomas  originate  from  the 
parovarium  or  paroophoron,  the  majority  of  observers  have  not  been  impressed  with  the 
mesonephric  characters  of  these  tumors.  Neither  the  location  of  the  tumors  nor  the 
arrangement  of  the  ducts  nor  the  character  of  the  epithelium  seem  to  be  sufficient 
evidence  to  prove  the  mesonephric  origin,  since  very  similar  structures  are  seen  in  sub- 
mucous  tumors  and  in  others  for  which  a  Mullerian  origin  is  extremely  probable  (Meyer, 
v.  Franque).  Cohen  saw  the  characteristic  arrangement  of  tubules  in  a  submucous 
tumor  of  which  the  epithelium  was  clearly  derived  from  the  endometrium,  and  he  found 
the  pigment  in  adenomyoma  to  be  ferruginous,  while  that  of  Giralde's  organ  is  iron  free. 
Aschoff  found  no  uniformity  in  the  location  of  the  so-called  paroophoral  type  of  adeno- 
myoma, and  Kossmann  and  Lockstadt  found  a  general  resemblance  between  uterine 
glandular  tissue  and  the  epithelial  structures  in  all  adenomyomas.  Pick  states  that 
there  are  both  adult  and  embryonal  types  of  adenomyoma,  and  such  a  distinction  appears 
to  be  not  infrequent,  but  the  distribution  of  these  types  does  not  accord  with  the  other 
features  which  might  separate  two  varieties  of  adenomyoma.  The  predominance  of 
muscular  tissue  is  more  readily  explained  by  a  Mullerian  origin,  for  muscle-cells  are 
scanty  in  the  Wolffian  structures,  and  Pick  regards  this  element  as  quite  secondary  and 
unessential  in  the  anlage  of  mesonephric  tumors. 

3.  Remnants  of  the  Wolffian  duct  (Gartner's  duct)  seem  to"  give  origin  to 
certain  extra-uterine  adenomyomas.    It  has  been  shown  by  Recklinghausen, 
Ricker,  Pick,  and  others  that  the  whole  region  of  the  uterovaginal  canal 
may  contain  isolated  epithelial  groups  which  are  probably  derived  from  the 
Wolffian  duct.    Borst  found  heterotopic  Wolffian  alveoli  in  the  iliac  lymph- 
nodes.     Klein  traced  a  persistent  Wolffian  duct  in  two  infants.    The  proxi- 
mal portion  traversed  the  broad  ligament  beneath  the  Fallopian  tube  to 
the  uterus,  and  terminated  in  the  uterine  muscle  at  the  os  internum.    The 
distal  portion  passed  along  the  side  of  the  uterus  to  the  cervix,  curved  back- 
ward over  the  fornix,  and  passed  downward  in  the  wall  of  the  vagina  to  the 
hymen.    The  canal  was  lined  by  cubical  epithelium  and  supported  by  smooth 
muscle,  and  Klein  concludes  that  this  structure  may  give  rise  to  various 
tumors  along  its  course,  as  cysts,  myoma,  adenomyoma,  and  adenocarci- 
noma.     Cervical  and  vaginal  adenomyomas  especially  have  been  referred  to 
this  origin  (Breus,  Herpf,  Pf annenstiel) .    Yet,  except  for  their  unusual  posi- 
tion, the  same  difficulties  exist  in  proving  this  origin  as  for  the  mesonephric 
type,  since  the  structure  of  these  tumors  does  not  differ  essentially  from  that 
of  the  Mullerian  type  (Cullen). 

4.  Besides   the   epithelial   alveoli,    subperitoneal   myomas   may   contain 
acini  lined  by  cubical  endothelium  derived  from  inclusions  of  the  peritoneum 
(Aschoff,  Meyer). 

Summarizing  the  evidence,  one  may  conclude  that  simple  myoma  uteri 
arises  chiefly  from  a  disturbance  in  the  development  of  the  tubes,  uterus, 
and  vagina  from  Miiller's  ducts,  which  often  leads  at  the  same  time  to  gross 
deformities  and  infantile  characters  in  these  organs. 


216  NEOPLASTIC  DISEASES 

Adenomyoma  arises  chiefly  from  the  fetal  or  postembryonal  inclusion  of 
Miillerian  epithelium  in  the  tumor  process.  Extra-uterine  adenomyomas  in 
the  broad  and  round  ligaments  and  cervix  may  also  arise  from  the  meso- 
nephric  elements  or  from  the  Wolffian  duct,  but  neither  the  position  nor  struc- 
ture of  these  tumors  permits  their  positive  identification  in  every  instance. 
The  growth  of  many  myomas  is  controlled  by  their  relation  to  blood-vessels 
from  which  they  are  derived.  The  chief  exciting  factor  is  intermittent  hy- 
peremia  connected  with  irregularities  in  the  sexual  functions. 

Myoma  in  the  Alimentary  Tract. — The  esophagus  was  the  seat  of  small 
multiple  leiomyomas  containing  also  striated  muscle-fibers  and  ganglion- 
cells  in  a  case  described  by  Pickler.  A  larger  single  tumor  was  observed  by 
Illig.  Both  were  connected  with  the  inner  muscular  coat.  Eising's  case 
was  complicated  with  adenocarcinoma. 

In  the  stomach  Miodowski  observed  a  bulky  myoma  which  led  to  severe 
hemorrhage.  He  found  2  similar  cases  in  the  literature.  Hansemann  has 
reported  a  malignant  gastric  myoma  with  metastases  in  liver  and  pancreas. 
In  a  large  tumor  studied  by  Cohen  there  were  islands  of  pancreas.  Laboulbene 
saw  4  small  myomas  in  the  same  stomach.  Many  gastric  sarcomas  are  prob- 
ably of  myogenic  origin  (q.  v.). 

In  the  intestine  leiomyoma  is  not  uncommon.  The  tumors  are  single  or 
multiple.  Nazzari  saw  40  small  tumors  in  one  case  and  1 20  in  another.  Steiner 
found  them  either  subperitoneal  or  submucous,  the  latter  type  causing  stenosis 
or  intussusception,  the  former  producing  diverticula.  In  Mercer's  case  fatal 
hemorrhage  occurred.  Cohen  found  islands  of  pancreas  in  an  intestinal 
myoma  which  probably  belonged  with  the  adenomyomas  of  Trappe.  Both 
gastiic  and  intestinal  myomas  are  apt  to  be  associated  with  uterine  myoma, 
and  they  appear  to  originate  from  isolated  segments  of  the  musculature, 
connected  with  blood-vessels  or  epithelial  structures.  According  to  Boet- 
ticher  and  Lode  3  types  of  intestinal  myomas  may  be  distinguished:  (i) 
Small  multiple  nodular  or  polypoid  tumors  arise  from  local  proliferation  in 
the  muscularis;  the  mucosa  is  free;  (2)  broad  thick  tumor  masses  form  in  the 
muscle  layers,  while  the  mucosa  becomes  adherent  to  the  tumor;  (3)  larger 
polypoid  subserous  myomas  may  project  into  the  peritoneum. 

Dermatomyoma. — A  wide  variety  of  myomas  is  observed  in  the  skin. 
They  occur  on  the  buttock  and  extremities,  at  embryonal  fissures  (Babes), 
in  the  scrotum  and  labia  (m.  dartiques)  (Besnier,  Forster,  Challard).  They 
may  be  associated  with  keloid  (Babes)  or  lymphangioma  (Axel,  Key),  neuroma 
(Czerny),  and  xanthoma  (Chambard,  Gouilloud).  Politzer  has  shown  that 
certain  xanthomas  result  from  fatty  degeneration  of  smooth  muscle-fibers. 
In  some  cases  the  blood-vessels  are  very  numerous  and  neoplastic,  produc- 
ing angiomyomas  (Hess).  The  tumors  are  usually  small  and  multiple,  firm, 
movable,  cutaneous  or  subcutaneous  nodules  or  masses.  They  may  be  pain- 
ful and  tender.  They  usually  occur  in  adults,  but  Hess  observed  early  cases 
and  Marc  describes  a  congenital  lymphangiectatic  myoma.  The  origin  has 
been  traced  to  the  arrectores  pilorum  (Judassohn,  Walters)  or  to  the  cutaneous 
arterioles  (Hess,  Marc).  Borst  suggests  that  some  of  the  dermatomyomas  are 
really  neurofibromas.  Sobotka  traced  the  process  from  simple  hypertrophy 
of  the  arrectores  up  to  tumor  growth,  followed  by  degeneration. 

In  the  urinary  bladder  and  passages  myomas  constitute  a  considerable 
proportion  of  the  tumors  occurring  in  those  organs. 

In  the  bladder  they  may  reach  large  dimensions  and  their  location  is 
either  subserous  or  submucous  (Stein,  Terrier,  Hartmann).  In  an  infant 
Kaufmann  found  a  myoma  of  the  trigonum  containing  cartilage.  A  large 
myocarcinoma  is  reported  by  Volkmann.  In  the  ureter  Buttner  observed  a 


MYOMA  217 

large  pure  myoma.  In  the  testis  Rindfleisch  described  a  myoma  which  con- 
tained nerve-fibers  and  ganglion-cells,  and  Becker  reported  i  case  of  doubtful 
nature. 

In  chronic  prostatitis  there  is  often  extensive  hypertrophy  of  smooth 
muscle  tissue  which  may  approach  the  neoplastic  grade.  True  myomas  of 
this  organ  have  not  been  clearly  separated  from  this  inflammatory  overgrowth. 

In  the  kidney  small  multiple  myomas  and  myolipomas  occur  in  capsule 
or  cortex  and  appear  to  be  derived  from  fragments  of  capsule  tissue  (Miil- 
ler,  Lark  in).  Jacobsens  has  collected  several  cases  which  were  associated 
with  cerebral  sclerosis.  In  the  breast  leiomyoma  has  been  observed  by  Ab- 
ramow  and  Ribbert. 

RHABDOMYOMA 

Tumors  of  striated  muscle  are  characterized  by  their  rare  occurrence, 
embryonal  type,  and  common  association  with  other  constituents  in  mixed 
tumors.  They  occur  in  very  wide  distribution  and,  while  the  genito-urinary 
system  furnishes  the  largest  proportion,  few  muscular  regions  escape  an 
occasional  development  of  rhabdomyoma,  and  the  homologous  growths  are 
fully  equaled  in  number  by  heterotopic  forms.  They  usually  occur  in  early 
life,  some  are  congenital,  and  a  few  examples  have  been  first  noted  in  advanced 
or  old  age  (Wolfensberger,  Fujinami). 

In  form  they  appear  as  single  or  multiple,  nodular  or  voluminous,  flat  or 
rounded,  circumscribed  or  diffuse,  and  even  polypoid  growths.  They  are 
usually  soft  and  grayish  on  section,  and  markings  produced  by  muscle  bun- 
dles alternate  with  abundant  connective-tissue  stroma.  Very  cellular  forms 
are  more  opaque,  yellowish  or  reddish,  soft,  and  often  diffuse.  The  mixed 
rhabdomyomas  present  the  varied  appearance  of  teratomas.  A  cystic  rhabdo- 
myoma of  the  elbow  has  been  described  by  Billroth. 

The  structure  of  rhabdomyoma  presents  chiefly  a  system^  of  parallel 
bundles  or  intertwining  strands  of  striped  muscle-fibers,  supported  by  adult 
or  embryonal  connective  tissue.  The  fibers  may  encircle  blood-vessels  or 
other  structures,  but  are  more  often  diffuse.  The  cells  of  rhabdomyoma  sel- 
dom exhibit  adult  characters.  They  are  usually  thin  and  much  elongated 
and  rarely  they  are  branching  (Zenker,  Billroth).  Both  long  and  cross 
striation  may  be  pronounced  jor  the  cross  striation  may  be  present  in  a  part 
of  the  cell  only  or  be  entirely  missing  in  embryonal  and  spindle-shaped  cells 
which  still  retain  longitudinal  fibrillation.  Or  the  cells  may  closely  resemble 
smooth  muscle-cells.  In  large  vacuolated  cells  Ribbert  describes  concen- 
tric striation  of  the  perinuclear  cytoplasm.  In  a  testicular  tumor  he  ob- 
served long  tubular  fibers,  the  walls  of  which  were  of  striated  or  hyaline  mus- 
cle fibrils  and  the  core  of  granular  sarcoplasm  with  many  nuclei  in  axial 
positions.  The  ends  of  the  fibers  may  be  swollen,  rounded,  and  contain 
multiple  nuclei.  In  the  more  embryonal  types  the  cells  are  spindle-shaped, 
shorter,  and  even  round,  and  they  may  lose  their  acidophile  character  and 
all  resemblance  to  muscle-cells.  Yet  such  marked  anaplasia  is  seldom  if 
ever  universal,  certain  foci  commonly  retaining  cells  of  definite  myogenic 
character.  Even  the  round-cells  of  lymph-node  metastases  may  retain  traces 
of  striation  (Wolfensberger,  Eberth),  or  the  metastases  may  consist  of  cells 
showing  no  features  of  muscle-cells  (Benenati).  In  many  myomas  the  cells 
contain  an  abundance  of  glycogen  which  is  evidence  of  their  embryonal  char- 
acter (Marchand). 

The  nuclei  follow  a  type  of  large  vesicular  chromatic  bodies,  single  or 
multiple,  which  lie  in  a  central  area  of  granular  cytoplasm.  Or  they  may 
project  from  the  cell  border  like  nuclei  of  sarcolemma.  A  definite  sar- 


218 


N  EOF  LAST  1C  DISEASES 


colemma  is  wanting,  but  traces  of  such  a  structure  with  its  nuclei  have  been 
seen, in  rare  cases  (v.  Franque,  Marchand).  The  stroma  is  either  loose  adult 
connective,  or  embryonal,  sarcomatous  or  myxosarcomatous,  and  in  the 
teratomas  bone,  cartilage,  and  various  other  tissues  may  be  present.  Blood- 
vessels are  usually  abundant  and  sometimes,  as  in  a  large  polypoid  vaginal 
tumor  described  by  Kaschewarowa,  they  are  overdeveloped. 

In  parts  of  certain  rhabdomyomas  it  is  difficult  to  determine  whether  one 
has  to  deal  with  voluntary  muscle-fibers  which  have  lost  their  striation  or 
with  genuine  smooth  muscle  tissue.  The  undifferentiated  cells  may  closely 
resemble  smooth  muscle.  Moreover,  rhabdomyoma  occurs  especially  where 


FIG.  61. — SpideijCeUjwith  multiple  nuclei  and  centrosomes,  believed  to  be  derived  from 
heart  jmuscle,  in  rhabdomyosarcoma  of  ovary.      (After  Himwich.) 

smooth  muscle  tissue  exists  (kidney,  testis).  To  many  observers  it  has  ap- 
peared that  smooth  muscle  tissue  may  give  rise  to  striped  muscle-fibers  in 
tumors  (Eberth,  Rindfleisch,  Arnold,  Marchand).  In  a  myosarcoma  uteri 
v.  Franque  saw  islands  of  striated  muscle  together  with  smooth  muscle  and 
spindle-cell  sarcoma,  and  he  concluded  that  the  striped  muscle  arose  by  meta- 
plasia of  smooth  muscle.  Yet  Girode  and  Nehrkorn  both  saw  islands  of 
striated  muscle  in  the  normal  myometrium,  and  the  embryology  of  this  organ 
provides  the  possibility  that  portions  of  striped  muscle  tissue  may  be  in- 
cluded in  its  structure.  Arnold,  in  supporting  a  suspicion  that  metaplasia 
of  smooth  may  produce  striated  muscle,  derived  a  rhabdomyoma  testis  from 
the  cremaster  muscle,  but  the  tumor  lay  within  the  albuginea,  wrhile  this 


MYOMA 


219 


muscle  lies  without  the  organ.  The  embryology  of  muscle  tissue,  voluntary 
muscle  being  derived  from  mesothelial  plates  and  involuntary  muscle  from 
the  mesenchyme,  does  not  favor  the  idea  that  one  form  may  pass  into  the 
other.  While  many  earlier  observations  suggested  the  change  of  smooth  into 
striped  muscle,  most  recent  studies  have  not  favored  this  view  (Ribbert, 
Hauser,  Kolisko). 

Himwich  has  described  from  this  laboratory  a  large  rhabdomyosarcoma 
of  the  ovary  of  an  infant,  which  recurred  soon  after  extirpation.  The  struc- 
ture presented  many  phases  of  the  development  and  degeneration  of  striated 
muscle-cells.  Large  areas  of  the  tumor  had  the  appearance  of  a  cellular  myxoma, 
suggesting  that  pure  myxoma  may  arise  from  this  source.  Other  portions 


FIG.  62. — Striated  giant-cell  in  rhabdomyosarcoma. 

were  composed  of  well-developed  striated  muscle-cells,  and  many  large  giant- 
cells  with  concentric  and  cross  striation  were  encountered.  Most  of  the  giant- 
cells  were  extensively  vacuolated,  forming  the  so-called  spider-cells  which  are 
found  exclusively  in  rhabdomyoma  of  the  heart.  On  this  account  the  author 
concluded  that  the  ovarian  tumor  represented  was  of  teratoid  origin,  and 
derived  from  the  heart  muscle  of  a  twin  fetus. 

The  course  of  rhabdomyoma  is  usually  progressive  and  in  the  sarcomatous 
and  teratoid  forms  it  is  rapid.  The  more  adult  types  may  become  encap- 
sulated or  assume  the  polypoid  forms,  but  the  embryonal  tumors  infiltrate 
surrounding  tissue,  multiplying  muscle-cells  being  often  preceded  by  a  zone 
of  proliferating  connective  tissue. 


220 


N  EOF  LA  STIC  DISEASES 


Degenerative  changes,  glycogenic,  hyaline,  or  amyloid,  may  occur  without 
interfering  with  the  growth.  The  malignant  tumors  of  the  kidney  and  testis 
reach  large  dimensions  and  produce  metastases  and  cachexia,  but  the  metastases 
are  usually  derived  from  other  elements  of  the  tumor. 

CLINICAL  FORMS  OF  RHABDOMYOMA 

Adenomyo sarcoma  of  Kidney. — The  kidney  is  the  commonest  seat  of  tumors 
containing  striated  muscle,  but  since  none  of  them  has  yet  appeared  in  pure 
form  they  will  be  described  under  tumors  of  the  kidney. 

In  the  urinary  bladder  polypoid  rhabdomyomas  have  been  described  by 
Cattani,  Vincenzi,  Stumpf,  and  Monckberg.  They  occurred  in  children 
or  young  adults,  and  formed  movable  growths  about  the  urethral  orifice 
or  trigone. 

Rhabdomyoma  uteri  appears  almost  exclusively  as  an  element  in  the  poly- 
poid vaginal  sarcoma  of  children  and  adults  (Sarcoma  botryoides,  Pfan- 


FIG.  63. — Structure  of  congenital  rhabdomyoma  of  heart.     (From  a  section  of  Wolbach's 

case.) 

nenstiel).  This  process  affects  the  vagina  in  children  and  chiefly  the  cervix 
in  adults  (Gow,  Pick).  It  may  exist  at  birth  (Demme)  and  first  appears 
as  a  rather  broad  thickening  of  the  submucosa  which  soon  becomes  polypoid, 
v.  Franque  reported  a  somewhat  similar  tumor  located  on  the  fundus  uteri 
in  a  multipara.  The  symptoms  are  hemorrhage,  fetid  discharge,  and  pro- 
trusion of  a  polypoid  tumor  from  the  vagina,  with  dysuria,  pain,  fever,  and 
cachexia.  The  vagina  is  eventually  filled  with  ulcerating  masses  and  there 
are  bulky  extensions  into  the  pelvis,  and  occasionally  to  regional  lymph- 
nodes,  rarely  to  skin  or  lung  (Kalustow,  Rosthorn).  In  Demme's  case  a 
benign  polyp  after  five  years  suddenly  became  malignant.  The  usual  histology 
is  that  of  a  large  spindle-cell  sarcoma,  with  many  blood-  and  lymph-vessels, 
myxomatous  tendencies,  and  areas  of  striated  muscle. 

Pfannenstiel  believed  he  could  trace  the  development  of  muscle-cells 
from  the  spindle-cells.     Kolisko  found  muscle  tissue  in  all  of  3  cases  and 


MYOMA 


221 


believed  it  to  be  present  in  all  cases.  Islands  of  cartilage  have  been  observed 
in  the  primary  tumors  (Rein,  Pernici)  or  only  in  recurrences.  The  remark- 
able clinical  characters  of  this  tumor  render  it  a  very  well-defined  disease. 
The  early  appearance  and  complex  histological  structure  of  the  tumors  show 
that  their  origin  must  be  referred  to  some  embryogenic  disturbance  of  the 
cervix  and  vagina,  but  the  nature  of  this  disturbance  has  never  been  clearly 
defined. 

In  the  testis  rhabdomyoma  occurs  in  the  form  of  nodular  tumors  as  large 
as  a  walnut  or  a  child's  head.  They  may  replace  the  entire  organ  or  dis- 
place it  to  one  side,  or  be  found  outside  the  tunica  albuginea.  In  several 
cases  the  muscle  tissue  was  associated  with  epithelial  structures,  and  one 
of  Ribbert's  cases  was  combined  with  carcinoma  and  sarcoma.  Neumann 


FlG.  64. — Rhabdomyosarcoma  of  voluntary  muscle  following  fracture  of  femur.     (After 

Mutter.} 

and  Ribbert  found  many  spindle-  and  round  cells  which  were  not  readily 
identified  as  myomatous,  and  Neumann  suggests  that  some  spindle-cell 
sarcomas  regarded  as  fibroblastic  may  really  be  of  myogenous  origin. 
Benenati  describes  a  large  rhabdomyoma  of  an  undescended  testis  with 
round-cell  metastases  in  the  regional  lymph-nodes.  The  tumor  contained 
spindle-cell  and  round-cell  areas  as  well  as  striped  muscle.  Stoerk  observed 
a  very  malignant  case  with  myomatous  metastases  in  distant  lymph-nodes. 
Wood  found  cartilage  and  epithelial  cysts  as  well  as  muscle.  All  these 
observations  lead  one  to  accept  the  view  that  rhabdomyoma  testis  occurs 
only  as  a  one-sided  development  of  a  teratoma.  Rokitansky  and  Neumann 
derived  their  tumors  from  the  gubernaculum  of  Hunter,  but  these  growths 
were  attached  to  the  lower  pole  of  the  tunica  and  were  not  strictly  tumors 
of  the  testis. 


222  NEOPLASTIC  DISEASES 

Congenital  rhabdomyoma  of  the  heart  is  a  very  characteristic  condition, 
of  which  12  cases  have  been  reported  (Wolbach,  Lit.).  They  occur  as  multiple 
sharply  circumscribed  areas  or  tumors,  lying  within  the  wall  or  projecting 
internally  or  externally.  Ponfick  pointed  out  that  they  are  associated  with 
diffuse  sclerosis  of  the  cerebral  cortex  and  with  disturbances  of  nutrition. 
Cesaris-Demel  found  also  nodules  in  the  kidney  composed  of  embryogenic 
renal  tissue,  and  Wolbach  observed  multiple  neuroglia  rests  in  the  spinal 
meninges. 

The  structure  of  the  tumor  presents  a  peculiar  spongy  tissue  in  which 
it  is  difficult  to  make  out  the  relation  of  certain  large  vacuoles  to  cells  and 
fibrils.  The  vacuoles  have  been  shown  to  lie  in  the  very  large  cells  of  which 
the  tumor  is  composed  (Seifert,  Wolbach).  The  cells  are  large  rounded 
masses  containing  large  nuclei  and  nucleoli,  surrounded  by  partly  striated 
cytoplasm  which  extends  in  many  fibrils  between  the  vacuoles  to  the  cell 
border.  They  resemble  early  embryonal  heart  muscle-cells  (Kolisko),  and 
similar  cells  may  be  found  in  the  fetal  myocardium  (Wolbach).  The  cross 
striations  are  formed  of  fuchsinophile  granules  grouped  in  the  sarcous  ele- 
ments, and  the  long  striations  are  made  up  of  alternating  sarcous  elements 
and  basophile  fibrillary  material.  Either  of  these  elements  may  be  in  excess. 
The  resemblance  of  the  cells  to  Purkinje's  cells  and  those  of  the  conducting 
bundles  of  the  heart  is  mentioned  by  Knox  and  Shorer.  That  the  tumors 
arise  from  an  embryogenic  disturbance  in  the  structure  of  the  heart  is  obvious. 
Kolisko  mentions  the  early  and  extensive  changes  in  the  morphology  of  the 
heart  as  favoring  errors  in  development.  Bonome  traces  the  pathogenesis 
to  fetal  malnutrition  resulting  in  cerebral  atrophy  and  sclerosis,  and  to  fibrous 
overgrowth  in  the  heart,  which  separates  nests  of  embryonal  cells  from  which 
the  tumors  develop. 

Miscellaneous  Rhabdomyomas. — Tumors  containing  striated  muscle 
have  been  observed  in  isolated  cases  in  many  other  organs  and  tissues;  in  the 
esophagus  (Wolfensberger,  Glinski);  in  the  stomach  (Brodowski),  in  the 
tongue  (Pende),  parotid  gland  (Prudden);  in  the  breast  (Billroth);  in  the 
prostate  (E.  Kaufmann);  in  place  of  the  left  lung  (Helbing).  Rhabdomyomas 
of  the  skeletal  muscles  in  various  parts  of  the  body,  orbit,  neck,  pelvis,  but- 
tocks, and  different  portions  of  the  extremities  have  been  collected  by  Fuji- 
nami  from  reports  of  various  authors,  and  Benenati  gives  an  extensive 
chronological  list  of  cases.  Among  the  regions  affected  are  the  spinal  vertebrae 
and  pectoralis  major  (Buhl),  upper  arm  (Billroth),  tibia  (Lambl),  thigh 
(Fujinami),  and  nose  (Erdmann). 

Of  1 6  cases  of  rhabdomyoma  derived  from  adult  voluntary  striated  muscle 
in  which  the  cells  were  said  to  have  retained  cross  striation,  reported  up 
to  1913,  Kuttner  rejects  6  and  regards  the  others  as  questionable.  Tumors 
composed  of  more  anaplastic  cells  in  which  cross  striation  was  lost  and  whose 
origin  from  muscle-cells  was  established  on  other  grounds,  are  very  rarely 
reported.  Miiller  has  reported  from  this  laboratory  one  such  case  following 
repeated  trauma  of  a  long  ununited  fracture  of  the  femur.  The  tumor  was 
composed  of  large  acidophile  spindle-cells,  some  of  which  approached  the 
dimensions  of  muscle-cells.  A  few  cases  of  similar  origin  are  reported. 


CHAPTER  XVI 

ANGIOMA 

Angioma  is  a  tumor  composed  of  newly  formed  vessels.  Both  blood-  and 
lymph-vessels  are  subject  to  neoplastic  growth,  giving  the  two  classes  of 
tumors — hemangioma  and  lymphangioma. 

HEMANGIOMA 

The  determination  of  the  scope  of  neoplastic  processes  affecting  blood- 
vessels presents  unusual  difficulties.  Vessels  occupy  an  altruistic  position 
in  the  physiology  of  organs,  subordinating  themselves  to  more  specialized 
structures.  Possessing  less  natural  autonomy  they  may  be  expected  to  dis- 
play pronounced  neoplastic  properties.  Thus  practically  normal  blood- 
vessels support  highly  malignant  tumor  tissue.  The  supply  of  vessels  in  a 


FIG.  65. — Plexiform  angioma  of  skin.     Slowly  growing  and  benign. 


tissue  or  organ  varies  extremely  in  both  normal  and  pathological  conditions. 
Not  being  composed  of  a  simple  tissue,  tumors  of  vessels  must  be  organoid 
in  character.  The  growth  of  vessels  is  markedly  influenced  by  the  element 
of  mechanical  pressure  of  the  circulation,  which  is  absent  in  other  tumors. 
Finally,  the  nutrition  of  vessels,  especially  of  those  subject  to  tumor  growth, 
is  provided  in  a  different  manner  from  that  existing  in  other  tissues.  Thus 
the  physiology  of  vessels  necessitates  special  standards  in  the  interpretation 
of  tumor  processes,  and  this  peculiarity  has  led  to  much  difference  of  opinion 
as  to  what  constitutes  an  angioma. 

From  the  angiomas  may  at  once  be  excluded  several  processes  marked  by 
overgrowth  of  vessels. 

223 


224  NEOPLASTIC  DISEASES 

Hypertrophic  granulation  tissue  presents  an  extensive  new  growth  of 
vessels  in  sinuses,  abscess  walls,  suppurating  cysts,  and  in  closed  tissues, 
with  circumscribed  enlargement  of  tissue.  Yet  it  is  self-limiting,  regresses 
upon  removal  of  the  irritant,  and  the  structure  of  the  vessels  shows  absence 
of  the  histological  signs  of  a  neoplasm.  In  rare  instances,  however,  without 
clinical  data  it  may  be  difficult  to  separate  this  process  from  angioma,  but  a 
definite  relation  between  chronic  granulation  tissue  and  any  of  the  charac- 
teristic vascular  tumors  can  rarely  be  established.  On  the  other  hand,  there 
are  many  indications  that  certain  sarcomas  arise  from  granulation  tissue. 

Chronic  varicosities  are  established  in  veins  and  arteries  in  several  con- 
ditions which  do  not  constitute  tumors,  as  varicose  veins  in  the  limbs,  sper- 
matic cord,  and  broad  ligament,  and  in  diffuse  aneurysms  which  follow  trauma. 
In  hemorrhoids  the  varicosities  are  the  result  of  venous  stasis  and  chronic 
inflammation.  In  inflammatory  polyps  extensive  development  of  veins  often 
results  from  venous  stasis. 

Excessive  development  of  blood-vessels  occurs  in  many  tumors  as  a  result 
of  venous  stasis  or  unusual  demands  for  nutrition.  Very  often  such  vessels 
present  a  normal  or  nearly  normal  structure  and  do  not  exhibit  neoplastic 
growth.  Such  tumors  are  not  true  angiomas,  but  their  vascularity  may  be 
indicated  by  the  term  "angiomatosum,"  as  fibroma  angiomatosum.  The 
demands  for  nutrition  in  rapidly  growing  cellular  tumors  may  produce  a  type 
of  growth  which  is  composed  chiefly  of  blood-vessels  sheathed  by  masses  of 
tumor-cells,  and  which  is  often  called  perithelioma,  or  telangiectatic  sarcoma. 
This  rather  characteristic  structure  is  not  confined  to  any  one  class  of  tumors 
and  it  is  not  essentially  a  tumor  of  blood-vessels. 

Over  against  these  processes  in  which  there  is  excessive  development  of 
more  or  less  normal  vessels  stands  a  large  class  of  tumors  in  which  a  neo- 
plastic process  affects  the  walls  of  vessels  and  usually  also  the  supporting 
connective  tissue,  and  these  constitute  the  true  angiomas. 

In  general,  angiomas  are  of  congenital  or  early  development,  slow  growth 
and  benign  course,  and  they  occur  under  rather  characteristic  clinical  condi- 
tions. 

Hemangioma  Simplex.  Vascular  Nevus  (Telangiectasis). — This  type  of 
angioma  occurs  in  several  forms. 

Nevus  vinosus,  or  the  port-wine  stain,  consists  of  a  circumscribed  or  diffuse 
dilatation  and  new  growth  of  superficial  capillaries  and  venules  of  the  derma 
over  which  the  epidermis  is  usually  thin  and  delicate.  The  dilated  capil- 
laries lie  immediately  beneath  the  epidermis  so  that  the  color  of  the  blood 
is  imparted  to  the  skin.  They  are  usually  congenital  and  the  face  is  the  chief 
locality  affected.  A  similar  process  affects  the  subcutaneous  tissue  and  fat, 
where  it  fails  to  yield  a  discoloration  of  the  skin.  According  to  Unna,  nevus 
vinosus  is  to  be  separated  from  the  true  angiomas  of  the  skin,  since  it  con- 
sists of  a  simple  telangiectasis  of  venous  capillaries  and  does  not  progress 
after  birth.  Nevertheless  it  and  the  deeper  congenital  nevi  have  often  been 
the  source  of  extensive  plexiform  and  cavernous  angiomas.  It  may  be  classed 
with  Albrecht's  hamartomas. 

Plexiform  angioma  consists  of  a  new  growth  of  dilated  capillaries  in  which 
the  length  of  the  vessels  is  increased,  but  the  number  of  new  cells  is  not  in 
great  excess.  Small  veins  and  arterioles  are  also  involved.  This  process 
causes  a  definite  enlargement  and  tumor  of  the  subcutaneous  tissue,  with 
flat  or  warty  projections  of  the  skin.  Circumscribed  tumors  of  this  class 
occur  in  the  skin  of  the  face  and  especially  in  the  eyelids  of  young  children. 
In  a  few  cases  multiple  and  diffuse  tumors  with  considerable  new  growth 
of  connective  tissue  have  occurred,  chiefly  in  the  arms  and  face  of  children 


ANGIOMA 


225 


and  adults,  and  have  been  described  under  the  terms  "elephantiasis  heman- 
giomatosa"  or  "nevus  vase,  mollusciformis"  (Seifert,  Fox,  Kaposi,  Unna).  In 
Jackson's  case  the  process  followed  the  course  of  the  facial  nerve.  The  plexi- 
form  angioma  or  deep  nevus  is  located  in  the  derma  or  subcutaneous  tissue 
or  in  the  fat  tissue  and  commonly  extends  from  one  to  the  other.  It  may 
even  invade  the  muscles  and  bones  and  eventually  involve  considerable  areas 
and  even  a  large  portion  of  a  limb.  Occurring  in  embryonal  fissures  in  face, 
cheek,  lip,  and  neck,  it  has  been  called  fissural  angioma. 

Angioma  often  begins  in  the  vessels  about  the  sweat-glands  which  may 
become  atrophic  and  fibrosed  or  hypertrophic.  An  imperfect  formation  of 
lobules  may  be  observed  in  relation  to  the  cutaneous  glands,  or  from  natural 


FIG.  66. — Simple  cellular  angioma,  or  angio-endothelioma. 

anatomical  septa  in  the  fat  tissue.  The  new  vessels  have  the  characters  of 
arterioles  rather  than  venules,  but  many  sizes  and  types  of  vessels  may  occur 
in  the  same  tumor.  Cellular  hyperplasia  in  the  vessel  walls  is  constant. 
The  endothelium  is  much  increased  and  appears  in  one  or  more  layers.  It 
is  sometimes  exfoliated  or  degenerated,  and  dilated  vessels  may  be  lined  by 
giant-cells.  Elastin  is  deficient  or  absent,  and  muscular  tissue  is  usually 

deficient.  ,  ,.„ 

Angioma  of  the  muscles  occurs  in  subjects  under  30  years  of  age,  chiefly 
in  the  triceps  femoris  and  forearm,  occasionally  in  other  regions.  It  produces 
moderate  enlargement  of  the  part  with  turgescence  and  impairment  of  func- 
tion. Muscatello  describes  four  histological  varieties:  (i)  Capillary  and  pro- 
gressive; (2)  arterial,  (3)  venous,  (4)  cavernous.  Pupovac  observed  multi 
15 


226  NEOPLASTIC  DISEASES 

plication  of  lymph-  as  well  as  blood-vessels.  In  a  series  of  46  cases  tabulated 
by  Sutter  the  above  histological  varieties  were  variously  combined.  The 
process  usually  began  with  a  proliferation  of  muscle-cells  in  the  walls  of  venules 
and  in  several  cases  there  were  polypoid  myomatous  outgrowths  into  the 
lumen  and  fusion  of  contiguous  vessel  walls  with  subsequent  dilatation  of 
channels.  The  atrophic  muscle-fibers  were  replaced  by  fat-cells.  Angioma 
of  muscles  may  extend  to  other  tissues.  I  have  examined  a  plexiform  angioma 
involving  the  subcutaneous  tissue,  fat,  and  nearly  all  the  muscles  of  the  fore- 
arm of  a  young  girl. 

Hemangioma  hypertrophicum  (Ziegler)  is  a  cellular  form  of  capillary  angioma 
occurring  chiefly  in  the  skin.  Nauwerck  described  a  very  similar  tumor 
occurring  in  the  femur.  It  consists  of  a  large  number  of  small  vessels  lined 
by  hyper  trophic  and  neoplastic  endothelium.  The  vessels  usually  main- 
tain a  scanty  lumen,  but  the  proliferation  of  endothelium  may  obliterate 
the  lumen  and  yield  compact  groups  of  cells.  In  this  form  the  tumor  is  vir- 
tually an  endothelioma  and  in  this  and  the  transitional  forms  it  may  be  des- 
ignated as  hemangio-endothdioma.  Distention  of  the  cellular  vessels  may  also 
occur,  giving  a  cavernous  variety  of  the  tumor.  In  many  simple  angiomas, 
especially  in  the  growing  edges  and  in  fat  lobules,  the  structure  is  that  of 
hemangioma  hypertrophicum.  Pure  tumors  of  this  type  are  usually  pro- 
gressive and  if  very  cellular  may  exhibit  local  malignancy. 

Histogenesis. — Ribbert  has  analyzed  in  detail  the  origin  and  growth  of 
simple  angioma.  By  means  of  interstitial  injection  he  finds  that  the  vessels 
have  few  or  no  lateral  anastomoses,  while  the  injection  mass  passes  freely 
into  the  efferent  artery  and  afferent  veins,  but  not  into  the  tissue  surrounding 
the  tumor.  This  result  indicates  that  the  tumor  process  resides  in  an  iso- 
lated segment  of  the  vessel  walls  and  produces  elongation  and  varicosities 
in  a  more  or  less  closed  territory  without  gradual  involvement  of  surrounding 
vessels.  Where  the  tumor  forms  a  new  lobule  or  invades  fat  or  other  tis- 
sues it  is  not  by  extension  of  the  tumor  process  to  the  healthy  vessels  of  the 
new  area  but  by  the  projection  of  new  vessels  which  grow  out  from  the  tumor 
while  the  vessels  of  the  invaded  part  are  compressed  and  occluded.  The  mi- 
croscopical structure  shows  that  the  process  affects  both  the  walls  of  the  vessel 
and  the  supporting  connective  tissue.  In  the  invaded  fat  lobules  Ribbert 
finds  isolated  tumor  vessels  connected  by  long  strands  with  the  main  tumor, 
while  between  the  fat-cells  parallel  rows  of  endothelial  cells  appear  which 
later  become  thickened  and  canalized.  These  new  structures  seem  to  have 
no  connection  with  the  normal  vessels  of  the  invaded  tissue. 

Thoma  refers  much  of  the  growth  of  angioma  to  mechanical  factors. 
Increase  of  blood-pressure  and  loss  of  support  to  vessel  walls  from  changes 
in  the  surrounding  tissue  tend  to  excite  new  growth  of  vessels,  while  increased 
rapidity  of  flow  favors  elongation  and  dilatation  of  the  wall.  Many  authors 
(Rokitansky,  Borst)  consider  that  many  simple  so-called  angiomas  represent 
simple  hypertrophy  of  vascular  segments  without  neoplastic  overgrowth. 
These  factors  are  doubtless  important  in  determining  the  course  of  angiomas, 
but  they  cannot  account  for  their  origin,  which  must  be  referred  to  a  develop- 
mental anomaly  in  the  structure  of  certain  vascular  segments  which  do  not 
fit  into  the  circulatory  system,  and  which  retain  embryonal  characters.  The 
congenital  origin  of  the  great  majority  of  angiomas  speaks  strongly  in  favor 
of  a  tissue  predisposition  as  a  prominent  factor  in  their  genesis. 

Virchow  believed  that  angiomas  result  from  the  action  of  local  irritation 
on  imperfectly  formed  vessels,  as  those  in  embryonal  fissures.  Unna  was 
led  to  believe  that  nevus  vinosus  especially  occurs  in  areas  which  have  been 
subjected  to  abnormal  pressure  during  fetal  life.  The  relation  to  nerve- 


-LVG/01/,1 


227 


trunks  has  suggested  to  many  a  neurotic  theory  of  origin.    In  not  a  few  cases; 
a  traumatic  origin  is  clearly  indicated  (Lowenthal,  Lit.). 

Cavernous  Angioma. — When  the  vascular  channels  are  widely  dilated 
and  the  connective  tissue  septa  are  thin,  the  angioma  is  designated  as  cavern- 
ous. This  process  is  of  frequent  occurrence  in  many  situations  and  in  nearly 
all  tissues  and  organs.  In  the  skin  cavernous  angiomas  produce  circum- 
scribed or  diffuse,  flat  or  elevated  lesions,  involving  the  derma  and  subcuta- 
neous tissue.  If  superficial,  they  are  dark  red  in  color.  If  covered  by  cor- 
rugated and  thickened  epidermis,  they  become  warty.  Changes  in  the  circu- 
lation affect  both  the  size  and  color  of  the  tumors.  Many  of  them  are  dis- 
tinctly erectile  and  pulsating.  Thrombosis  and  the  formation  of  calcine 


FlG.  67. — Metastasizing  angioma,  secondary  nodules  in  lung.     (Borrmann.) 

phleboliths  occur  in  dilated  sinuses.  The  smaller  tumors  are  usually  encap- 
sulated and  stationary,  but  there  are  many  cases  of  diffuse  cavernous  angioma 
in  which  a  capsule  is  missing  and  the  limits  of  the  process  gradually  extend 
over  many  years. 

The  cavernous  angioma 'first  appears  as  a  circumscribed  tumor  developing 
often  on  the  basis  of  a  congenital  nevus  and  tends  to  enlarge  steadily  over  a 
period  of  many  years.  They  may  be  observed  at  birth  or  appear  at  any  age. 
When  allowed  to  progress  they  may  attain  very  large  dimensions,  and  suc- 
cessively invade  neighboring  tissues  and  organs.  In  some  of  the  older  cases, 
extraordinary  results  were  produced.  Gascoyen  observed  an  angioma  of 
the  parotid  which  progressed  for  many  years,  produced  a  large  polypoid 


228 


NEOPLASTIC  DISEASES 


tumor  externally,  while  a  pharyngeal  portion  eventually  caused  death  by 
suffocation.  Autopsy  showed  several  nevi  of  the  intestinal  serosa  and  mucosa 
and  one  in  the  liver.  Cruveilhier  described  a  cavernous  angioma  involving 
the  skin,  muscles,  tendons,  synovial  membranes,  nerves,  and  periosteum 
of  nearly  the  whole  arm  of  a  65-year-old  hemiplegic.  Falkowski  reports 
peculiar  cavernomas  of  liver  and  spleen  and  angiomas  of  skin  in  an  infant. 

The  subcutaneous  angiomas  may  gradually  involve  the  skin  and  the 
deep  fascias,  and  some  which  first  appear  subcutaneously  originate  in  much 
deeper  tissues,  or  they  establish  wide  communications  with  deep  venous 
trunks. 

Multiplicity  of  cavernous  angioma  is  a  prominent  feature  in  some  cases. 
The  minute  senile  angiomas  of  the  skin  usually  appear  in  considerable  num- 
bers. Large  multiple  cavernomas  of  widely  separated  regions  occurred  in  a 
case  of  Hildebrand's.  The  smaller  cavernous  angiomas  are  often  multiple, 


FlG.  68. — Structure  of  metastasizing  angioma.      (Borrmann.) 

as  many  as  40  or  even  100  having  been  observed  in  one  subject  (Esmarch, 
Schuh). 

Sharply  contrasted  with  the  multiple  benign  cavernous  angiomas  is  a 
group  of  metastasizing  cavernous  or  more  cellular  angiomas  which  exhibit 
certain  peculiar  features  of  malignancy,  and  are  eventually  fatal,  chiefly 
through  internal  hemorrhage  and  anemia.  Here  belongs  the  remarkable 
case  observed  by  Borrmann  in  which  angioma  of  the  skin  of  the  breast  in  a 
subject  of  23  years  recurred  repeatedly  after  operation  and  finally  proved 
fatal  with  numerous  secondary  tumors  in  both  lungs.  The  original  tumor 
had  the  structure  of  simple  angioma,  but  the  secondary  growths  were  more 
cellular. 

In  a  case  observed  by  the  writer  the  breast  was  greatly  enlarged  by  a 
bulky  cavernous  angioma,  several  tumors  appeared  on  the  skin  and  mucous 
membranes,  and  there  were  evidences  of  pulmonary  involvement.  The 
structure  was  very  similar  to  that  in  Borrmann's  case. 

In  Shennan's  remarkable  case,  of  6  years'  duration,  marked  by  numerous 


ANGIOMA 


229 


hemoptyses,  there  were  found  at  autopsy  cavernous  angiomas  involving 
the  whole  of  the  spleen,  much  of  the  lungs,  the  thymus  and  mediastinal  nodes, 
liver  and  bone-marrow,  while  many  miliary  angiomas  occurred  in  other  tis- 
sues. The  structure  was  generally  not  malignant  in  appearance,  but  the 
small  tumors  and  some  of  the  larger  were  doubtless  metastatic,  and  exhibited 
a  local  invasive  tendency. 

The  course  of  cavernous  angioma  is  usually  slowly  progressive.  Begin- 
ning in  congenital  nevi  or  in  deep  tissues,  at  any  period  of  life,  they  slowly 
enlarge  by  distention  of  the  original  vessels  and  by  formation  of  new  vessels. 
The  growth  is  sometimes  accelerated  at  the  menstrual  period  and  during 


FIG  69  — Metastasizing  angioma  of  left  breast.    Note  tumors  of  jaw,  neck,  under  ear, 
and  at  right  axilla.     There  were  tumors  also  in  pharynx  and  lungs. 

gestation.  Free  anastomoses  with  large  arteries  or  veins  may  become  estab- 
lished and  severe  or  fatal  hemorrhage  may  occur.  A  capsule  forms  about 
many  tumors  which  are  then  apt  to  remain  stationary.  Spontaneous  regres- 
sion may  result  from  contraction  of  the  capsule,  thrombosis,  inflammation 
or  ulceration,  or  a  cure  may  be  affected  by  continuous  pressure,  ligature  of 
vessels,  or  excision.  Very  slight  interference  is  sometimes  sufficient.  Inter- 
current  diseases  or  cachexia  may  initiate  the  regression.  Recurrence  after 
operation  has  often  followed  incomplete  removal.  A  certain  local  malignancy 
is  also  exhibited  by  tumors  which  extend  from  one  tissue  to  another,  leading 
even  to  the  erosion  of  bones,  and  occasionally  pressure  symptoms  becorr 
serious. 


230  NEOPLAST1C  DISEASES 

The  structure  of  cavernous  angioma  presents  chiefly  a  series  of  anastomos- 
ing vascular  channels  inclosed  by  thin  septa.  The  appearance  on  section 
may  be  roughly  compared  to  that  of  a  sponge.  Yet  in  less  advanced  cases 
it  is  possible  to  recognize  simple  spherical  sacculations,  and  tubular  dilata- 
tions, all  connected  with  one  main  afferent  and  one  efferent  vessel.  Large 
cystic  dilatations  may  occur,  filled  with  blood  or  serous  fluid.  The  walls 
exhibit  the  structure  of  venules  or  less  often  of  arterioles.  Hyperplasia  of 
cells  may  lead  to  nodular  growths  of  new  tissue  projecting  into  the  lumen. 
Many  authors  have  described  the  budding  of  new  vessels  on  the  advancing 
edges  of  cavernous  angioma.  In  progressing  cases  certain  areas  of  the  tumor 
may  show  the  numerous  cellular  vessels  of  simple  or  plexiform  angioma,  so 
that  it  is  not  always  possible  to  separate  cavernous  from  simple  angioma. 


FIG.  70. — Cavernous  angioma  of  liver. 

v.  Recklinghausen  and  others  locate  the  earliest  stages  of  the  cavernous 
angioma  in  the  walls  of  the  veins,  while  many  believe  the  capillaries  are  first 
affected  (Bosrt).  I  have  drawn  the  impression  that  either  veins  or  capillaries 
may  be  involved  in  different  cases. 

Histo genesis. — In  the  development  of  cavernoma  Rindfleisch  and  Borst 
attribute  chief  importance  to  a  fibrocellular  growth  in  and  about  the  walls 
of  the  capillaries.  The  retraction  of  this  new  tissue  tends  to  shorten  the 
vessel,  dilatation  resulting  from  mechanical  pressure.  The  same  relation 
between  connective-tissue  growth  and  vascular  dilatation  is  observed  in 
cavernous  fibromas,  so  that  the  cavernoma  has  been  likened  to  a  fibroma 
with  excessive  development  of  vessels.  Loss  of  muscular  and  elastic  tissue 
in  the  new  or  altered  vessels  must  also  greatly  favor  the  dilatation.  In  re- 
gressing cases  a  fibrous  capsule  forms  or  fibrous  areas  appear  in  the  tumor, 
the  sinus  walls  thicken  and  contract,  and  eventually  only  scar  tissue  remains. 


ANGIOMA  231 

The  question  of  the  neoplastic  nature  of  cavernous  angioma  has  been 
extensively  discussed.  When  one  examines  a  stationary  cavernoma  of  the 
liver  it  is  difficult  to  recognize  any  definite  feature  of  a  tumor  and  many 
have  assumed  that  these  and  a  considerable  proportion  of  other  localized 
dilatations  of  vessels  should  be  separated  from  the  angiomas  and  referred  to 
mechanical  factors.  There  is  no  doubt  that  simple  varices  may  simulate 
the  structure  of  cavernous  angiomas  and  have  often  been  classed  with  this 
tumor.  The  gross  dissection  of  certain  angiomas  strongly  suggests  that 
simple  saccular  and  tubular  dilatations  of  preexisting  veins  will  explain 
their  origin.  Yet  Virchow  traced  the  earliest  stages  of  cavernoma  of  liver 
to  islands  of  proliferating  connective  tissue  surrounding  cellular  capillaries, 
and  Ribbert  finds  on  the  edges  of  cavernoma  new  vessels  which  communicate 
freely  with  those  of  the  tumor,  but  imperfectly  with  those  of  the  surrounding 
tissue.  Local  varices  can  usually  be  distinctly  separated  from  angioma  in 
the  same  tissue.  The  usual  origin  of  cutaneous  angioma  is  from  congenital 
simple  or  plexiform  angioma  which  is  admittedly  a  neoplasm.  It  is  thus 
apparent  that  in  the  growth  of  cavernous  angioma  there  are  essential  factors 
other  than  mechanical  dilatation  of  vessels,  and  it  is  most  reasonable  to  re- 
gard these  factors  as  partaking  of  the  neoplastic  order.  Albrecht  regards 
cavernoma  of  liver  as  an  ill-fitted  but  practically  normal  segment  of  tissue 
which  possess  a  limited  capacity  for  aberrant  growth.  For  this  and  many 
other  benign  tumors  he  introduced  the  term  hamartoma. 

The  clinical  features  of  cavernous  angioma  fall  into  several  rather  wrell- 
defined  groups.  The  cutaneous  tumors  form  the  most  numerous  group.  They 
are  located  in  the  derma  or  subcutaneous  tissues,  chiefly  in  regions  where 
the  skin  is  loose.  While  no  region  of  the  body  escapes,  the  chief  locations 
are  the  face,  scalp,  labia,  scrotum,  prepuce,  extremities,  and  folds  of  the 
knees,  axilla,  and  buttocks.  The  influence  of  embryonal  fissures  noted  in 
the  occurrence  of  simple  angioma  is  observed  also  with  the  cavernous  type. 
The  wide  variations  in  the  origin,  growth,  size,  number,  and  complications 
of  these  tumors  is  elaborately  set  forth  in  the  detailed  reports  of  cases  col- 
lected by  Virchow. 

Submucous  cavernomas  occur  chiefly  in  the  buccal  region.  The  gum 
is  the  seat  of  a  common  cavernous  tumor  which  may  follow  violent  extraction 
of  molar  teeth.  It  usually  remains  of  moderate  dimensions,  but  may  gradu- 
ally extend  until  it  involves  a  considerable  portion  of  the  alveolar  tissues 
and  establishes  connections  with  large  veins.  At  this  stage  its  extirpation 
is  difficult  and  has  produced  fatal  hemorrhage. 

In  the  tongue  cavernous  angioma  arises  usually  in  the  tip  of  the  organ 
and  may  extend  until  it  produces  an  erectile  tumor  of  large  dimensions  (Reiche). 
Both  lymph-  and  blood-vessels  participate  in  the  process  in  certain  cases  of 
angiomatous  macroglossia  (Wegner).  A  form  of  angioma tous  ranula  has 
been  described  by  Delbeau.  The  lips  are  frequent  seats  of  congenital  nevi 
and  of  cavernous  angiomas. 

Orbital  angiomas  affect  either  eyelid  and  may  involve  the  conjunctiva. 
In  the  retroorbital  fat  a  few  diffuse  and  circumscribed  cavernous  angiomas 
have  been  described  (Morton,  Schuh,  di  Ricci).  These  tumors  may  extend 
along  the  optic  nerve  into  the  eyeball  (Quackenboss). 

Angioma  of  bone  is  rare,  although  overgrowth  of  vessels  is  a  prominent 
feature  of  many  malignant  bone  tumors,  and  bone-tissues  are  often  eroded 
by  extensions  from  angioma  of  adjacent  tissues.  The  extensively  cavernous 
tumors  of  the  long  bones,  especially  of  humerus  and  tibia,  must  be  classed 
historically  as  sarcomas,  although  some  of  them  may  be  successfully  treated 
by  curetage  or  ligation  of  the  main  vessels.  True  cavernous  angioma  may 


232  NEOPLASTIC  DISEASES 

arise  in  the  periosteum  or  in  the  marrow  (Virchow,  Kauffmann).  They  in- 
vade the  outer  layers  or  cause  absorption  of  the  shaft.  Extensive  angiomas 
of  the  skull  have  been  observed  by  Kauffmann  and  by  Schoene,  and  of  the 
vertebrae  by  Gerhardt,  Kauffmann,  and  Muthmann.  I  have  studied  one 
cavernous  angioma  of  the  head  of  the  humerus  which  appeared  beneath  a 
thin  shell  of  bone  2  years  after  trauma.  In  a  case  of  slowly  progressive  para- 
plegia I  found  a  cavernous  angioma  of  a  dorsal  vertebra,  which  permitted 
collapse  of  the  body  and  gave  rise  to  a  protruding  tumor  which  compressed 
the  cord. 

In  the  glands  angioma  occurred  in  the  parotid  in  the  case  of  Gascoyen, 
and  in  several  cases  the  breast  has  been  extensively  transformed  into  caver- 
nous tissue  by  tumors  arising  in  the  fat  (Virchow,  Image,  Borst,  Hake). 

In  the  internal  organs  cavernous  angioma  occurs  chiefly  in  the  liver, 
rarely  in  the  spleen  (Albrecht),  kidney,  and  uterus  (Virchow).  Dowd  has 
collected  13  cases  of  angioma  of  the  spleen,  illustrating  small  tumors  found  at 
autopsy,  very  large  growths  removed  at  operation,  malignant  tumors  produc- 
ing metastases,  multiple  benign  tumors  in  spleen,  liver,  omentum,  and  skin, 
and  a  progressive  anemia  accompanying  the  large  growths. 

The  common  cavernoma  of  the  liver  is  of  much  theoretical  interest,  but 
rarely  produces  symptoms.  They  are  single  or  multiple,  as  small  as  a  pea 
or  as  large  as  a  child's  head  (Ribbert),  and  usually  lie  just  beneath  or  project- 
ing from  the  surface.  They  are  often  associated  with  angioma  of  other  or- 
gans. Their  frequency  increases  with  the  age  of  the  subjects,  but  congenital 
cases  rarely  occur.  Veeder  and  Austin  describe  a  remarkably  extensive 
multiple  congenital  hemangioma  of  the  liver.  Virchow  believed  that  they 
might  spontaneously  disappear,  leaving  scars.  The  structure  shows  central 
sinuses  separated  by  thin  fibrous  or  cellular  septa  which  may  contain  islands 
of  liver  cells.  On  the  edges  are  Smaller  vessels  communicating  with  the  sinuses. 
The  tumor  is  sharply  marked  off  from  the  parenchyma.  Ribbert  finds  that 
interstitial  injections  of  the  tumor  or  of  the  surrounding  parenchyma  do  not 
pass  from  one  tissue  to  the  other,  the  tumor  vessels  showing  a  marked  inde- 
pendence of  the  normal  vessels  of  the  organ.  Yet  the  tumor  may  be  filled 
by  injections  through  the  portal  or  hepatic  veins  or  hepatic  artery  (Virchow). 

The  origin  and  nature  of  the  cavernoma  of  the  liver  has  long  been  a  sub- 
ject of  discussion,  the  later  phases  of  which  have  been  maintained  by  Ribbert 
and  by  Schmieden.  On  the  whole,  the  argument  seems  to  favor  the  conten- 
tion of  Ribbert,  that  these  growths  are  partial  neoplasms  originating  from 
embryogenic  disturbances,  through  which  a  displaced  segment  of  the  organ 
comes  to  possess  a  limited  power  of  aberrant  growth.  As  already  stated, 
Virchow  traced  their  inception  in  areas  of  proliferating  vascular  connective 
tissue.  The  progressive  dilatation  of  vessels  naturally  results  from  absence 
of  muscular  and  elastic  tissue  in  the  walls. 

In  the  ovary  Gottschalk  describes  a  diffuse  bilateral  cavernous  transfor- 
mation. Orth  observed  a  remarkable  case  of  multiple  congenital  hemangiomas 
in  both  ovaries,  skin,  and  other  organs  of  a  child.  In  the  placenta  various 
tumors  have  been  described  as  fibroma,  myxoma,  and  angioma.  They  appear 
to  be  essentially  overgrowths  of  blood-vessels  with  more  or  less  admixture 
of  fibrous  or  mucinous  stroma.  They  are  often  multiple  and  may  reach  con- 
siderable dimensions,  causing  hemorrhage  and  interfering  with  the  normal 
growth  of  the  fetus,  but  none  has  proved  malignant.  (Albert,  Lit. ;  Williams, 
Lit.) 

Angioma  of  the  brain  occurs  in  two  main  forms,  as  (i)  a  more  or  less  diffuse 
varicosity  of  the  vessels  of  the  meninges,  and  (2)  a  true  angioma,  simple  or 
cavernous,  of  the  brain  tissue.  La  Villette  has  collected  18  cases  of  both 


ANGIOMA  233 

types  in  various  situations.  Several  cases  have  occurred  in  the  region  of  the 
corpus  striatum  (Virchow,  Luschka).  They  are  probably  of  congenital  origin, 
and  in  Hebold's  case  the  intracranial  was  associated  with  cutaneous  angiomas. 
They  are  of  slow  growth  and  usually  produce  only  general  symptoms.  Werg- 
man's  cavernous  angioma  of  the  left  cerebellar  pedicle  led  to  fatal  hemorrhage. 
Orbison  reported  a  racemose  angioma  of  cerebral  pia  invading  the  brain  tissue 
and  giving  a  long  history  of  epilepsy.  Several  cases  of  angioma  in  the  sub- 
stance of  the  pons  are  recorded  by  LaFora  and  by  Enders.  One  of  LaFora's 
cases  terminated  after  severe  general  and  focal  symptoms  lasting  one  month. 
The  structure  is  that  of  simple  or  cavernous  angioma. 

Angioma  arteriale  racemosum  consists  of  a  dilatation  and  complex  inter- 
twining of  many  new  formed  and  altered  vessels  of  small  caliber  with  sub- 
sequent involvement  of  normal  vessels  (Deetz).  The  condition  occurs  in 
infants  or  adults,  and  of  87  cases  collected  by  Schuck  84  occurred  on  the 
head,  a  few  on  the  extremities.  They  usually  arise  in  close  connection  with 
the  large  carotid  artery.  The  external  appearance  was  likened  by  Virchow  to 
a  pulsating  mass  of  earthworms.  Arising  externally  they  extend  over  the 
neck  and  scalp,  erode  the  skull  and  penetrate  the  cranium,  and  in  several 
cases  they  have  involved  the  cerebral  and  meningeal  vessels.  The  walls  of 
the  vessels  show  a  variety  of  changes,  as  fatty  degeneration  and  loss  of 
muscle-tissue  of  the  media  (Heine),  hypertrophy  of  media  (Lablee)  hyper- 
trophy of  interna  (Kretchmann),  or  hypertrophy  of  all  coats.  Emanuel 
described  leiomyomatous  outgrowths  of  the  media  with  degeneration,  calcifi- 
cation, and  formation  of  aneurysms.  Deetz  found  uniform  hypertrophy  of 
small  arterioles  and  new  growth  of  cellular  capillaries.  The  exact  position 
of  this  process  is  difficult  to  determine,  but  most  authors  assume  that  it 
arises  from  a  congenital  tissue  abnormality  and  that  it  belongs  in  the  class 
of  partial  tumors. 

LYMPHANGIOMA 

Lymphangioma  is  a  tumor  composed  of  lymph-vessels. 

It  is  therefore  an  organoid  structure  consisting  of  endothelial  cells  and 
supporting  connective  tissue,  both  of  which  are  involved  in  the  neoplastic 
process.  Lymph-nodules  or  foci  of  round  cells  are  often  present  to  complete 
the  parallel  with  a  lymphatic  structure.  Lymphangioma  has  also  been  asso- 
ciated with  minute  islands  of  lipoma,  proliferating  smooth  muscle-cells  may 
be  found  in  the  septa,  and  Ritschl  found  an  island  of  cartilage  in  an  inter- 
muscular  lymphangioma,  observations  which  suggest  an  embryogenic  origin. 
New  formed  lymph-vessels  are  also  present  in  many  benign  and  malignant 
tumors,  especially  with  endothelioma  and  sarcoma. 

The  clinical  conditions  which  fall  in  the  general  class  of  lymphangioma 
include  a  variety  of  slowly  growing,  usually  congenital,  single  or  multiple 
tumors  of  the  skin,  subcutaneous  tissues,  deep  areolar  tissues  and  muscles, 
of  the  neck,  trunk,  lips,  tongue,  eye,  and  orbit,  and  mediastinal  and  retro- 
peritoneal  regions.  In  the  pathogenesis  of  these  conditions  many  factors  are 
concerned  and  it  is  thus  more  difficult  to  distinguish  between  lymphangioma 
and  lymphangiectasis  than  between  true  and  spurious  hemangioma. 

Ribbert's  definition  of  lymphangioma  as  an  isolated  group  of  vessels 
growing  from  their  own  resources  and  more  or  less  disconnected  from  sur- 
rounding channels  can  seldom  be  directly  applied.  In  some  typical  examples 
of  lymphangioma  the  tumor  has  been  found  freely  accessible  to  injections 
through  afferent  and  efferent  vessels  (Langhans). 

Proliferating  buds  of  endothelium  forming  new  lymph-vessels  have  been 
fully  recognized  in  certain  cases  by  Nasse,  Schmidt,  and  Borst,  but  such 


234 


N EOF LAST  1C  DISEASES 


structures  are  usually  missing.  Size  is  not  a  reliable  criterion,  since  in  some  of 
the  large  cystic  growths  the  signs  of  a  neoplasm  are  least  distinct.  More- 
over, simple  occlusion  of  large  lymph  paths  may,  although  rarely,  be  fol- 
lowed by  extensive  varicosities  resembling  lymphangioma.  The  appearance 
of  the  stroma  sometimes  suggests  a  neoplastic  growth,  but  more  often  it  is 
fibrous  or  comparatively  acellular.  The  general  clinical  features  seem  to 
offer  an  important  means  of  recognition  of  true  lymphangioma,  and  many 
would  include  in  the  class  only  such  processes  as  show  a  congenital  origin  and 
a  progressive  course,  and  absence  of  traumatic  and  inflammatory  factors. 


FIG.  71. — Lymphangioma  of  voluntary  muscle;  excavation  of  muscle-fibers  by  lymph- 
vessels.     Giant-cells. 

The  histological  structure  of  lymphangioma  was  first  fully  described  by 
Wegner,  who  recognized  three  groups  of  cases:  i.  Lymphangioma  simplex 
consists  of  an  anastomosing  network  of  spaces  and  vessels  of  small  and 
medium  caliber.  The  septa  are  either  reduced  to  thin  strands  of  acellular 
connective  tissue,  or  they  are  thicker  and  participate  in  the  proliferation. 
The  endothelium  is  flat  or  cubical  and  rarely  it  may  appear  in  multiple  layers 
or  in  the  form  of  projecting  buds  (Freudweiler) . 

2.  Lymphangioma  cavernosum  consists  of  a  system  of  closed  communi- 
cating lymph-spaces  supported  by  thin  walls  or  thicker  septa,  lined  by  flat 
endothelium  and  filled  with  fluid  or  coagulated  lymph  occasionally  mixed 
with  blood. 


ANGIOMA  235 

3.  Lymphangioma  cystoides  consists  of  a  congeries  of  large  and  small  cysts 
lined  by  flat  endothelium  and  filled  with  lymph.  Some  of  the  cysts  may  be 
closed  and  the  main  lymphatic  vessels  are  usually  occluded. 

The  great  majority  of  lymphangiomas  fall  readily  among  these  classes, 
most  of  them  being  of  the  cavernous  type.  In  not  a  few  cases  there  is  new 
growth  of  blood-vessels  not  communicating  with  the  lymphatic  system,  and 
forming  a  mixed  hemolymphangioma  (Nasse,  Sutter,  Novack). 

In  the  development  of  lymphangioma  several  factors  seem  to  be  concerned. 
Wegner  believed  that  three  modes  of  origin  could  be  traced:  (a)  passive  dilata- 
tion with  inflammatory  hyperplasia  of  preexisting  vessels,  lymphangiectasis,  (b) 
neoplastic  growth  of  vessels,  and  (c)  heteroplastic  formation  of  lymph-vessels 
in  granulation  tissue. 

(a)  Lymph  stasis  doubtless  influences  the  course  of  many  lymphangiomas, 
especially  the  large  cystic  type  with  occluded  vessels,  to  a  less  extent  the 
saccular  ectasise  of  the  cavernous  forms,  but  it  has  not  been  accepted  as  a 
sufficient  explanation  of  any  of  the  characteristic  varieties  of  lymphangioma. 
Ribbert  argues  that  any  marked  pressure  would  inhibit  the  growth  of  endo- 
thelium, and  it  is  clear  that  with  free  afferent  and  efferent  vessels  the  stasis 
must  be  slight.  Ribbert  assumes  that  lymphatic  and  other  cystic  tumors 
develop  as  a  result  of  a  process  of  growth  located  in  the  walls  which  steadily 
enlarges  the  circumference  of  the  cysts  and  prevents  the  passive  accumu- 
lation of  fluids.  Secondary  dilatation  of  new-formed  vessels  must  be  re- 
garded as  an  important  factor  in  cavernous  and  cystic  lymphangiomas. 
Intermittent  attacks  of  inflammation  influence  the  course  and  structure  of 
many  lymphangiomas  (Kuttner) . 

(6)  The  evidence  of  new  formation  of  vessels  is  conclusive,  for  in  many 
cases  have  been  observed  hypertrophic  and  proliferating  endothelium, 
multiple  layers  of  endothelium,  and  sprouts  of  endothelium  growing  out  into 
the  connective  tissue  with  subsequent  canalization.  Borst  depicts  the  for- 
mation of  new  lymph- vessels  in  a  small  fibromatous  tumor  in  fat  tissue  where 
lymph-vessels  are  normally  scanty.  In  a  type  of  cutaneous  lymphangioma 
the  predominance  of  endothelium  has  led  many  to  designate  the  process  as 
endothelioma  and  other  types  of  endothelioma  arise  from  lymphatic  en- 
dothelium. The  occasional  occurrence  of  definite  fibroma  and  lipoma  in 
lymphangiomas  illustrates  the  organoid  character  of  these  tumors  and  demon- 
strates the  neoplastic  growth  of  lymph- vessels. 

(c)  The  heteroplastic  formation  of  lymph-vessels  in  granulation  tissue 
has  not  been  satisfactorily  demonstrated. 

In  the  origin  of  lymphangioma  it  must  be  assumed  that  there  exists  a 
local  predisposition  resulting  from  an  embryogenic  disturbance  similar  to 
that  assumed  for  hemangioma.  Of  the  nature  of  this  disturbance  nothing  is 
definitely  known,  but  the  congenital  origin  of  most  lymphangiomas  is  a  strik- 
ing feature  in  their  etiology.  A  partial  isolation  of  a  segment  of  lymph- 
vessels  with  imperfect  development  and  retention  of  abnormal  powers  of 
growth  may  be  supposed  to  exist.  The  occurrence  of  cartilage  in  one  re- 
ported lymphangioma  indicates  that  the  isolation  may  be  complete.  I  have 
seen  a  circumscribed  lymphangioma  2  cm.  in  diameter  attached  to  the  sper- 
matic cord.  The  vessels  were  lined  by  large  cuboidal  endothelium  and  sup- 
ported by  embryonal  connective  tissue.  In  a  congenital  flat  tumor  of  the 
subcutaneous  tissue  of  the  cheek  I  found  many  lymph-follicles  and  diffuse 
lymphoid  tissue  in  the  septa  of  a  cavernous  lymphangioma.  The  structure 
suggested  an  abortive  attempt  at  the  formation  of  a  lymph-node. 

The  clinical  forms  of  lymphangioma  are  numerous  and  difficult  to 
classify. 


236 


NEOPLASTIC  DISEASES 


Simple  lymphangioma,  consisting  of  moderately  dilated  and  slightly  hyper- 
plastic  vessels  in  which  a  neoplastic  element  is  either  wanting  or  feebly  devel- 
oped, occurs  in  many  situations,  chiefly  in  the  skin.  In  elephantiasis  dilated 
lymph- vessels  contribute  largely  to  the  increased  bulk  of  the  tissues.  In  the 
lymph-scrotum  of  filariasis  the  swelling  is  referable  to  lymphangiectasis  and 
edema,  and  may  be  traced  to  occlusion  of  lymphatic  trunks  by  the  parent 
worms.  The  process  commonly  involves  the  bladder  with  chyluria  and  the 
presence  of  filaria  embryos  in  the  urine.  The  tissues  show  only  inflammatory 
reaction  and  the  process  is  not  a  tumor. 

In  the  skin  of  face  and  neck  congenital  lymphangiectasis  produces  small 
or  large  flat  or  wart-like  prominences  which  after  trauma  may  exude  serous 
fluid.  They  consist  of  dilated  lymphatics  of  the  derma.  The  endothelium 


•  vj-,  *•«*•»*••»*"    lF*r 

1&^£-:>  V> 

IpK^ 

^8pK*» :-  •> 

^;;-:;^ 


FIG.  72. — Structure  of  a  congenital  angiolymphoma  occurring  in  skin  of  cheek  of  an 

infant. 


is  slightly  hyperplastic,  but  their  chief  neoplastic  character  is  the  occasional 
relation  to  embryonal  fissures  and  their  congenital  origin.  In  a  case  of  Haug's 
the  tongue  was  involved  and  there  was  a  congenital  auricular  fistula. 

In  lymphangioma  cutis  circumscripta  the  skin  of  face,  chest,  or  extremities 
is  the  seat  of  numerous  small  projecting  translucent  vesicopapules  which  on 
section  prove  to  consist  of  many  small  cellular  lymph- vessels.  The  endothe- 
lium is  hypertrophic  and  proliferating,  and  the  channels  are  small  and  filled 
with  fluid  or  hyaline  masses.  There  is  extensive  new  formation  of  imperfect 
lymph-vessels  and  the  process  is  a  true  neoplasm  (Fox,  Hutchinson,  Noyes, 
Torok,  Freudweiler,  Waelsch). 

Lymphangioma  tuber osum  multiplex  was  described  by  Kaposi  as  a  small 
superficial  multiple  tumor  of  cellular  lymph-vessels.  Beneke's  case  falls  in 


ANGIOMA 


237 


that  histological  group.  The  nature  of  other  cases  in  derma tological  literature 
is  not  clear  (Crocker,  Perry,  Kromayer). 

In  the  eye  lymphangiectasiae  of  congenital  or  inflammatory  origin  occur 
in  the  conjunctiva.  They  may  reach  considerable  dimensions  and  occasion- 
ally there  are  evidences  of  considerable  new  formation  of  vessels  (Steudener, 
Bull,  Wintersteiner,  Sachs). 

Lymphangioma  cavernosum  occurs  chiefly  in  the  skin,  but  also  in  the  inter- 
muscular  septa  and  in  the  mucous  membranes.  The  dilated  vessels  are  filled 
with  coagulable  lymph  often  mixed  with  blood,  and  the  contents  may  be 
thrombosed,  or  hyaline,  or  extensively  calcific.  On  analysis  the  aspirated 


FlG.  73. — Superficial  diffuse  lymphangioma  of  entire  tongue,  existing  since  infancy  in 

a  boy  of  19  years. 

fluid  shows  a  considerable  content  of  blood-proteins  and  salts,  many  lympho- 
cytes and  exfoliated  endothelial  cells,  and  usually  cholesterin  crystals.  It  lacks 
the  digestive  ferments  of  pancreatic  cysts  (Sick,  Bryck,  Zeyneck).  The  septa 
are  thin  and  acellular  or  thicker  and  composed  of  proliferating  connective 
tissue,  containing  round-cells,  lymph-nodules,  and  often  much  smooth  muscle- 
tissue.  New  growth  of  small  vessels  is  often  associated  with  the  larger  ones. 
The  tumors  are  small  and  circumscribed  or  extend  diffusely  over  considerable 
areas.  . 

In  the  skin  elephantiasis  lymphangiectatica  may  exhibit  extensive  dilata- 
tion of  old  and  new  formed  lymph-vessels. 

The  most  frequent  forms  of  cavernous  lymphangioma  occur  in  the  lip, 


238  NEOPLASTIC  DISEASES 

cheek,  and  tongue,  and  are  designated  as  macrocheilia,  macromelia,  and 
macroglossia.  They  are  usually  congenital  and  produce  irregular  and  some- 
times extensive  enlargement  of  the  tissues.  The  pharynx  and  larynx  may 
also  be  involved  (Suchstorff,  Nasse). 

Chylangioma  of  the  mesentery  is  a  cavernous  lymphangioma  containing 
milky  fluid  which  arises  from  congenital  or  acquired  obstruction  to  the  lacteal 
vessels  (Kruse,  Schmidt,  Ritter).  Multiple  dilatations  of  the  submucous 
lymphatics  of  the  intestine  were  observed  by  Krauss,  and  extensive  grades 
of  this  condition  have  been  reported  by  Blatteis,  Thalheimer,  and  Takano. 

Cavernous  lymphangioma  occasionally  occurs  in  the  conjunctiva,  eye- 
lids, and  orbit  (Michel,  Steudener,  Sachs).  Klein  described  a  case  occurring 
in  the  vagina. 

Extensive  cavernous  lymphangioma  of  the  foot  resembling  elephantiasis, 
multiple  lymphangioma  of  the  ringer,  hands  and  pleura,  and  hyperplasia  of 
many  lymph-nodes,  were  associated  in  a  remarkable  case  reported  by  Bryck. 

Lymphangioma  cysticum  is  a  multilocular  cystic  tumor  which  occurs  chiefly 
in  the  neck  and  sacral  region.  They  are  usually  of  congenital  origin  and 
exist  at  birth  or  shortly  develop  into  tumors  of  considerable  bulk  and  wide 
extent. 

Hygroma  cysticum  colli  is  a  lymphangioma  which  usually  arises  in  the 
submaxillary  region  and  ramifies  upward  towrard  the  parotid  and  ear,  inward 
toward  the  median  line,  and  downward  to  the  supraclavicular  fossa  and  even 
into  the  pleura  and  mediastinum  (Nasse,  Suckstorff).  One  class  of  these 
tumors  occurs  deep  in  the  neck,  reaches  below  the  sternal  notch  and  seems 
to  be  connected  with  the  thyroid  (Otto).  In  one  case  which  came  to  my 
notice  the  cyst  lay  close  to  the  trachea  and  reached  from  the  sternal  notch  to 
the  inferior  thyroid  artery.  Lymphangioma  of  the  neck  must  be  distinguished 
from  hydrocele  colli,  which  is  a  simple  dilatation  in  a  branchial  cleft,  lined 
by  epithelium  and  walled  by  fibrous  tissue  containing  lymphoid  tissue  (Fro- 
benius).  The  axilla  and  thoracic  wall  are  occasionally  the  seat  of  cystic 
lymphangioma  (Nasse).  Bilateral  congenital  cystic  lymphangioma  of  the 
back  of  the  neck  has  been  described  by  Frobenius. 

Retro  peritoneal  and  mesenteric  lymphangioma  occurs  in  children  and  adults 
as  a  multilocular  cavernous  and  cystic  tumor,  originating  along  the  spinal 
column  and  ramifying  into  the  pelvis  behind  the  kidney  or  colon,  upward  to 
the  liver,  spleen  and  pancreas,  and  into  the  mesentery  or  omentum  (Takano, 
Lit.).  The  receptaculum  chyli  and  thoracic  duct  have  been  found  unaffected 
by  the  process  (Sick,  Smoler,  Schwarzenberger) .  Lion  has  reported  a  case 
of  lymph-cyst  of  the  broad  ligament.  In  a  case  of  the  writer's  the  broad 
ligaments  were  chiefly  involved  with  extensions  throughout  the  pelvis  and 
along  the  lumbar  spine. 

The  very  early  stages  and  exact  origin  of  these  tumors  have  not  been 
demonstrated,  and  as  Hedinger  points  out,  they  require  differential  diagnosis 
from  a  variety  of  other  abdominal  cysts.  Their  neoplastic  nature  seems 
assured,  since  the  walls  contain  cellular  connective  tissue,  often  much  smooth 
muscle-tissue,  and  lymph-follicles.  After  partial  removal  the  remaining 
portion  may  rapidly  increase  in  bulk.  Along  the  edges  of  the  growths  Sick 
found  proliferating  areas  of  cavernous  lymphangioma.  He  assumes  that 
they  arise  from  misplaced  and  embryonal  islands  of  connective  tissue  and 
lymph-vessels.  In  the  omentum  and  mesentery  of  newborn  cats  and  pigs 
Ranvier  has  demonstrated  such  misplaced  islands  of  tissue. 

In  the  wall  of  the  stomach  and  gastrohepatic  ligament  Reimers  and  Tilger 
have  found  small  lymph-cysts  which  they  referred  to  obstruction  of  vessels 
following  gastric  ulcer. 


ANGIOMA 


239 


Sacral  hygroma  is  a  cystic  tumor  developing  in  the  region  of  the  sacrum 
and  usually  connected  with  defects  in  the  spinal  canal.  Some  of  them  are 
probably  aberrant  meningoceles.  Borst  found  a  large  multilocular  cystic 
tumor  in  front  of  a  defective  sacrum  and  connected  by  a  strand  of  tissue  with 
the  spinal  canal.  Virchow  described  an  external  pedunculated  hygroma 
attached  to  the  sacrum  of  a  negro  infant  and  containing  a  lymph-cyst  and 
portions  of  nervous  tissue.  Attached  by  a  pedicle  to  the  liver  of  a  child  of 


FIG.  74. — Papillary  growth  in  a  cervical  lymph-node  which  was  the  seat  of  chronic 
lymph  stasis.     Papillary  nbro-endothelioma. 

5  years   Maresch  found  a  large  cavernous  and  cystic  lymphangioma.     In 
the  adrenal  and  in  the  uterine  musculature  lymph-cysts  have  been  described 

by  Sick. 

In  the  ovary  Kroemer  finds  lymphangioma  of  small  dimensions  not  in- 
frequent. Besides  telangiectatic  fibroma  he  describes  two  large  cystic  lymph- 
angiomas,  in  one  of  which  the  endothelial  cells  were  prominent,  suggesting  the 
designation  fibro-endothelioma. 


CHAPTER  XVII 
SARCOMA 

General  Characters. — Sarcoma  is  a  malignant  tumor  composed  of  cells 
of  the  connective-tissue  type. 

This  definition  is  based  on  the  morphology  of  the  tumor-cells  and  on  their 
histogenesis.  It  accomplishes  the  main  object  of  separating  a  large  group 
of  malignant  tumors  from  the  carcinomas,  but  it  overrides  certain  embryo- 
logical  considerations. 

Thus  it  permits  the  inclusion  of  gliosarcomas  which  are  of  ectodermal 
origin,  and  it  accepts  as  sarcoma  certain  tumors,  chiefly  of  endothelial  origin, 
while  rejecting  others.  This  portion  seems  justified  by  the  history  of  the 
development  of  the  conceptions  of  sarcoma,  as  ably  sketched  by  Malherbe, 
by  certain  anatomical  and  clinical  features  of  the  group,  and  by  the  peculiar 
part  played  by  the  blood-vessels  in  the  growth  of  many  sarcomas.  Never- 
theless, it  cannot  be  claimed  that  the  effort  to  stretch  the  scope  of  the  term 
"sarcoma"  over  an  extensive  field  of  neoplasms  has  been  entirely  successful. 

The  diseases  included  in  this  group,  such  as  angiosarcoma,  lymphosarcoma, 
and  gliosarcoma,  are  of  such  varied  origin  and  character  that  some  writers 
have  urged  the  elimination  of  the  term  sarcoma.  This  radical  reform  has 
not  received  approval,  since  there  are  many  common  features  among  sarcomas 
and  the  group  as  a  whole  is  well-defined  from  carcinomas.  Yet  future  investi- 
gation will  doubtless  reveal  many  new  and  more  precise  facts  regarding  the 
etiology,  conditions  of  incidence,  histogenesis,  and  clinical  course  which  will 
warrant  the  recognition  of  many  sarcomas  as  specific  pathological  entities. 

The  original  conception  of  sarcoma  as  a  tumor  of  fungating,  soft  or  fleshy 
character  reflected  truly  the  gross  character  of  most  sarcomas,  but  the  defini- 
tion based  on  histogenesis  is  much  more  significant.  Even  this  conception 
of  sarcoma  we  believe  is  destined  to  be  replaced  by  etiological  criteria. 

Since  there  is  often  much  difficulty  in  determining  the  origin  of  cellular 
tumors  the  accepted  scope  of  sarcomas  has  been  subject  to  much  revision. 
In  recent  years,  especially,  many  tumors  once  interpreted  as  sarcomas  have 
been  proved  to  be  of  epithelial  origin.  Further  inroad  has  resulted  from  the 
identification  as  endotheliomas,  of  many  tumors  once  regarded  as  sarcoma, 
but  it  appears  unlikely  that  the  separation  between  the  latter  groups  will 
be  rendered  complete. 

In  fact,  the  finer  analysis  of  the  origin  and  composition  of  many  sarcomas 
reveals  a  prominent  participation  of  endothelium  in  many  tumors  of  distinct 
mesoblastic  characters.  In  such  cases  the  characters  of  the  tumor-cells  rather 
than  their  embryonal  antecendents  should  determine  the  classification. 

Even  the  spindle-cell  sarcomas  have  not  escaped  suspicion,  especially 
in  epithelial  organs,  since  it  is  a  fact  too  often  ignored  that  squamous  and 
glandular  epithelium  may  assume  a  fusiform  shape  during  the  vicissitudes  of 
tumor  growth. 

Gross  Anatomy. — The  majority  of  sarcomas  are  bulky,  soft,  and  vascular. 
In  general,  the  bulky  character  results  from  the  principle  that  sarcomas  tend 
to  grow  expansively  upon  a  scaffolding  of  new  blood-vessels  rather  than  to 
infiltrate  preexisting  tissues  as  do  carcinomas.  The  soft  consistence  reflects 
the  cellular  structure  of  a  rapidly  growing  tumor.  The  vascularity  reveals 

240 


SARCOMA  241 

to  the  naked  eye  the  prominence  of  blood-vessels  as  an  essential  part  of  the 
growth. 

Some  specific  varieties  of  sarcoma  fail  to  display  the  usual  features.  Fibro- 
sarcoma  is  firm,  resistant,  and  non- vascular;  osteogenic  sarcoma  may  be 
as  hard  as  ivory.  In  fact,  there  are  so  many  variations  in  the  appearance 
of  sarcoma  that  general  statements  are  of  little  value  and  the  gross  characters 
are  best  detailed  in  connection  with  specific  tumors.  As  a  rule  the  gross 
appearance  depends  largely  upon  the  tissue  of  origin,  according  to  which 
one  recognizes  fibrosarcoma,  chondrosarcoma,  osteosarcoma,  liposarcoma, 
myxosarcoma,  angiosarcoma,  myosarcoma,  and  lymphosarcoma.  All  adult 
mesoblastic  derivatives  are  represented  in  the  tissues  of  origin.  Gliosarcoma 
occupies  an  especially  peculiar  position.  While  its  cells  of  origin  are  derived 
from  neural  epithelium,  the  form  and  function  of  the  adult  glia-cells,  and 
especially  the  characters  of  the  tumors,  do  not  encourage  efforts  to  reform 
current  nomenclature  in  this  group. 

Sarcomas  are  usually  single,  but  multiple  tumors  arise  in  bone-marrow, 
nerve-trunks,  and  skin.  Certain  angiosarcomas  are  multiple  or  diffuse,  and 
some  forms  represent  systemic  diseases,  as  lymphosarcoma  and  myeloma. 

Characters  of  Growth.— The  growth  of  sarcomas  is  usually  rapid  and 
locally  destructive.  The  abundant  blood-supply  favors  extremely  active 
cell  growth,  so  that  the  tumors  soon  reach  a  large  size,  and  their  bulk  is  often 
sharply  increased  by  edema,  hemorrhage,  or  mucoid  degeneration.  After 
reaching  a  certain  limit  the  excessive  circulation  fails  and  large  areas  of 
necrosis  form  from  infarction.  The  further  growth  of  the  tumor  then  depends 
on  its  capacity  to  infiltrate  or  produce  metastases. 

Hence  some  sarcomas  regress  after  extensive  central  necrosis  and  not  a 
few  are  remarkably  susceptible  to  toxic  agents  or  to  absorbents  such  as  x-ray 
or  iodid  of  potash.  Hemorrhage  from  the  fragile  vessels  is  prominent  in 
many  vascular  tumors.  Into  the  extravasated  blood-mass_  sarcoma-cells 
are  often  observed  to  grow,  replacing  the  clot. 

Following  necrosis,  sarcomatous  tissue  is  very  susceptible  to  infection 
and  many  cases  terminate  with  local  suppuration  and  gangrene  or  with  general 
sepsis.  Accordingly,  fever  is  often  observed  throughout  the  course  of  malig- 
nant sarcomas,  but  in  some  instances  it  appears  to  result  from  specific  intoxi- 
cation and  not  from  infection. 

Most  sarcomas  grow  expansively,  the  central  portions  increasing  with 
the  peripheral.  Hence  they  are  rather  sharply  marked  off  from  the  surround- 
ing tissue,  although  rarely  presenting  a  capsule. 

Infiltrative  growth  on  the  periphery  fuses  the  tumor  with  the  surround- 
ing tissue  so  that  it  is  difficult  to  extirpate  and  commonly  recurs  after  opera- 
tion. The  more  malignant  growths  infiltrate  widely  through  fascial  planes, 
along  vessels  and  nerves  and  directly  through  the  soft  tissues.  Penetration 
of  the  skin  is  followed  by  more  rapid  fungating  growth  with  ulceration  and 
hemorrhage.  Cellular  bone-sarcomas  rapidly  destroy  bony  tissue  and  perfor- 
ate joint  cavities.  To  the  attack  of  other  sarcomas  bone  is  resistant.  I  have 
observed  very  wide  infiltration  of  a  spindle-cell  periosteal  sarcoma  which 
produced  a  large  tumor  of  the  ilium  and  spread  beneath  the  periosteum  over 
the  entire  ilium,  pubes,  and  upper  third  of  the  femur.  The  extensions  of 
lymphosarcoma  and  of  myeloma  are  partly  by  infiltration  and  largely  by 
systemic  development  of  new  tumors. 

Metastases  are  observed  in  the  advanced  stages  of  most  sarcomas  and 

it  is  characteristic  of  the  disease  that  with  rare  exceptions  the  embolic  cells 

travel  through  the  blood-vessels.     Except  in  lymphosarcoma  the  occurrence 

of  metastases  in  lymph-nodes  justifies  the  suspicion  that  the  tumor  is  not  a 

16 


242  NEOPLASTIC  DISEASES 

sarcoma.  The  strong  tendency  of  sarcoma-cells  to  grow  upon  a  framework 
of  blood-vessels  determines  the  early  invasion  of  these  vessels  which  occurs 
even  in  sclerosing  osteogenic  sarcoma,  while  the  expansive  growth,  as  opposed 
to  the  infiltration  of  preexisting  tissues  in  carcinoma,  explains  the  usual  failure 
to  invade  lymphatics.  Sarcoma  tissue  itself  is  usually  devoid  of  lymphatics. 

Cell-emboli  thus  pass  readily  into  the  vessels  and  lodge  first  in  the  lungs 
which  are  the  chief  seat  of  sarcoma tous  metastases,  and  later  they  reach 
liver,  kidney,  spleen,  and  other  organs  and  tissues. 

General  miliary  sarcomatosis  may  result  from  discharge  of  very  numerous 
loose  cells,  but  it  is  much  less  frequent  than  general  carcinomatosis.  Mechan- 
ical pressure  of  actively  growing  sarcoma  sometimes  forces  tumor-tissue 
into  the  blood-vessels  and  thus  leads  to  metastases  when  the  infiltrating 
power  and  capacity  for  independent  growth  of  the  cells  appears  to  be  limited. 
Thus  myxosarcoma  of  the  thigh  may  be  forced  into  the  saphenous  and  iliac 
veins  and  form  a  continuous  mass  filling  vena  cava,  pulmonary  veins,  and 
even  reaching  the  heart.  The  same  extensions  of  sarcoma  of  the  kidney  have 
been  observed. 

Some  sarcoma-cells  seem  comparatively  resistant  to  any  destructive 
influence  that  may  be  exerted  by  the  blood.  They  have  frequently  been 
found  in  the  peripheral  blood.  In  the  blood-vessels  invaded  by  sarcoma 
thrombosis  is  not  as  common  as  in  carcinoma.  Borst  states  that  they  have 
a  certain  capacity  to  grow  in  the  lumen  without  connection  with  the  vessel 
wall.  These  considerations  may  tend  to  explain  the  frequency  of  metastases 
by  blood-vessels.  The  metastases  of  sarcoma  often  occur  much  earlier  than 
is  generally  conceived,  and  this  fact  adds  to  the  gravity  of  the  prognosis  after 
surgical  operation.  In  a  considerable  series  of  cases  at  the  Memorial  Hospital 
the  #-ray  photograph  of  the  lungs  has  revealed  pulmonary  nodules  in  appar- 
ently operable  cases,  especially  of  bone  sarcoma,  and  in  not  a  few  which  had 
just  recovered  from  operation. 

Structure. — Sarcomas  are  chiefly  histioid  tumors.  With  the  exception 
of  mixed  or  teratoid  growths,  a  definite  arrangement  of  elements  in  organoid 
form  is  missing.  Yet  considerable  differentiation  of  tissues  occurs  in  the 
more  mature  types.  Fibrosarcoma  may  present  areas  resembling  cellular 
connective  tissue;  bony  trabeculae  appear  in  many  osteosarcomas;  embryonal 
fat  tissue  occurs  in  liposarcoma;  while  angiosarcoma  produces  many  func- 
tionating blood-vessels. 

With  increasing  anaplasia  the  form  and  function  of  the  originating  cells 
are  gradually  lost. 

The  controlling  factor  in  the  structure  of  sarcomas  is  found  in  the  natural 
tendencies  of  the  cells  of  origin  to  reproduce  the  mother  tissue.  Many  authors 
have  traced  in  the  growth  of  sarcoma  a  repetition  of  the  embryonal  develop- 
ment of  the  affected  tissue. 

In  many  cases  the  origin  of  the  tumor  is  readily  determined  by  the  presence 
of  cellular  connective  tissue,  cartilage,  bone,  or  fat. 

In  other  cases  the  tumor  is  highly  cellular  and  reveals  few  traces  of  the 
original  form  or  function  of  its  cells,  and  in  the  most  anaplastic  types  the 
cells  are  round  and  completely  undifferentiated. 

According  to  cell  form,  sarcomas  may  be  divided  into  spindle-cell,  round- 
cell,  and  giant-cell  groups,  but  these  terms  convey  little  information,  and, 
unless  the  tissue  or  origin  can  be  stated,  no  significant  diagnosis  has  been 
reached.  Since  any  one  of  the  three  above  types  of  structure  may  arise  in  sar- 
comas from  each  mesoblastic  tissue,  it  is  desirable  to  avoid  terms  referring 
solely  to  the  morphology  of  the  cells. 

According   to   histogenesis   sarcomas   may   be   classified   as   fibroblastic, 


SARCOMA  243 

angiosarcoma,  chondrosarcoma,  osteosarcoma,  liposarcoma,  myosarcoma, 
myxosarcoma,  lymphosarcoma,  and  gliosarcoma.  In  typical  cases  the  struc- 
ture of  each  of  these  forms  is  specific. 

In  general,  the  structure  of  sarcomas  presents  an  imperfect  development 
of  the  tissue  of  origin.  The  cells  are  usually  larger  and  always  more  numerous. 
Very  large  spindle-cells  belong  chiefly  to  malignant  fibroblastic,  angioblastic, 
and  myxosarcomas.  Quite  small  spindle-cells  also  appear  in  tumors  of  these 
same  origins.  Giant-cells  of  various  types  appear  in  many  sarcomas,  especially 
in  the  tumors  of  bone  and  smooth  muscle.  In  muscle  they  result  chiefly  from 
hypertrophy  of  tumor-cells;  in  bone-tumors  they  have  been  interpreted  as 
giant  osteoclasts;  in  bone-marrow  tumors  they  are  likened  to  the  myelo- 
plaques;  in  many  cases  they  evidently  form  by  cell  fusion  in  poorly  nourished 
areas;  in  the  epulis  they  represent  fused  endothelium  surrounding  foreign 
material;  while  amitotic  nuclear  division  is  responsible  for  many. 

The  origin  and  significance  of  the  different  forms  of  giant-cells  is  best 
considered  in  connection  with  specific  tumors,  since  in  many  respects  they 


FIG.  75.— Large  spindle-cell  fibroblastic  sarcoma. 


are  peculiar  in  each  tumor  and  form  an  important  means  of  diagnosis. 
Wakabayashi  found  the  same  groups  of  chromosomes  and  lack  of  mitoses  in 
seven  types  of  sarcoma  as  he  observed  in  tuberculosis  and  syphilis.  Howard, 
studying  the  morphology  of  many  giant-cells,  observed  in  the  behavior  of 
the  nuclei  many  resemblances  to  protozoan  nuclei. 

Round-cells  appear  in  lymphosarcoma,  gliosarcoma,  and  myelosarcoma, 
but  it  is  doubtful  if  true  round-cell  tumors  arise  from  any  other  mesoblastic 
tissues.  While  very  cellular  and  anaplastic  growths  composed  of  indifferent 
spheroidal  cells  arise  from  many  tissues,  perfectly  fixed  portions  of  these 
tumors  regularly  show  the  cells  to  be  spindle  or  polyhedral,  and  the  effort 
should  be  made  to  detect  these  features  so  as  to  exclude  the  tumor  from  the 
group  of  true  round-cell  growths. 

Such  distinctions  are,  however,  rarely  attempted  and  the  term  round-cell 
sarcoma"  is  in  very  general  use  and  enjoys  recognition  from  practically  all 
writers.  Malherbe,  however,  separates  sharply  between  round-cell  sarcomas, 
which  he  regards  as  exclusively  lymphoid,  and  true  fibroblastic  tumors. 


244  NEOPLASTIC  DISEASES 

Virchow  stated  that  a  round-cell  tumor  could  safely  be  identified  as  sarcoma 
only  when  a  definite  intercellular  stroma  was  demonstrated.  Borst  describes 
the  cells  of  small  round-cell  sarcomas  as  identical  with  the  round-cells  infil- 
trating granulation  tissue,  but  the  source  of  these  cells  he  left  undetermined. 
Highly  malignant  small  round-cell  tumors  arise  in  the  intermuscular  septa, 
periosteum,  submucous  stroma,  meninges,  skin,  kidney,  testicle,  and  liver 
(Borst),  and  are  said  to  represent  the  highest  degree  of  sarcomatous  degenera- 
tion (Rindfleisch) .  Yet  it  has  never  been  shown  and  appears  unlikely  that 
any  fixed  connective-tissue  cells  in  such  numerous  situations  give  origin  to 
such  tumors. 

From  my  own  observations  I  have  been  forced  to  conclude  that  with  rare 
exceptions  such  round-cell  growths  are  either  lymphosarcomas  or  small  cell 
carcinomas.  They  usually  invade  lymph-nodes. 

It  is  chiefly  among  the  sarcomas  of  bone  that  small  round-cell  tumors 
appear  which  suggest  an  origin  from  periosteal  fibroblasts,  but  here  the 
proximity  of  bone-marrow  provides  a  possible  origin  from  lymphoid  cells. 
Many  of  the  "round-cell"  sarcomas  of  bone  are  diffuse  endotheliomas. 

Much  the  same  uncertainties  surround  the  origin  of  most  of  the  so-called 
large  round-cell  sarcomas.  These  tumors  may,  as  a  rule,  be  divided  among 
endotheliomas,  tumors  of  lymphoid  cells,  carcinomas,  and  sarcomas  of  which 
the  cells  are  not  strictly  round. 

The  round-cell  tumors  of  the  testis  and  thyroid  are  among  the  epithelial 
growths  commonly  misinterpreted  as  large  round-cell  and  alveolar  sarcoma. 

The  nuclei  of  sarcoma-cells  exhibit  the  widest  variations  in  size,  form, 
chromatin  content,  nucleolar  elements,  and  methods  of  division;  all  of  which 
features  reflect  rapid  and  lawless  growth  and  the  accompanying  degenerative 
processes.  All  the  abnormalities  observed  in  carcinoma  cells  are  duplicated 
or  even  exaggerated  in  sarcoma.  In  pronounced  grade  they  are  specific  of 
a  malignant  tumor  process,  but  not  of  sarcoma.  Favre  and  Regaud  find  the 
same  mitochondria  granules  in  sarcoma  cells  as  in  carcinoma. 

Degenerative  changes  in  the  cells  of  sarcoma  occur  chiefly  in  areas  of 
necrosis  from  infarction.  In  actively  growing,  well-nourished  zones  the 
cell  cytoplasm  is  usually  less  subject  to  fatty  and  hydropic  degeneration 
than  in  carcinoma.  Yet  under  appropriate  conditions  the  cells  undergo 
the  usual  forms  of  cytoplasmic  decay.  The  most  common  change  is  a  mucoid 
transformation  of  cells  and  stroma  which  affects  nearly  all  forms  of  sarcoma, 
especially  those  arising  from  connective  tissue.  Extensive  deposits  of  blood- 
pigment  may  lead  to  confusion  with  melanoma.  Calcific  deposits  are  com- 
paratively rare,  except  in  osteogenic  tumors.  Glycogen  is  found  in  the  cells 
of  many  rapidly  growing  sarcomas  (Brault). 

The  arrangement  of  the  cells  reflects  the  structure  of  the  mother  tissue 
and  often  gives  a  clue  to  the  origin,  yet  in  cellular  growths  all  traces  of  the 
originating  tissue  may  be  lost.  Prominent  in  many  sarcomas  is  the  tendency 
of  the  cells  to  grow  about  blood-vessels  simulating  the  type  of  angiosarcoma 
or  perithelioma.  The  specific  structure  of  these  latter  tumors  may  be  all 
but  duplicated  by  tumors  which  have  no  angioblastic  relations  whatever. 
On  the  growing  edges  of  infiltrating  sarcomas  the  cells  are  commonly  gathered 
about  the  small  blood-vessels.  A  true  alveolar  arrangement  is  rarely  if  ever 
assumed  by  sarcomas.  While  it  cannot  be  asserted  that  the  small  spheroidal 
or  polyhedral  sarcoma-cells  never  appear  in  groups  surrounded  by  stroma, 
the  history  of  most  alveolar  sarcomas  has  terminated  in  their  identification 
as  carcinomas  or  endotheliomas. 

The  stroma  of  sarcomas  is  derived  from  remnants  of  preexisting  tissue, 
from  blood-vessels  appropriated  for  the  nutrition  of  the  tumor  or  new  formed 


SARCOMA  245 

as  an  integral  part  of  the  neoplasm,  and  from  the  specific  intercellular  sub- 
stance derived  from  the  tumor-cells.  In  relatively  adult  growths  an  inter- 
cellular stroma  is  regularly  laid  down  by  the  cells,  and  in  tumors  of  bone, 
cartilage,  mucoid  tissue,  and  glia-tissue  it  may  form  an  easily  recognized 
element.  Yet  in  very  cellular  tumors  the  attempt  to  demonstrate  a  stroma 
commonly  fails,  and  it  would  appear  that  the  diagnostic  significance  of  this 
element  in  sarcomas  has  been  overstated.  W.  C.  White  found  a  fine  inter- 
cellular reticulum  very  constant  in  sarcomas,  but  absent  in  carcinomas.  He 
identifies  the  reticulum  of  lymphosarcoma  with  white  fibrous  tissue.  Seelig, 
in  specimens  digested  by  pancreatin,  found  a  rather  abundant  fine  reticulum 
in  many  sarcomas,  but  failed  to  note  any  constant  differences  in  the  reticulum 
of  lymphosarcoma  from  that  of  other  round-cell  sarcomas.  Bielschowsky's 
stain  is  particularly  effective  in  demonstrating  a  reticulum  in  sarcoma  as 
well  as  in  carcinoma. 

The  blood-vessels  form  the  most  important  part  of  the  stroma.  They 
are  of  various  forms  and  sources.  Following  the  analogy  with  granulation 
tissue  the  blood-vessels  may  represent  elongations  of  those  of  the  originating 
tissue  about  which  the  tumor-cells  grow.  Such  vessels  may  be  venous, 
arterial  or  capillary,  and  their  walls  are  composed  of  adult  normal  cells.  In 
the  course  of  their  growth  they  may  become  varicose  or  sinusoidal  and  the 
walls  thin  and  fragile.  Some  of  the  well-formed  vessels  are  probably  appro- 
priated directly  from  the  invaded  tissue.  As  the  tumor  develops,  the  ad- 
ventitia  of  the  vessels  is  lost  in  the  stroma  of  the  neoplasm.  Eventually, 
nothing  but  a  swollen  endothelial  cell  separates  blood-current  from  tumor- 
tissue.  Malherbe  describes  the  apparent  sarcomatous  transformation  of  the 
muscle-cells  of  vessel  walls  and  points  out  the  diagnostic  importance  of  the 
swollen  condition  of  the  cells  in  the  vessel  walls  of  sarcoma.  Many  blood- 
spaces  and  channels  appear  to  be  formed  by  modified  tumor-cells,  but  such 
structures  are  extremely  fragile  and  leave  the  tumor-tissue  subject  to  inter- 
stitial hemorrhage. 

In  a  large  group  of  angiosarcomas  and  of  peritheliomas  the  tumor-cells 
exhibit  true  angioblastic  properties  and  the  tumors  are  composed  essentially 
of  a  congeries  of  very  cellular  blood-vessels. 

The  continued  growth  of  most  sarcomas  is  closely  dependent  upon  the 
capacity  of  the  cells  to  excite  the  development  of  blood-vessels. 

Where  the  vascular  channels  fail,  growth  ceases,  and  when  they  become 
occluded  anemic  necrosis  promptly  follows.  Yet  some  very  cellular  actively 
growing  small  spindle-cell  sarcomas  contain  few  vessels. 

Lymph  circulation  in  sarcomas  is  very  deficient  and  according  to  Ziegler 
lymph-vessels  cannot  be  demonstrated.  Yet  in  some  varieties  clefts  and 
canals  appear  which  probably  represent  lymph  pockets  or  channels,  and  some 
cutaneous  sarcomas  have  abundant  lymph- vessels  (Unna).  Nerve-trunks 
invaded  by  sarcoma  undergo  pressure  atrophy. 

In  neurosarcomas  fragments  of  myelin  sheaths  and  axis-cylinders  may 
long  persist.  Definite  new  formation  of  nerve-fibers  in  sarcoma  has  not  been 
demonstrated. 

Etiology. — Of  the  specific  etiology  of  sarcoma  little  is  definitely  known. 
These  tumors  demonstrate  the  very  great  proliferative  capacity  of  meso- 
blastic  cells  released  from  the  restraints  to  growth.  This  capacity  may  reason- 
ably be  estimated  as  even  greater  than  with  most  epithelial  tissues. 

It  is  commonly  assumed  that  normal  adult  cells  are  incapable  of  such 
great  proliferation  as  occurs  in  sarcoma,  and  the  further  assumption  is  then 
necessitated  that  sarcomas  as  a  rule  grow  from  isolated,  or  superfluous,  or 
embryonal  cell  groups.  Thus  when  trauma  is  followed  by  an  extremely  mahg- 


246  NEOPLASTIC  DISEASES 

nant  bone-sarcoma,  the  violent  explosion  of  growth  capacity  seems  to  require 
some  element  which  is  not  attributable  to  normal  cells  regenerating  after 
contusion.  The  raiity  of  any  definite  observations  of  the  beginnings  of  such 
sarcomas  is  a  strong  defense  of  this  hypothesis.  Moreover,  there  are  many 
instances  in  which  sarcomas  are  known  to  arise  from  isolated  or  embryonal 
cell  groups,  especially  in  the  mixed  tumors  of  teratoid  type. 

On  the  other  hand,  it  may  be  urged  that  the  regenerative  capacities  of 
mesoblastic  cells  are  very  great,  especially  in  youth  when  most  sarcomas 
occur.  It  must  be  admitted  that  the  existence  of  isolated  cell  groups  as  the 
source  of  many  sarcomas  has  not  been  proved. 

Sarcoma  has  been  observed  to  follow  x-ray  injury  in  rats,  and  in  mice 
the  continued  growth  of  carcinoma  is  said  to  have  excited  sarcomatous  pro- 
liferation of  the  tumor-stroma.  Finally,  increasing  observations  of  very 
early  sarcomas  and  of  presarcomatous  lesions  of  inflammatory  origin  favor 
the  view  that  sarcomas  often  arise  from  previously  normal  adult  cells. 

It  is  clear  that  no  general  rule  can  be  applied  in  this  field  and  that  the 
evidence  must  be  worked  out  separately  in  each  form  of  sarcoma. 

Presarcomatous  Lesions. — The  occurrence  of  atypical  productive  in- 
flammatory lesions  leading  to  sarcoma  must  be  regarded  as  fully  in  accord 
with  established  views  regarding  the  nature  of  sarcoma.  Many  sarcomas 
show  such  marked  histological  resemblances  to  inflammatory  processes  that 
pathologists  have  long  been  inclined  to  accept  in  a  certain  sense  the  inflam- 
matory or  even  the  parasitic  origin  of  certain  sarcomas.  The  lymphosar comas 
especially  stand  in  this  position,  and  Borst,  among  others,  anticipates  the 
ultimate  identification  of  this  group  of  neoplasms  with  the  infectious  granu- 
lomas.  In  such  an  event  the  sarcoma  must  be  regarded  as  an  indirect  result 
of  the  parasite,  much  as  some  carcinomas  are  an  indirect  sequel  of  chronic 
irritation.  Syphilis  and  tuberculosis  are  the  most  prominent  infections  which 
lead  to  sarcoma. 

Relation  of  Tuberculosis  and  Syphilis  to  Lymphosar  coma. — Clinical  observa- 
tions have  long  indicated  that  tuberculous  lymphadenitis  may  pass  rapidly 
or  after  several  recurrences  into  lymphosarcoma.  Ricker  in  a  case  terminat- 
ing after  14  years  found  typical  tuberculosis  associated  with  lymphosarcoma 
of  neck,  lungs,  adrenals,  and  spinal  cord.  Miiller  saw  general  sarcomatosis 
from  a  primary  tumor  of  the  breast,  miliary  tubercles  being  nearly  coexten- 
sive with  wide-spread  sarcomatous  tumors.  The  rather  frequent  discovery 
of  tubercle  bacilli  in  lesions  supposed  to  be  pure  lymphosarcoma  suggests 
that  a  very  slight  difference  separates  some  of  such  tumors  from  the  immedi- 
ate or  distant  presence  of  tubercle  bacilli  or  their  toxins.  I  have  followed 
a  case  of  cervical  tumors  originally  tuberculous,  recurring  four  times  in  6 
years  and  terminating  with  the  picture  of  endothelioma  of  lymph-nodes. 
In  this  study  it  was  shown  that  an  infectious  granuloma  may  cause  prolifera- 
tion of  the  reticulum  cells,  producing  large-cell  lymphosarcoma,  or  of  the 
sinus  endothelium  producing  endothelioma  of  lymph-nodes,  and  it  was  also 
shown  that  exactly  similar  tumors  of  lymph-nodes  occur  in  the  axilla  without 
any  histological  evidence  of  granuloma.  Various  diphtheroid  bacteria  may 
be  isolated  from  such  tumors. 

The  transformation  of  Hodgkin's  granuloma  into  sarcoma  has  been  de- 
scribed by  various  authors,  but  I  have  found  evidence  that  most  of  these 
tumors  arise  from  the  thymus  where  again  they  are  implicated  with  granuloma. 

The  difficulty  of  distinguishing  from  sarcoma  certain  late  syphilitic  lesions 
in  bone  and  muscle  is  mentioned  by  many  authors,  especially  by  v.  Hanse- 
mann.  The  clinical  diagnosis  of  syphilis  is  rendered  difficult  by  the  recurrence 
of  the  lesions  after  operation,  by  their  multiplicity,  and  by  the  resistance  to 


SARCOMA 


247 


syphilitic  treatment,  while  the  structure  presents  very  marked  cellular  over- 
growth of  round-cells  or  spindle-cells.  Yet  the  syphilitic  process  tends  toward 
necrosis  and  cicatrization  rather  than  progressive  growth.  There  are  many 
indications  that  true  sarcoma  develops  from  such  lesions,  but  satisfactorV 
proof  is  lacking. 

In  the  healing  of  fractures  and  of  wounds  of  the  periosteum  the  histolog- 
ical  picture  shows  very  active  growth  of  bone,  giant-cells  and  connective- 
tissue  cells,  and  regenerating  capillaries,  and  may  distinctly  resemble  sar- 
coma. The  actual  transition  into  sarcoma  has  not  been  traced. 

Traumatic  myositis  ossificans  appears  to  occupy  a  position  intermediate 
between  inflammatory  and  neoplastic  processes  (Berndt).  The  clinical 


FIG.  76. — Structure  of  rapidly  forming  callus  developing  in  muscle  tissue  2  weeks  after 
fracture  of  clavicle.     Note  resemblance  to  osteogenic  sarcoma. 


history  of  established  cases  is  that  of  a  self-limiting  productive  inflamma- 
tion, but  the  histology  of  the  early  lesions  may  be  difficult  to  distinguish 
from  bone-sarcoma.  It  appears  that  the  division  of  cases  is  accidental,  some 
of  the  lesions  progressing  as  myositis,  others  going  on  as  traumatic  sarcoma. 
I  have  observed  the  two  conditions  combined.  Central  giant-cell  sarcoma  of 
bone  has  often  been  interpreted  as  a  form  of  productive  inflammation,  but  its 
various  phases  show  every  gradation  from  the  benign  to  a  malignant  process. 
Kolisko  finds  that  osteitis  fibrosa  may  be  followed  by  progressive  changes 
leading  to  giant-cell  sarcoma  of  moderate  malignancy. 

Many  clinical  observations  point  to  the  development  of  sarcoma  from 
granulation  tissue,  and  the  histological  study  of  granulation  tissue  and  of 


248  NEOPLASTIC  DISEASES 

organizing  blood-clots  occasionally  reveals  pictures  which  closely  approach 
the  structure  of  sarcoma.  Heukelom  has  traced  in  considerable  detail  the 
gradual  transformation  of  the  cells  of  granulation  tissue  into  sarcoma-cells. 
Occasionally  one  finds  small  tumors  following  trauma  and  containing  much 
blood-pigment,  of  which  the  structure  is  distinctly  sarcomatous. 

Against  the  hypothesis  of  the  origin  of  sarcoma  from  previously  normal 
cells  stands  the  opinion  of  Birch-Hirschfeld,  Borst,  and  others  that  sarcomas 
do  not  develop  from  previously  normal  cells,  but  from  embryonal  cell  groups. 
This  view  must  be  regarded  as  an  hypothesis  without  adequate  proof.  Acker- 
mann  was  unable  to  find  any  evidence  of  the  origin  of  a  series  of  sarcomas 
from  embryonal  cells. 

It  seems  highly  probable  that  sarcomas,  like  carcinomas,  arise  through 
exaggerated  inflammatory  and  regenerative  overgrowth  of  tissue-cells.  While 
in  many  cases  the  cells  of  origin  are  adult,  theoretical  considerations  suggest 
that  in  some  instances  they  are  embryonal. 

In  the  former  group  only  would  specific  presarcomatous  stages  be  expected. 

The  clinical  transformation  from  benign  into  malignant  mesoblastic 
tumors  has  repeatedly  been  observed,  but  the  exact  nature  of  the  changes  is 
somewhat  uncertain.  There  is  no  doubt  that  in  a  small  proportion  of  cases 
of  fibroma,  uterine  myoma,  neurofibroma,  and  lymphangioma,  a  long-stand- 
ing and  quiescent  tumor  eventually  displays  rapid  growth  and  the  structure 
proves  highly  cellular  and  malignant.  In  rare  instances  there  is  every  indica- 
tion that  the  slowly  growing  cells  have  taken  on  greatly  increased  powers  of 
growth.  In  other  cases  it  has  been  assumed  that  the  malignant  process  arises 
de  now  in  some  element  of  the  tumors,  as  the  blood-vessels.  For  the  assump- 
tion that  the  sarcoma  develops  from  embryonal  cell  groups  included  in  the 
benign  tumors  there  seems  to  be  very  insufficient  basis. 


CHAPTER  XVIII 
CLINICAL  TYPES  OF  SARCOMA 

Spindle-cell  Sarcoma;  Fibroblastic  Sarcoma.— This  common  tumor 
represents  the  purest  form  of  fibroblastic  neoplasm.  It  is  of  wide-spread 
occurrence,  developing  in  nearly  all  situations  where  supporting  connective 
tissue  is  found.  The  chief  locations  are  in  the  subcutaneous  and  submucous 
tissues,  the  fasciae  and  muscles,  periosteum,  and  in  the  parenchymatous 
organs. 

In  the  gross  these  tumors  are  usually  single,  but  occasionally  multiple. 
The  form  is  rounded  or  lobulated  and  the  borders  are  not  sharply  marked. 
The  consistence  is  hard  in  the  fibrous  and  small  cell-growths,  softer  and  more 
elastic  with  the  large  cell-tumors.  The  hard  tumors  are  opaque  and  non- 
vascular,  the  soft  ones  are  vascular,  succulent,  reddish,  and  variously  altered 
by  secondary  changes.  The  minute  markings  are,  as  a  rule,  not  distinctive. 
In  size  one  encounters  very  small  nodules  in  the  earliest  stages  and  bulky 
fungating  and  necrosing  growths  in  the  later  periods.  In  the  skin  they  form 
multiple,  nodular,  or  globular  growths  which  may  become  polypoid. 

The  rate  of  growth  varying  with  the  structure  may  be  very  slow  or  very 
rapid.  Cessation  of  growth  is  rare,  but  cutaneous  tumors  may  be  sponta- 
neously extruded.  Extremely  rapid  and  bulky  tumors  are  observed  espe- 
cially after  injuries.  Being  poorly  circumscribed,  local  recurrence  frequently 
follows  removal  even  with  the  comparatively  benign  forms.  Metastases  in 
lungs,  liver,  and  other  organs  frequently  occur  with  large  cell-growths,  and 
rarely,  as  in  Walter's  case,  one  is  surprised  to  find  secondary  growths  from 
apparently  benign  small  spindle-cell  sarcoma. 

The  structure  falls  into  two  main  classes  which  differ  also  in  their  clinical 
features:  (i)  small,  and  (2)  large  spindle-cell  sarcoma. 

The  small  cell-tumors  are  slowly  growing,  relatively  benign  neoplasms 
which  approach  the  structure  of  fibrosarcoma  on  the  one  hand  and  on  the 
other  may  approximate  the  type  of  large  cell-tumors.  Their  rate  of  growth, 
density,  and  malignancy  usually  accord  with  these  distinctions.  The  large 
cell-tumors  show  more  active  growth,  are  softer,  more  vascular,  readily  suffer 
from  necrosis,  ulceration  and  hemorrhage,  and  often  recur  locally  and  produce 
metastases. 

The  spindle-cells  of  either  type  resemble  fusiform  fibroblasts.  They  are 
much  smaller  than  normal  fibroblasts  and  more  densely  packed  in  the  small 
cell-growths,  but  reach  very  large  dimensions  and  are  loosely  arranged  in 
the  large  cell  type.  The  cytoplasm  is  granular,  opaque,  and  acidophile,  the 
nuclei  vesicular  and  provided  with  one  or  more  small  nucleoli. 

In  the  compact  tumors  cell  borders  are  distinguished  with  difficulty  and 
nuclei  occupy  most  of  the  field,  but  when  the  texture  is  looser  the  cells  exhibit 
elongated  processes  and  an  intercellular  stroma  becomes  visible.  This  stroma 
when  well  developed  is  composed  of  fibroglia  fibrils  demonstrable  by  Van 
Gieson's  or,  better,  by  Mallory's  stain.  It  may  become  abundant  or  be  re- 
duced to  a  trace  or  be  altogether  absent.  Much  of  it  radiates  from  the  blood- 
vessels. Its  diagnostic  importance  is  not  great.  Besides  the  specific  stroma  of 
the  tumor,  remnants  of  invaded  tissue  often  appear  and  these  with  the  blood- 
vessels often  determine  the  arrangement  of  the  cells. 

249 


250  NEOPLASTIC  DISEASES 

The  cells  may  run  diffusely,  but  as  a  rule  they  lie  in  broad  bundles  or 
narrower  columns  following  blood-vessels  or  inclosed  in  connective-tissue 
septa,  or  coursing  in  various  directions  so  that  longitudinal,  cross,  and  oblique 
sections  appear  in  the  same  field.  Virchow  and  others  have  employed  many 
terms  to  designate  these  structural  details  as  sarcoma  lamellosum,  fascicula- 
ttim,  trabeculare,  radiare.  As  a  rule  these  features  do  not  give  any  clue  to  the 
histogenesis. 

The  spindle-cell  sarcoma  tends  to  infiltrate  surrounding  tissues,  the  cells 
pushing  their  way  between  fat-cells,  vessels,  or  gland  structures,  all  of  which 
suffer  atrophy.  The  walls  of  vessels  may  be  infiltrated,  penetrated  and  de- 
stroyed, and  since  the  vessels  are  an  easy  prey  metastases  by  these  channels 
are  common  (Goldmann,  Hedinger).  Bone  is  penetrated  by  way  of  the 
Haversian  canals,  and  readily  absorbed. 

The  blood-vessels  of  spindle-cell  sarcoma  increase  with  the  larger  size 
of  the  cells  and  the  more  rapid  growth.  They  present  a  variety  of  structural 
types.  Scanty  but  well-formed  vessels  predominate  in  small  cell-tumors, 
but  in  others  the  vessels  may  be  very  numerous  and  the  walls  are  composed 
of  single  layers  of  endothelial  cells  supported  by  little  or  no  adventitia.  In 
several  forms  the  vascular  paths  consist  of  a  system  of  sinuses  walled  only 
by  tumor-cells.  Thus  hemorrhage  is  common  and  metastases  by  way  of 
blood-vessels  is  facilitated.  While  in  many  cases  the  vessels  appear  not  to 
belong  to  the  neoplastic  process,  as  they  become  more  abundant  the  cells 
usually  appear  hypertrophic  and  their  nuclei  hyperchromatic.  The  indica- 
tions of  lymph-paths  are  usually  wanting,  but  Unna  describes  abundant 
dilated  lymph-spaces  in  certain  cutaneous  sarcomas.  In  defective  lymph- 
paths  v.  Heukelom  saw  a  factor  in  the  pathogenesis  of  sarcoma,  but  Lubarsch 
properly  interprets  the  absence  of  lymph-channels  when  it  exists  as  a  result 
and  not  the  cause  of  the  sarcomatous  process. 

Secondary  changes  in  spindle-cell  sarcoma  are  not  prominent.  Fibrosis 
may  appear  in  slowly  growing  small  cell-tumors  and  an  arrest  of  growth  may 
rarely  be  established.  Wide  fibrous  areas  sometimes  appear  in  large  cell- 
tumors  as  a  local  result  of  occlusion  of  vessels.  More  often  hemorrhage  and 
necrosis  follow  rupture  or  thrombosis  of  vessels,  and  pseudomelanosis  fre- 
quently recalls  old  extravasations  of  blood.  Chronic  edema  affects  old  and 
large  tumors  in  which  venous  stasis  occurs,  and  a  pseudomyxomatous  change 
may  overtake  small  foci  or  the  whole  tumor.  Edema,  fatty  degeneration, 
and  simple  necrosis  combine  to  produce  cysts  with  serous  or  blood-stained 
contents. 

In  many  soft  vascular  tumors  the  cells  are  polymorphous,  small  and  large 
spindle,  polyhedral  and  round-cells  appearing  in  foci  or  throughout.  Such 
growths  are  often  called  round-cell  sarcoma,  but  a  true  round-cell  sarcoma  of 
fibroblastic  origin  probably  does  not  occur.  Likewise  polynuclear  cells  may 
form  and  reach  considerable  dimensions,  but  the  term  "giant-cell  sarcoma"  is 
better  limited  to  other  classes  of  tumors. 

Types  of  nuclear  division  are  extensively  illustrated,  especially  in  the 
large  cell-tumors.  They  occur  in  the  elongated  spindle-cells  and  especially 
in  large  round-cells  mingled  with  them.  Increasing  numbers  of  round-cells 
result  from  multiplication  of  dividing  cells  and  constitute  a  sign  of  malig- 
nancy. Many  of  the  anomalies  of  cell  division  in  tumors  appear  in  the  fibro- 
blastic sarcomas  (Stroebe). 

The  diagnosis  of  spindle-cell  sarcoma  seldom  presents  difficulty,  but  there 
are  some  notable  exceptions  to  this  rule  and  the  proper  terminology  is  still 
a  matter  of  discussion.  Typical  structures  occurring  in  ordinary  situations,  as 
skin,  bone,  etc.,  are  readily  identified.  When  cell-fibrils  become  prominent 


CLINICAL  TYPES  OF  SARCOMA  251 

and  are  of  adult  type  the  tumor  is  relatively  benign  and  deserves  the  designa- 
tion fibrosarcoma.  The  numerous  small  cells  and  abundant  fibrils  serve  to 
distinguish  most  fibrosarcomas  from  cellular  fibromas  which  show  more 
resemblance  to  large  spindle-cell  sarcoma.  From  myosarcoma  the  fibro- 
blastic  tumors  may  be  distinguished  by  their  location,  the  large  vesicular 
nuclei,  and  lack  of  acidophile  quality  of  the  cytoplasm.  Yet  the  myogenous 
origin  of  certain  spindle-cell  sarcomas  has  often  been  suggested  and  is  well 
worthy  of  consideration  (testis,  kidney).  Very  vascular  tumors  may  be 
called  telangiectatic  or  angiosarcoma,  but  the  latter  term  has  repeatedly 
been  condemned  as  wrongly  inferring  an  origin  from  blood-vessels.  The 
malignant  (sarcomatous)  angiomas  have  quite  a  different  structure  and 
origin.  From  typical  perithelioma  the  large  spindle-cell  sarcoma  can  some- 
times be  distinguished  with  difficulty,  but  the  perivascular  units  of  radiating 
cells  and  the  characteristic  large  giant-cells  of  the  former  growth  are  usually 
unmistakable. 

Large  spindle-cell  sarcoma  may  be  closely  simulated  by  various  tumors 
whose  existence  must  be  specially  noted.  Malignant  epithelial  tumors  *of 
the  thyroid  are  very  prone  to  assume  the  spindle-cell  type,  as  do  also  the 
embryonal  forms  of  the  so-called  hypernephroma.  Metastatic  malanoma 
may  appear  as  a  spindle-cell  or  large  round-cell  unpigmented  tumor.  Not 
a  few  epidermoid  carcinomas  present  spindle-cells  throughout  most  of  their 
substance. 

Diffuse  endothelioma  may  exactly  reproduce  the  structure  of  fibroblastic 
sarcoma,  but  the  location  of  the  former  growths,  the  appearance  of  typical 
endothelial  characters  in  small  areas,  the  arrangement  of  the  cells,  and  their 
minute  structure  usually  but  not  always  permit  a  positive  separation  of  these 
closely  allied  types. 

Histogenesis. — In  the  origin  of  spindle-cell  sarcoma  the  adventitial  cells 
of  the  blood-vessels  appear  to  take  a  prominent  part.  The  early  stages  of 
these  tumors  have  many  times  been  traced  to  foci  of  vascular  proliferating 
connective  tissue  which  has  been  identified  on  doubtful  evidence  with  granu- 
lation tissue.  Some  of  these  tumors  appear  to  follow  trauma,  and  the  proc- 
esses which  result  from  solution  of  continuity,  extravasation,  and  absorp- 
tion of  blood  often  bear  considerable  resemblance  to  sarcoma.  In  organizing 
blood-clots  there  may  be  very  active  growth  of  vessels  about  and  into  the 
clot,  and  it  may  be  supposed  that  an  exaggerated  growth  of  these  structures 
leads  in  certain  cases  to  sarcoma.  Likewise  in  some  established  and  sponta- 
neous tumors  the  cells  appear  to  be  derived  from  proliferating  adventitial 
fibroblasts.  Such  appearances  are  rather  frequent  and  occasionally  con- 
vincing, and  Babes  and  Ackermann  have  expressed  the  opinion  that  fibro- 
blastic sarcomas  in  general  originate  from  blood-vessels.  Lubarsch  also 
described  spindle-cell  sarcomas  in  young  subjects  which  on  close  analysis 
reveal  themselves  as  obliterating  cellular  angiomas. 

The  part  played  by  endothelial  cells  in  the  genesis  of  sarcoma  has  been 
variously  estimated,  but  in  the  pure  spindle-cell  tumors  they  are  not  promi- 
nent. Many  endotheliomas,  however,  closely  resemble  this  type  of  sarcoma, 
and  since  it  is  desirable  to  adhere  to  the  fibroblastic  origin  of  spindle-cell 
sarcoma  the  endothelial  tumors  must  be  excluded  from  this  group  as  long  as 
endothelial  characters  are  retained. 

Smooth  muscle  tissue  may  also  give  origin  to  tumors  of  spindle-cells, 
as  in  myosarcoma  uteri,  but  these  tumors  also  must  be  separately  classified. 
The  intermuscular  fasciae  and  the  peri-  and  endomysium  give  rise  to  fibro- 
blastic sarcoma.  Those  occurring  in  the  muscles  of  the  thigh  produce  bulky 
tumors  with  a  notable  tendency  toward  mucoid  degeneration.  It  appears 


252  NEOPLASTIC  DISEASES 

probable  that  in  certain  situations  (e.  g.,  testis)  spindle-cell  sarcoma  repre- 
sents a  one-sided  development  of  teratoma,  but  to  what  extent  this  principle 
applies  elsewhere  remains  to  be  determined. 

Sarcoma  of  the  Skin. — The  skin  is  the  primary  seat  of  a  variety  of  sarcomas 
or  sarcomatoid  processes,  the  exact  nature  and  position  of  which  have  not 
been  determined. 

Some  of  these  are  of  spontaneous  origin,  extend  by  displacement  of  normal 
tissues,  grow  progressively,  produce  metastases  and  cachexia,  exhibit  the 
definite  histology  of  a  malignant  tumor  usually  composed  of  spindle-cells, 
and  belong  clearly  in  the  group  of  sarcomas.  Others,  while  producing  single 
or  multiple  tumor-like  growths,  progress  by  infiltrating  the  tissues,  may 
often  regress  or  disappear,  do  not  produce  metastases  although  appearing  in 
numerous  foci,  and  they  present  in  their  earliest  stages  or  throughout  the 
histology  of  an  inflammatory  lesion  which,  however,  may  sometimes  assume 
a  more  or  less  distinct  neoplastic  character.  These  conditions  are  often  called 
sarcoids  of  the  skin. 

Of  the  latter  group  many  types  have  been  described  (Pollard,  Lit.),  of 
which  some  have  been  finally  disposed  of  among  infectious  granulomas. 
Such  are:  (i)  mycosis  fungoides,  types  of  which  are  often  mistaken  for  sarcoid 
(Paltauf) ;  (2)  multiple  benign  sarcoid  of  Boeck,  which  proves  to  be  a  form  of 
tuberculosis;  (3)  various  cases  of  benign  sarcoid  which  consist  of  diffuse  lympho- 
cytic  infiltrations,  and  which,  while  sometimes  reaching  considerable  dimen- 
sions, show  a  distinct  tendency  toward  regression  (Spiegler,  Joseph,  Pollard). 
Numerous  other  peculiar  cases  have  failed  to  receive  a  final  interpretation. 

The  chief  general  significance  of  the  study  of  these  cases  lies  in  the  evi- 
dence which  they  offer  that  various  inflammatory  conditions  may  closely 
approach  the  true  sarcomatous  process.  Spontaneous  regression  is  perhaps 
not  a  sufficient  ground,  as  Fano  claims,  for  the  exclusion  of  such  processes 
from  the  group  of  tumors,  since  other  true  sarcomas  may  occasionally  regress, 
but  the  entire  clinical  and  histological  picture  justifies  the  current  view  that 
these  processes  are  pseudoneoplasms.  Not  clearly  separable  from  the  re- 
gressing sarcoids,  but  distinguished  from  them  by  its  capacity  to  develop  gen- 
uine malignant  tumor  characters  is  the  multiple  hemorrhagic  sarcoma  of 
Kaposi. 

Multiple  Hemorrhagic  Sarcoma  (Kaposi). — This  interesting  malady, 
first  fully  described  by  Kaposi  in  1872,  has  attracted  much  interest  from 
dermatologists.  Recently  the  data  have  been  fully  analyzed  by  Mariani. 

Observed  chiefly  in  southern  Europe,  in  elderly  subjects,  it  exhibits  a 
definite  relation  to  certain  predisposing  factors,  as  general  or  local  vascular 
lesions,  sclerosis,  ectasiae,  hemorrhagic  diathesis,  edema,  and  to  trauma  and 
alcoholism.  A  prodromal  stage  is  marked  by  local  cyanosis,  edema  and 
slight  inflammation,  or  by  definite  vascular  ectasiae  (De  Amicis).  In  the 
stage  of  tumor  growth  multiple  soft  bluish  nodules  or  flat  infiltrations  form  in 
the  derma  of  the  outer  surface  of  hands,  feet,  cheeks,  nose,  and  elsewhere. 
They  are  often  painful,  inflamed,  and  may  ulcerate,  involving  deeper  tissues 
and  even  eroding  bones.  The  nodules  may  be  very  numerous,  Babes  observ- 
ing 450  in  one  patient.  Hemorrhage  often  occurs,  leaving  pigmentation 
prominent  in  some  cases.  The  disease  progresses  from  the  extremities  up- 
ward, some  areas  showing  a  tendency  to  heal,  especially  under  arsenic.  The 
lesions  may  be  symmetrical.  In  the  stage  of  cachexia  the  cutaneous  lesions 
may  become  numerous  or  diffuse  and  in  several  fatal  cases  secondary  nodules 
appeared  in  the  pharynx,  gastro-intestinal  tract  and  liver,  kidney,  pancreas, 
lungs,  and  serous  membranes  (Phillipsohn,  Mariani,  Lit.).  Most  of  the  cases 
are  eventually  fatal  from  hemorrhage,  diarrhea,  fever,  and  cachexia. 


CLINICAL  TYPES  OF  SARCOMA  253 

The  histological  structure  exhibits  in  the  early  stages  chiefly  new  and 
dilated  lymph-  and  blood-vessels  and  infiltration  by  lymphocytes,  plasma- 
cells,  mast-cells,  and  edema,  and  the  lesion  resembles  that  of  an  infectious 
granuloma.  According  to  W.  Pick  the  early  lesion  is  indistinguishable  from 
elephantiasis  lymphangiectatica.  Proliferation  of  endothelium  and  peri- 
vascular  spindle-  and  round-cells  may  appear  early  and  become  so  prominent 
as  to  lead  to  the  diagnosis  of  angiosarcoma,  etc.  In  the  later  stages  spindle- 
cells  may  predominate  and  the  lesion  is  indistinguishable  from  spindle-cell 
fibroblastic  sarcoma  (Pick).  In  all  stages  vascular  ectasiae,  hemorrhage,  and 
pigmentation  are  constant  or  frequent. 


FlG.  77. — Multiple  hemorrhagic  sarcoma.     Kaposi.     (After  W.  Pick,  A.  D.,  87.) 


Regarding  the  nature  of  this  disease  opinions  are  naturally  at  variance, 
but  the  conclusion  seems  well  founded  that  we  have  here  to  do  with  an  infec- 
tious granuloma  of  unknown  origin,  which  in  its  later  stages  in  predisposed 
subjects  and  under  suitable  conditions  may  take  on  genuine  neoplastic  prop- 
erties. Justus  seems  to  have  carried  the  agent  through  five  generations  of 
rabbits  with  the  production  of  typical  lesions.  The  secondary  growths  in 
the  viscera  are  probably  not  metastases,  but  extensions  to  new  originating 

foci.  .   ,    ,. 

Beginning  in  local  lesions  in  the  extremities  in  which  an  infectious  agent 
is  probably  concerned  and  aided  by  the  various  predisposing  factors.,  the 
entire  vascular  system  seems  to  be  overtaken  by  degeneration  with  over- 


254 


NEOPLASTIC  DISEASES 


growth  of  vasoformative  cells  leading  in  many  instances  to  true  tumor  for- 
mation. In  the  histogenesis  the  numerous  discussions  have  dealt  with  all  the 
data  regarding  the  interrelations  of  endothelium,  perithelium,  fibroblasts, 
plasma-cells,  and  polyblasts,  but  the  final  tumor  product  is  a  spindle-cell 
sarcoma,  which  on  account  of  its  early  history  and  tendency  toward  regression 
has  often  been  called  sarcoid. 

Spindle-cell  Sarcoma  of  Skin. — These  tumors  appear  as  single  large 
growths  which  tend  to  become  pedunculated  or  as  multiple  small  nodules 
widely  distributed.  Appearing  in  the  derma  or  subcutaneous  tissue  they 
form  circumscribed  nodules  or  masses  which  vary  widely  in  color,  consist- 
ence, as  well  as  in  number  and  position.  Some  are  hard,  opaque,  and  fibrous, 


FIG.  78. — Multiple  hemorrhagic  sarcoma.     Kaposi. 

A.  D.,  98.) 


Intestinal  lesion.     (After  Mariana, 


others  soft,  reddish,  vascular,  and  edematous.  Both  the  single  and  multiple 
tumors  are  usually  of  slow  growth  and  relatively  benign,  but  either  type  may 
develop  greater  malignancy  and  terminate  with  metastases  and  cachexia 
(Unna).  As  a  rule  these  tumors  show  a  limited  capacity  for  growth,  and 
while  recurring  locally  are  not  directly  fatal.  Fibrosis  (Linser),  peduncula- 
tion,  and  spontaneous  extrusion  may  occur.  Ulceration  and  necrosis  are  rare. 
They  appear  at  almost  any  age,  and  Maldovan  and  Fernet  describe  congenital 
cases. 

The  structure  is  in  many  instances  that  of  the  simplest  form  of  small  or 
large  spindle-cell  tumor,  but  many  variations  from  this  type  are  encoun- 
tered. Blood-vessels  may  be  numerous  and  the  tumor-cells  may  appear  to  be 


CLINICAL  TYPES  OF  SARCOMA 


255 


derived  from  their  adventitial  cells.  Varying  in  this  direction  spindle-cell 
sarcoma  of  the  skin  approaches  angiosarcoma  and  perithelioma,  from  which 
types  they  are  not  always  sharply  separable.  In  one  group  endothelial 
proliferation  appears  to  be  prominent  and  yields  many  rounded  and  poly- 
hedral cells  (Johnston).  Chronic  edema  may  lead  to  secondary  myxo- 
matous  characters.  Unna  describes  a  rich  supply  of  lymph-spaces  in  some 
tumors. 

The  arrangement  of  cells  also  varies  greatly.  They  may  be  closely  packed, 
of  small  size,  with  little  stroma,  and  quite  diffusely  arranged.  An  inter- 
fascicular  form  is  yielded  by  cells  whose  axis  is  determined  by  the  course  of 
blood-vessels  (Unna).  The  cells  may  form  whorls  or  intertwining  bundles 
which  have  suggested  an  origin  from  nerve-trunks.  The  cells  penetrate  sur- 


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FIG.  79.— Structure  of  multiple  hemorrhagic  sarcoma.     (After  Mariani.) 

rounding  tissues  and  develop  new  outlying  nodules,  or  they  may  remain  well 
circumscribed.  In  the  central  portion  of  all  true  sarcomas  of  the  skin  Unna 
finds  elastic  fibrils  missing. 

The  histogenesis  of  cutaneous  spindle-cell  sarcoma  is  a  complex  question, 
and  it  has  not  been  possible  to  clearly  define  the  subgroups  probably  exist- 
ing in  this  class  according  to  their  exact  origin.  Yet  the  fibroblastic  nature 
of  the  typical  form  seems  reasonably  certain.  Many  have  concluded  that 
the  adventitial  cells  of  blood-vessels  and  lymph-vessels  are  the  chief  seats  of 
origin.  In  certain  cases  I  have  been  impressed  with  the  evident  relation 
of  the  tumor-cells  to  numerous  abortive  blood-vessels  which  seemed  to  be- 
come lost  in  the  tumor-tissue.  Yet  Unna  believes  that  the  importance  of 
blood-vessels  in  the  origin  of  these  growths  has  been  overestimated,  espe- 
cially by  Babes.  The  connective  tissue  about  cutaneous  glands  rarely  seems 


256 


NEOPLASTIC  DISEASES 


to  be  specially  concerned.  That  an  endothelial  element  is  present  in  some 
cases  is  highly  probable,  especially  in  tumors  with  rounded,  polyhedral,  or 
giant-cells.  In  cases  of  multiple  symmetrical  tumors  with  cells  in  inter- 
twining bundles  an  origin  from  nerve-sheaths  and  an  endothelial  element  are 
indicated.  The  occurrence  of  congenital  cases  indicates  that  misplaced  or 
superfluous  cell  groups,  and  not  normal  tissues,  are  occasional  or  frequent 
points  of  origin.  Finally  it  is  clear  that  some  tumors  closely  resembling  nbro- 
blastic  sarcoma  belong  in  the  group  of  nevomelanomas,  and  that  the  highly 
malignant  cutaneous  sarcomas,  as  in  Pini's  case,  must  be  regarded  with  sus- 
picion from  this  standpoint. 

In  the  etiology,  various  forms  of  trauma  not  infrequently  precede  the 
solitary  sarcoma  (Lowenstein).  Virchow  (II,  245)  cites  many  cases  of 
sarcoma  arising  in  scar  tissue  which  had  been  subjected  to  long  irritation. 
For  the  multiple  tumors  a  tissue  predisposition  and  the  various  inflam- 


FIG.  80. — A  giant-cell  tumor  of  tendon  sheath,  probably  of  endothelial  origin. 


matory  and  nutritional  changes  illustrated  in  the  sarcoids  may  be  held 
responsible. 

Giant-cell  Sarcoma  of  Tendon  Sheaths  and  Aponeuroses. — The  specific 
structure  and  benign  clinical  course  of  a  group  of  giant-cell  sarcomas  of  tendon 
sheaths  of  the  hand  and  feet  have  long  been  recognized.  They  have  been 
fully  described,  especially  by  French  observers,  under  the  terms  "myeloma"  or 
"xanthosarcoma"  (Gross,  Paquet,  Reverdin,  Heurteaux,  Spiess,  Lit.). 

The  tumors  arise  chiefly  in  tendon  sheaths  and  aponeuroses  of  hands  and 
feet,  and  reach  moderate  dimensions  after  a  period  of  i  to  20  years.  Sudden 
increase  in  size  may  rouse  a  suspicion  of  malignancy,  but  they  seldom  reach 
the  size  of  an  egg.  They  are  well  encapsulated,  firm,  opaque  or  yellowish 
and  markedly  lobulated,  and  are  readily  shelled  out  by  operation.  They 
never  yield  metastases  and  rarely  recur  after  removal. 


CLINICAL  TYPES  OF  SARCOMA  257 

The  structure  presents  four  main  features:  (i)  Groups  of  spindle-  or 
polyhedral  cells  surrounded  by  dense  connective  tissue.  Some  of  the  tumors 
are  exclusively  of  this  type.  Although  the  tumor  may  be  quite  cellular  and 
free  from  giant-cells  it  still  maintains  its  benign  character.  (2)  Groups  of 
large  cells  containing  much  doubly  refractive  lipoid  material.  These  are  the 
so-called  xanthoma-cells.  They  may  be  so  abundant  as  to  duplicate  the 
appearance  of  xanthoma  of  the  skin,  and  their  origin  is  referred  to  prolif- 


FIG.  81. — Myxosarcoma  of  fascia  of  thigh. 

crating  fibroblasts  or  endothelium.  (3)  Giant-cells  of  very  large  size  up  to 
125  m.  are  commonly  present  in  abundance,  and  present  very  numerous 
small  vesicular  nuclei.  The  cytoplasm  is  granular,  acidophile  and  often 
contains  much  lipoid  material.  They  belong  to  the  class  of  foreign  body 
giant-cells.  (4)  Pigment  of  the  type  of  hemosiderin  frequently  collects  in  the 

tumor-cells.  ,  ,      . 

Etiological  factors  are  very  indefinite,  but  the  structure  and  benign  char- 

17 


258  NEOPLASTIC  DISEASES 

acter  of  the  process  suggests  that  the  tumors  arise  from  a  local  inflamma- 
tory process  connected  with  trauma  and  some  peculiar  disturbance  of  local 
lipoid  metabolism.  Flessig  denies  that  they  have  any  neoplastic  quality 
and  regards  them  as  a  form  of  granulation  tissue,  yet  similar  arguments 
apply  almost  equally  well  to  many  other  sarcomas.  They  have  often  been 
classed  with  xanthoma. 

Sarcoma  of  Muscles. — Primary  sarcoma  of  the  muscles  arises  from  the 
connective  tissue  and  vessels  of  the  perimysium  and  endomysium  and  usually 
takes  the  form  of  fibrosarcoma  or  myxosarcoma  with  small  or  large  spindle- 
cells,  and  often  with  a  marked  prominence  of  capillary  or  larger  blood-vessels. 
Occasionally  they  are  described-  as  round-cell  sarcoma  (Chambe,  Pasteau, 
Kuttner). 

They  occur  chiefly  in  young  adults,  the  rapidity  of  growth  varies  with 
the  structure,  but  is  often  rapid,  they  reach  a  large  size  if  undisturbed,  recur 
locally  after  operation,  and  the  cellular  forms  produce  metastases.  Chambe 
has  collected  39  cases  illustrating  many  features.  Many  cases  were  fatal. 
Virchow  observed  that  in  the  muscle  fasciae  slowly  growing  fibrosarcoma  or 
spindle-cell  sarcoma  predominate,  while  at  tendon  insertions  many  round- 
cell  and  malignant  tumors  appear.  A  characteristic  fibrosarcoma  arises  from 
the  sheath  of  the  rectus  abdominis  (Bodenstein,  Lit.). 

The  histogenesis  has  been  traced  in  certain  cases  to  the  interstitial 
tissue  (Birch-Hirschfeld),  and  the  remarkable  proliferative  tendency  of  this 
tissue  renders  such  an  origin  probable.  The  muscle-cells  usually  atrophy, 
but  Sokalow,  Guitton,  and  others  reported  the  transformation  of  muscle- 
cells  into  sarcoma-cells.  About  many  tumors  of  muscle  there  is  a  pro- 
nounced reactive  myositis  with  various  alterations  in  the  form  of  the  cells 
(W.  Schaffer). 

That  sarcoma  of  muscle  may  be  derived  from  groups  of  embryonal  and 
undifferentiated  muscle-cells  has  often  been  suggested  (Borst).  It  seems 
probable  that  with  myxosarcomas  and  malignant  growths  approaching  the 
round-cell  type  the  origin  is  from  misplaced  cell  groups  connected  with  bone 
formation.  In  a  series  of  bulky  sarcomas  of  the  thigh  I  have  observed  grada- 
tions in  structure  from  myxosarcoma  to  chondrosarcoma.  In  an  early  sar- 
coma of  muscle  I  found  very  many  small  blood-vessels  which  seemed  to 
be  the  source  of  the  spindle-cells  of  the  tumors.  Peabody's  study  of  Peters' 
cases  suggested  a  vascular  origin.  Sokalow  traced  some  tumors  to  the  sarco- 
lemma,  but  Cornil  and  Ranvier,  Malherbe,  and  most  authors  assume  that  they 
arise  from  the  interfibrillar  connective  tissue. 

Periosteal  sarcomas  of  many  types  commonly  invade  the  muscles  and  some 
may  appear  largely  intramuscular. 

Sarcoma  of  the  esophagus  is  a  rare  condition.  Howard  (1902)  analyzed 
12  cases.  Herxheimer,  1908,  refers  to  18  cases,  2  of  which  were  combined  car- 
cinoma and  sarcoma.  Hacker,  1909,  gave  a  complete  analysis  of  the  subject 
with  reference  to  21  cases.  They  occurred  usually  in  males,  in  the  upper  or 
lower  segment,  and  in  subjects  from  4  to  70  years  of  age,  and  were  rapidly 
fatal.  They  appear  either  as  an  ulcerative  process  or  as  a  polypoid  tumor. 
The  former  usually  contain  round  or  polyhedral  cells,  the  latter,  spindle-cells. 
Stephan  describes  a  peculiar  lymphosarcoma  in  an  infant.  In  Eucken's  case 
there  were  many  giant-cells.  With  the  round-cell  growths  metastases  are  early 
and  wide-spread  (Shaw,  Stark,  Rolleston).  The  spindle-cell  tumors  were  usu- 
ally free  from  metastases  (Targett,  Ogle,  Livingood,  Herxheimer). 

It  seems  probable  that  two  entirely  different  tumors  have  been  included 
in  this  group.  The  round-cell  growths  strongly  resemble  embryonal  carci- 
noma in  gross  appearance,  and  Stark  suspected  that  his  2  cases  might  be 


CLINICAL  TYPES  OF  SARCOMA  259 

carcinomatous.  One  case  of  this  type  with  bulky  metastases  in  the  liver 
strongly  suggested  to  me  a  carcinomatous  origin  (Norris).  The  spindle- 
cell  tumors  are  probably  genuine  sarcomas,  but  little  effort  has  been  made  to 
determine  their  origin.  Howard  regarded  his  spindle-cell  tumor  as  a  myo- 
sarcoma.  Wolfensberger  and  Glinsky  have  observed  mixed  tumors  of  the 
esophagus  composed  of  striated  muscle-,  spindle-,  and  giant-cells.  Herx- 
heimer  describes  combined  sarcoma  and  epithelioma  arising  apparently  from 
the  submucosa  and  the  epithelial  lining.  Metastases  were  wanting.  Baur 
describes  a  melanotic  sarcoma  of  esophagus. 

Sarcoma  of  Stomach. — The  reported  cases  of  sarcoma  of  the  stomach 
constitute  about  i  per  cent,  of  all  gastric  tumors.  On  analysis  the  cases  fall 
into  three  distinct  groups:  (i)  Spindle-cell  myosarcoma;  (2)  lymphosarcoma, 
and  (3)  miscellaneous  round-cell  or  alveolar  sarcomas,  the  nature  of  which  is 
uncertain.  Of  all  these,  150  cases  have  been  collected  by  Ziesche  and 
Davidsohn. 

i.  The  spindle-cell  myosarcomas  constitute  a  well-defined  group.  They 
form  solid  or  cystic  growths,  single  or  multiple,  which  project  from  the  wall 
of  the  stomach  into  the  peritoneum,  or  remain  interstitial,  or  protrude  into 
the  cavity  of  the  organ,  where  they  suffer  necrosis  and  ulceration.  Very 
early  small  growths  have  been  observed,  while  Brodowski's  tumor  grew  to  the 
size  of  a  child's  head  between  the  mesenteric  layers.  Cantwell's  case  weighed 
12  pounds  and  Baldy's  nearly  filled  the  abdomen.  Most  of  these  tumors  arise 
from  the  curvatures,  rarely  from  the  pylorus  (Manges,  Schlesinger). 

The  external  pedunculated  tumors  may  draw  the  stomach  out  into  a 
funnel  form;  the  interstitial  tumors  may  cause  dilatation;  and  Ewald  found 
the  organ  reduced  to  a  narrow  canal  surrounded  by  multiple  or  diffuse  masses 
of  fibrosarcoma.  Ulceration  and  hemorrhage  frequently  occur.  The  large 
tumors  are  often  cystic,  and  the  bulky  metastases  which  commonly  form  in 
the  liver  are  often  cystic  and  may  transform  this  organ  into  a  series  of  large 
cystic  tumors  (Hosch,  Lit.).  The  course  of  gastric  myosarcoma  is  relatively 
slow  in  the  typical  cases  (3-^  years),  but  with  greater  anaplasia  of  the  cells  the 
growth  is  often  quite  rapid. 

The  structure  varies  between  considerable  limits.  In  some  cases  the  type 
approaches  that  of  a  cellular  myoma  and  the  recognition  of  a  myogenous 
origin  is  readily  accomplished.  Or  the  cells  are  of  large  spindle  form  and 
the  designation  as  a  myosarcoma  depends  on  the  attitude  of  the  observer. 
Such  a  case  is  that  of  Hoesch-Kaufmann  which  appears  to  be  identical  in 
structure  with  others  described  as  large  spindle-cell  sarcoma.  There  is  little 
doubt  also  that  some  or  many  of  the  so-called  large  round-cell  sarcomas  are 
of  muscular  origin.  In  some  cases  careful  examination  has  revealed  typical 
myosarcoma  in  one  portion  of  the  tumor,  indifferent  spindle-cells  in  other 
portions,  and  elsewhere  only  round-cells  (Moser).  The  arrangement  of  the 
cells  in  intertwining  bundles  is  often  a  characteristic  feature.  The  grouping 
of  cells  about  blood-vessels  has  sometimes  suggested  that  the  tumor  arose  from 
the  walls  of  the  vessels  as  in  myoma  uteri  (Kaufmann,  Howard),  or  it  has 
led  to  the  diagnosis  of  angiosarcoma,  or  lymphangiosarcoma  (Steudel).  The 
gross  appearance  of  many  of  these  tumors  of  doubtful  nature  is  very  similar  to 
that  of  definite  myosarcoma. 

In  the  etiology  of  myosarcoma  a  congenital  anomaly  must  be  sought 
for  the  stomach  as  for  the  uterus.  Of  the  nature  of  this  embryogenic  dis- 
turbance there  are  scant  indications.  That  isolated  islands  of  muscular 
tissue  occur  in  the  stomach  is  shown  by  Alsleben's  report  of  an  adenomyoma 
in  the  pyloric  mucosa,  while  the  congenital  occurrence  of  myosarcoma  is 
probably  demonstrated  by  Finlayson's  case. 


260  NEOPLASTIC  DISEASES 

2.  Lymphomatous  tumors  of  the  stomach  occur  (i)  as  a  part  of  the  leu- 
kemic  process;  (2)  in  gastro-intestinal  pseudoleukemia;  (3)  as  a  part  of  gen- 
eral lymphosarcoma,  and  (4)  in  the  form  of  localized  lymphosarcoma.    They 
are  considered  in  detail  under  these  headings. 

3.  Miscellaneous  Sarcomas  of  Stomach. — In  not  a  few  gastric  sarcomas 
the  structure  has  appeared  not  to  fall  into  any  of  the  common  groups,  and  the 
tumor  has  been  variously  described  as  alveolar  or  mixed-cell,  or  angiosarcoma, 
or  myxosarcoma.    None  of  these  histological  features  deserves  special  recog- 
nition as  a  separate  variety  of  gastric  tumor. 

Dreyer  described  a  pyloric  tumor  composed  of  spindle-cells  and  carcinoma 
occupying  a  large  ulcerated  area  at  the  pylorus.  The  metastases  were  car- 
cinomatous.  Leube  also  observed  mixed  carcinoma  and  sarcoma.  Such 
observations  suggest  the  conclusion  that  carcinoma  of  the  stomach  may 
give  histological  appearances  resembling  sarcoma.  Cammidge  has  men- 
tioned 4  cases  of  this  type  and  concludes  that  many  so-called  sarcomas 
of  the  stomach  are  really  carcinomas  (Wilson).  This  criticism  appears  to  be 
justified  and  the  writer  would  urge  great  caution  in  interpreting  as  sarcoma 
any  tumor  associated  with  an  ulcer  and  of  which  the  gross  appearance  strongly 
suggests  carcinoma.  That  sarcoma  of  the  stomach  may  follow  ulcer  appears 
possible  (Moser,  Kehr),  but  this  relation  has  not  been  satisfactorily  proved; 
1 8  cases  of  metastatic  sarcoma  of  the  stomach,  chiefly  lymphoid  and 
melanotic,  have  been  collected  by  Ziesche  and  Davidsohn.  They  are  not 
uncommon. 

Sarcoma  of  Intestine. — The  small  and  large  intestines  and  the  rectum 
are  subject  to  the  same  types  of  sarcoma  as  the  stomach.  Baltzer  called 
attention  to  the  surgical  aspects  of  this  group  of  tumors  in  a  report  of  14  cases. 
Rademacher  (1908)  collected  140  cases.  Of  rectal  sarcomas  Key  found  55 
reports,  to  which  he  added  3.  The  majority  of  these  cases  were  studied 
exclusively  from  the  clinical  standpoint,  which  emphasizes  the  symptoms  of  an 
abdominal  tumor  causing  intestinal  obstruction.  The  nature  of  the  growths 
is  seldom  clearly  stated,  but  the  great  majority  appear  to  be  lymphomatous, 
while  a  considerable  proportion  are  fibroblastic. 

1.  Spindle-cell  sarcoma  arises  chiefly  from  the  muscular  coat,  and  pro- 
duces a  large,  solid  or  cystic  growth  lying  external  to  an  intact  mucosa.    A 
rather  well-defined  group  is  the  myxosarcoma  affecting  chiefly  the  cecum  and 
appendix  and  said  to  arise  from  the  submucosa.    It  may  contain  large  cysts. 
The  subserous  tissue  is  said  to  give  origin  to  certain  angiosar comas.    A  con- 
genital angiosarcoma  of  ileum  is  described  by  Stern,  and  a  subserous  angio- 
sarcoma of  the  splenic  flexure  by  Baltzer.    I  have  examined  a  large  spindle-cell 
vascular  sarcoma  of  the  omen  turn. 

2.  Miscellaneous  sarcomas  of  intestine  constitute  a  small  group  of  ill- 
defined  and  imperfectly  described  varieties.     An  interesting  case  is  that  of 
Lehmann,  who  designated  as  interfascicular  endothelioma  a  diffuse  thicken- 
ing of  the  entire  intestine  with   secondary   growths   in   liver.     Pigmented 
sarcomas  occur  in  the  rectum  and  ileum  (Sandner,  Treves),  but  the  source 
of  the  pigment  is  not  clear  and  intestinal  metastases  of  melanoma  of  the 
skin  are  common.      I   have   studied   one   slightly  pigmented   primary  sub- 
mucous  melanoma  arising  around  the  opening  of  the  appendix  in  a  child 
(cf.  Melanoma). 

3.  Lymphomatous  tumors  of  the  intestine  are  considered  under  that  head- 
ing.   They  arise  chiefly  in  the  ileum,  colon,  and  rectum.    Rarely  they  develop 
the  appendix  (Warren,  Carwardine). 

Sarcoma  of  Ovary. — Primary  sarcoma  is  a  comparatively  rare  tumor 
constituting  about  5  per  cent,  of  all  ovarian  neoplasms  (Kroemer).  Yet  in 


CLINICAL  TYPES  OF  SARCOMA  261 

this  small  group  many  histological  varieties  are  represented,  concerning  the 
histogenesis  of  which  little  is  known.  The  process  of  organization  of  blood- 
clot  in  the  corpus  luteum  and  of  regression  of  this  structure  offers  conditions 
very  favorable  to  the  development  of  sarcoma,  and  it  is  probable  that  this 
source  of  myxosarcoma,  perithelioma,  etc.,  has  not  been  given  due  atten- 
tion. Other  sarcomas,  especially  of  the  embryonal  type,  have  been  traced  to 
a  teratoid  origin. 

1.  Spindle-cell  sarcoma  is  a  well-defined  type  which  is  closely  related  to 
fibroma  and  probably  also  to  ovarian  myoma.    It  appears  as  a  diffuse  process 
affecting  the  whole  ovary  and  producing  either  a  solid  tumor  of  moderate 
dimensions  or  a  large  growth  containing  many  cysts.    The  surface  is  nodular 
or  lobulated  and  section  reveals  a  smooth  opaque  texture,  or  many  dilated 
vessels,  or  cysts  which  are  more  irregular  in  size  and  form  than  in  cystic 
adenoma.     Areas  ^  of  edema  and  mucoid  degeneration  may  be  present  and 
hemorrhage  or  infarction  may  follow  torsion. 

The  structure  presents  spindle-cells  of  moderate  dimensions  mingled 
usually  with  spheroidal  cells.  Trabeculse  of  adult  connective  tissue  separate 
the  tumor  into  lobules,  while  between  the  cells  there  is  little  demonstrable 
stroma.  The  cells  may  grow  diffusely,  but  more  often  they  are  definitely 
connected  with  small  blood-vessels  which  are  either  thin  walled  and  telan- 
giectatic  or  compressed  or  occluded  by  hyaline  degeneration.  The  main 
feature  of  some  tumors  is  the  abundance  of  hyaline  vessels  between  which  lie 
scanty  spindle-cells.  In  the  cystic  tumors  dilatation  of  lymph-vessels,  edema, 
and  liquefaction  necrosis  seem  responsible  for  the  irregular  cavities  which 
contain  serous  or  bloody  fluid  and  are  lined  by  a  ragged  layer  of  sarcomatous 
tissue  supported  by  connective  tissue.  Such  growths  may  be  interpreted  as 
cystic  lymphangiosarcomas.  The  spindle-cell  tumors  are  of  slow  growth  and 
relatively  benign. 

The  origin  of  the  spindle-cell  tumors  must  be  referred  to  the  ovarian 
stroma,  but  to  which  elements  is  uncertain.  The  perivascular"  arrangement 
of  the  cells  suggests  an  origin  from  the  walls  of  vessels,  but  not  an  endothelial 
character.  The  perithelial  tissue  has  been  suggested  as  a  possible  source,  but 
without  definite  basis,  since  the  tumors  are  usually  diffuse.  Smooth  muscle- 
cells  have  been  observed  in  round-cell  and  spindle-cell  sarcoma  and  it  appears 
probable  that  some  of  these  tumors  are  of  myogenic  origin  (Basso,  Gangolphe, 
Kroemer). 

2.  Round-cell  sarcoma  of  the  ovary  is  an  ill-defined  and  rare  form  of  malig- 
nant tumor  which  occurs  chiefly  in  young  subjects  or  children  and  proves 
rapidly  fatal.    The  tumors  are  single  or  bilateral,  reach  a  considerable  size,  are 
usually  solid  or  contain  softened  or  necrotic  areas.    They  are  soft,  edematous, 
infiltrated  with  blood,  and  exhibit  numerous  necrotic  foci.    The  structure  is  of 
small  round-cells  lying  diffusely  or  grouped  about  thin  vessels.    In  some  cases 
the  cells  are  of  larger  size  and  exhibit  an  alveolar  arrangement  (alveolar  sar- 
coma).    Or  spindle-cells,  small  round-cells,  large  spheroidal  cells,  and  giant- 
cells  may  be  variously  combined. 

In  none  of  these  cases  does  the  structure  offer  any  clue  to  the  histogenesis 
and  this  group  of  tumors,  therefore,  invites  subdivision  according  to  the 
histogenetic  principle.  It  seems  probable  that  some  of  the  tumors  with  in- 
different round-cells  are  to  be  interpreted  as  one-sided  developments  of  tera- 
toma,  but  to  which  forms  this  view  may  apply  it  is  difficult  to  decide.  One 
form  of  large  round-cell  sarcoma  of  the  ovary  closely  resembles  a  similar 
tumor  of  the  testis  and  is  probably  of  teratomatous  nature.  It  is  very  prone 
to  necrosis. 

It  also  seems  probable  that  some  so-called  alveolar  sarcomas  are  really 


262  NEOPLASTIC  DISEASES',; 

of  epithelial  origin  arising  from  the  cells  of  the  granular  layer  of  the  follicles, 
since  these  cells  in  adenomatous  tumors  readily  assume  a  small  round  form 
and  diffuse  arrangement.  That  the  theca  cells  of  the  ovarian  follicles  give 
rise  to  certain  sarcomas  is  claimed  by  Pinto,  but  this  origin  still  lacks  definite 
proof. 

The  relationship  of  cells  to  blood-  and  lymph-vessels  has  often  led  to  the 
designation  of  such  tumors  as  angiosarcoma  and  perithelioma.  In  favor  of 
this  view  is  the  frequency  of  angiomas  in  the  ovary  and  of  sarcomas  in  which 
the  blood-vessel  is  the  prime  unit,  yet  most  of  these  tumors  are  composed  of 
spindle-cells. 

Against  the  origin  from  vessels  is  the  well-known  tendency  of  all  tumor- 
cells  to  thrive  best  in  the  proximity  to  blood-vessels,  giving  spurious  angio- 
sarcoma. Nevertheless,  Kroemer  recognizes  a  special  group  of  ovarian  angio- 
sarcoma of  blood  and  lymph-vascular  origin.  They  are  difficult  to  distinguish 
from  the  group  of  perithelioma  (q.  v.).  In  this  field  also  one  encounters  evi- 
dences of  the  close  relationship  of  endothelioma  and  sarcoma.  The  existence 
of  a  true  ovarian  endothelioma  is  elsewhere  discussed. 

A  form  of  plexiform  sarcoma  is  described  by  Kroemer.  It  consists  of 
anastomosing  columns  of  syncytial  and  giant-cells  which  he  derives  from  the 
perivascular  cells  about  lymph- vessels,  a  lymphangiosarcoma.  The  endothe- 
lial  cells  of  the  vessels  proliferated  slightly  in  places,  but  tended  to  disappear 
from  the  field.  This  nice  histological  analysis  still  leaves  untouched  more 
important  questions  of  histogenesis. 

Finally,  among  the  polymorphous  cell  ovarian  sarcomas  there  remains  a 
rather  well-defined  type. 

Myxosarcoma. — Areas  of  secondary  myxomatous  change  are  frequently 
seen  in  other  forms  of  ovarian  sarcoma.  They  occur  about  the  blood-vessels 
and  lymph-vessels,  especially  of  fibrosarcoma  and  sometimes  become  so 
prominent  as  to  call  for  the  designation  of  myxosarcoma.  Yet  such  cases 
are  rare.  Segalowite  found  only  one  largely  myxomatous  tumor  among  300 
from  the  ovary,  and  Kroemer  states  that  a  pure  myxosarcoma  of  the  ovary 
does  not  exist.  An  interesting  observation  is  that  of  Walker,  who  records 
3  fatal  myxosarcomas  in  sisters. 

Myxomatous  areas  occur  especially  with  chondrosarcoma,  as  in  the  case 
of  Gibb,  which  was  probably  of  teratoid  origin,  and  myxomatous  changes 
in  the  stroma  of  ovaries  invaded  by  epithelial  tumors  is  so  common  as  to  lead 
Glockner  to  regard  it  as  a  specific  reaction  of  ovarian  tissue.  A  specific  variety 
of  myxomatous  tumor  of  the  ovary  has  been  described  by  Krunkenburg  with 
Marchand's  endorsement,  under  the  term  fibrosarcoma  mucocellulare  carcino- 
matodes  (see  section  on  Carcinoma  of  Ovary). 

Chondrosarcoma  occurs  in  the  ovary  as  a  one-sided  development  of  a 
mixed  tumor  or  of  a  teratoma.  or  as  a  metaplastic  growth  derived  from  the 
ovarian  stroma. 

The  former  class  is  illustrated  by  tumors  in  which  islands  of  cartilage  are 
associated  with  dermoids,  or  with  other  derivatives  of  the  ectoderm  or  ento- 
derm.  The  cartilaginous  elements  may  predominate,  and  a  characteristic 
case  of  this  sort  is  that  of  Reis  in  which  a  large  chondromatous  tumor  after 
extirpation  was  followed  by  a  rapidly  growing  carcinoma.  A  similar  origin 
probably  applies  to  Gibb's  myxochondrosarcoma  occurring  in  a  child  of  2\ 
years.  Donati  observed  very  large  giant-cells  in  a  tumor  containing  cartilage 
and  much  round-  and  spindle-cell  tissue.  Here  it  seems  impossible  to  decide 
whether  the  origin  was  teratomatous  or  metaplastic. 

Some  authors  assume  that  ovarian  and  other  chondromas  of  the  female 
genital  organs  arise  from  inclusion  of  the  Mtillerian  or  Wolffian  ducts  (Wilms), 


CLINICAL  TYPES  OF  SARCOMA  263 

and  Kehrer  states  that  such  tumors  contain  areas  of  embryonal  round-cell 
mesodermal  tissue  which  differentiate  into  various  tissues. 

That  cartilage  arises  by  metaplasia  from  the  ovarian  stroma  was  strongly 
suggested  by  the  old  observation  of  Kiwisch,  who  found  cartilaginous  plates 
in  the  outer  layers  of  a  bilateral  ovarian  fibroma.  Buet  also  described  car- 
tilaginous metaplasia  in  a  fibrochondro-osteoma  of  the  ovary.  These  processes 
were  diffuse,  involving  the  entire  ovary.  The  most  notable  evidence  of  meta- 
plastic  development  of  cartilage  in  the  ovary  is  furnished  by  the  case  of  Jung. 

In  a  multipara  of  48  years  with  cervical  endothelioma  (epithelioma?)  a  myomatous 
uterus  was  removed  with  one-half  of  one  ovary  which  was  very  slightly  enlarged.  This 
ovary  was  found  to  contain  several  islands  of  young  and  some  ossifying  cartilage  em- 
bedded in  edematous  connective  or  in  spindle-cell  sarcomatoid  tissue.  There  was  a 
prompt  recurrence  of  a  pelvic  tumor  at  the  site  of  the  ovary  containing  chiefly  chondro- 
sarcoma  with  areas  of  spindle-,  round,  and  large  polyhedral  cells.  Meyer  interprets  this 
case  as  a  teratoma,  Kehrer  as  a  mixed  growth  of  Wilms  type,  and  Jung  and  Kroemer 
as  a  metaplastic  chondrosarcoma.  The  diffuse  distribution  of  multiple  islands  of  car- 
tilage in  edematous  connective  tissue  of  the  ovary  seems  to  favor  a  metaplastic  origin. 

Sarcoma  of  the  uterus  occurs  in  two  rather  distinct  forms  which  it  is  de- 
sirable to  separate  because  of  their  anatomical  position,  histogenesis,  and 
clinical  features.  These  are:  (i)  mural  sarcoma,  and  (2)  sarcoma  of  the 
mucosa  (Virchow). 

It  was  early  recognized  that  certain  apparently  benign  uterine  tumors 
recurred  after  operation,  and  these  were  described  by  English  observers  as 
recurrent  fibroids  (Hutchinson,  Callender).  In  1864  Virchow  described  a 
group  of  uterine  sarcomas  and  these  tumors  have  since  been  fully  discussed 
by  Gusserow  (1870),  Tertillon  (1890),  Gessner  (1899),  Piquand  (1905),  and 
lately  by  Meyer  (1908). 

i.  Mural  Sarcoma. — This  tumor  occurs  chiefly  in  the  body,  less  often  in 
the  cervix  (12  per  cent.  Gessner).  It  may  appear  as  a  primary  sarcoma  or 
develop  secondarily  in  myoma.  In  either  case  the  growths  present  many  of 
the  features  of  uterine  myoma.  Thus  they  are  often  encapsulated,  more  fre- 
quently diffuse,  and  their  position  is  subserous,  interstitial,  or  submucous. 
The  cervical  and  submucous  tumors  are  usually  polypoid  and  the  interstitial 
growths  may  early  break  into  the  mucosa  and  thus  become  indistinguishable 
from  originally  submucous  tumors.  A  rare  type  encircles  the  tubal  orifice 
(Meyer).  All  varieties  may  be  single  or  multiple.  Multiple  sarcomatous 
fibromyomas  have  been  described  by  v.  Kahlden,  Gessner,  and  Busse.  The 
single  tumors  may  reach  a  very  large  size,  and  Terrillon  has  recorded  a  weight 
of  20  kilos.  The  submucous  tumors  and  especially  the  cervical  growths  may 
be  extensively  polypoid  or  even  papillary. 

On  section,  the  uterine  sarcomas  are  soft  and  opaque  as  compared  with 
myoma  and  are  subject  to  liquefaction  necrosis  and  hemorrhage.  Fatty 
degeneration,  thrombosis  of  vessels  and  infarction,  with  extensive  softening 
may  produce  large  cysts  in  which  suppuration  may  occur.  While  the  mucosa 
is  usually  intact,  many  of  the  tumors  which  project  into  the  cavity  become 
ulcerated  and  extensively  excavated.  Overdevelopment  of  blood-vessels 
or  lymph-vessels  is  observed,  and  Meyer  describes  a  markedly  lobulated 
tumor  in  which  the  lobules  were  separated  by  large  lymph-sinuses.  The 
more  circumscribed  tumors  have  the  general  outline  of  fibromyomas, 
but  diffuse  forms  infiltrate  the  wall,  the  mucosa,  and  the  neighboring 
structures. 

Metastases  appear  late  with  encapsulated  interstitial  tumors,  but  when 
the  parametrium  is  invaded  secondary  growths  often  appear  in  the  regional 


264  NEOPLASTIC  DISEASES 

areas  and  in  the  lungs  as  well  as  in  many  other  tissues  and  organs  (Lubman). 
Yet  Gessner  observed  regional  metastases  with  circumscribed  tumors.  The 
uterine  veins  and  lymphatics  have  been  found  thrombosed  by  tumor  masses 
without  metastases.  The  ovaries  may  be  extensively  invaded  through  the 
vessels  or  by  implantation. 

The  gross  anatomic  features  suggest  the  following  somewhat  serviceable 
classification: 

1.  Circumscribed  primary  sarcoma,  chiefly  subserous  or  interstitial. 

2.  Diffuse  sarcomas,  chiefly  submucous  or  infiltrating  the  wall  and  para- 
metrium,  with  metastases,  and  subject  to  hemorrhage  and  necrosis. 

3.  Polypoid  sarcomas  of  body  or  cervix. 

4.  Extra-uterine  single  or  multiple  myosarcoma. 

5.  Secondary  sarcoma  in  myoma. 


FIG.  82. — Polypoid  sarcoma  of  cervix  uteri  in  a  subject  of  52  years.     (After  McCann.) 

Structure. — The  structure  of  uterine  sarcoma  is  extremely  varied.  Many 
authors  have  described  them  as  myosarcoma,  spindle-cell,  round-cell,  mixed- 
cell,  and  giant-cell  growths  and  other  sub  varieties.  Yet  there  is  strong  reason 
to  believe  that  the  entire  group,  with  rare  exceptions,  is  of  myogenic  origin. 
It  is  well-known  that  the  malignancy  varies  with  the  cell  type,  reaching  its 
acme  in  round-cell  and  giant-cell  structures,  but  it  has  repeatedly  been  shown 
that  in  the  same  tumor  the  structure  of  different  portions  may  exhibit  several 
cell  types  and  that  different  tumors  illustrate  all  transition  phases  of  smooth 
muscle-cells  to  round-cells  and  giant-cells.  Even  in  well-formed  fibromyomas 
areas  of  round-cell  sarcoma  may  occur  (Meyer,  Moraller,  v.  Franque).  In  a 
case  of  large  polypoid  submucous  sarcoma  I  found  areas  of  adult  myoma, 
very  cellular  lobules  resembling  the  recurrent  myoma,  indifferent  spindle- 
cell  sarcoma,  numerous  areas  of  round-cells  (very  short  spindles),  and  in 
edematous  portions  alveolar  sarcoma  with  many  large  polyhedral  cells. 
Moraller  observed  a  notable  perivascular  grouping  of  round-cells.  Meyer  con- 
cludes that  the  round-cell  sarcoma  of  cervix  is  often  regarded  as  endothelioma. 


CLINICAL  TYPES  OF  SARCOMA 


265 


In  fact,  it  is  evident  that  in  this  field  too  much  importance  has  been  attached 
to  variations  in  cell  forms  and  too  little  to  histogenesis  and  gross  anatomy. 

From  the  prognostic  standpoint,  how- 
ever, considerable  significance  attaches  to 
the  cell  type  and  somewhat  characteristic 
clinical  varieties  of  uterine  sarcoma  are  often 
associated  with  the  predominance  of  cells 
showing  different  grades  of  anaplasia. 

(a)  Recurrent  myoma  is  a  term  that  may 
well  designate  a  tumor  occurring  chiefly  in 
the  cervix,  which  recurs  after  a  difficult  ex- 
tirpation and  which  contains  rather  long, 
loose   spindle-cells  and  scanty  imperfectly 
formed  long  giant-cells.     In  a  case  of  this 
type  the  structure  remained  uniform  after 
three  recurrences,while  the  pelvis  and  vaginal 
wall    were    slowly    infiltrated.      A    charac- 
teristic recurrent  myoma  of  the  broad  liga- 
ment occurs  in  the  form  of  multiple  nodules 
composed  of  well-formed  muscle-cells  with 
marked  vasoformative  tendencies.    The  cells 
are   short   spindles   with   long    nuclei   and 
strongly    acidophile    cytoplasm.      The    ar- 
rangement of  the  cells  is  quite  orderly,  the 
vessels  well  formed,  and  giant-cells,  hemor- 
rhage,  degeneration,   necrosis,   and  metas- 
stases  are  wanting. 

(b)  Large  spindle-cells  with  granular  cyto- 
plasm, large  vesicular  nuclei,  and  occasional 
giant-cells  compose  the  bulk  of  many  tumors 
which  invade  parametrium,  broad  ligament 
and  mucosa,  with  ulceration,  necrosis,  and 
cachexia.    In  some  cases  the  giant-cells  are 
very  numerous  and  of  enormous  dimensions. 

(c)  Predominance  of  round-cells  usually  marks  rapidly  growing  tumors 
which  are  locally  destructive,  produce  cachexia  from  necrosis  and  hemorrhage, 


FIG.  8; 


Recurring  myoma  of  cer- 
vix uteri. 


FIG.  84. — Section  of  a  recurrent  myosarcoma  of  vagina  and  cervix  uteri. 


and  early  yield  local  and  distant  metastases  (Meyer).    Yet  many  metastases 
contain  chiefly  spindle-cells.     Heinrich  found  both  spindle-cells  and  round 


266 


NEOPLASTIC  DISEASES 


cells  in  tubal  metastases  of  spindle-cell  tumors,  and  both  original  and  metas- 
tatic  tumors  contained  all  transitions  from  muscle-cells  to  spindle-cells,  giant- 
cells,  and  round-cells  in  the  cases  of  Busse  and  Masty. 

Histogenesis  and  Etiology. — While  many  efforts  have  been  made  to  incul- 
pate the  connective  tissue  of  the  uterus  in  the  genesis  of  sarcoma  there  is 
no  sufficient  evidence  to  show  that  these  tumors  include  any  of  fibroblastic 
origin. 

On  the  other  hand,  the  wide  variation  in  form  of  neoplastic  smooth  muscle- 
cells  demonstrated  in  these  and  other  myosarcomas  leaves  little  room  for 
doubt  that  the  entire  group  is  essentially  of  myogenic  origin.  Yet  there 

remains  the  possibility  that  the  group  of  cells 
giving  rise  to  the  tumor  contains  besides 
muscle-cells  a  portion  of  the  specific  stroma- 
cells  of  the  uterine  mucosa.  Such  isolated 
complex  groups  of  cells  have  been  shown  to 
give  rise  to  adenomyoma,  but  the  adenosar- 
comas  which  doubtless  originate  from  such 
cell  groups  have  quite  a  different  structure 
from  myosarcoma  and  contain  gland  alveoli 
(v.  Winckel,  Amann). 

In  certain  sarcomas  areas  of  small  round- 
cells  traverse  the  main  spindle-cell  tumor  in 
broad  but  sharply  circumscribed  bands,  and 
some  have  derived  these  bands  from  the  stroma 
of  the  mucosa.  Yet  the  adult  stroma  is 
probably  not  connected  with  the  origin  of 
any  of  these  tumors  and  similar  round-cells 
are  observed  in  encapsulated  intramural 
growths. 

Regarding  the  nature  of  the  embryogenic 
disturbance  giving  origin  to  sarcoma,  one 
must  refer  to  the  same  data  which  serve  for 
uterine  myoma.  (For  the  sarcoma tous  trans- 
formation of  myoma  see  Myoma  Uteri.) 

2.  Sarcoma  of  Uterine  Mucosa. — Two  main 
anatomic  forms  of  this  condition  are  commonly 
recognized,  viz.,  (i)  diffuse,  and  (2)  polypoid. 
The  latter  represents  a  natural  tendency  of 
growth  of  the  former,  and  there  is  no  essential 
distinction  between  them. 

Arising  from  fundus  or  cervix  the  diffuse 
forms  are  usually  wide-spread,  Piquand  find- 
ing the  entire  mucosa  involved  in  33  of  54  reported  cases,  while  a  portion 
or  even  the  whole  of  the  tubal  mucosa  may  be  affected  (Griffith,  Simpson). 
In  advanced  cases  polypoid  outgrowths  frequently  form.  From  a  broad  base 
bulky  tumors  may  develop  over  which  the  uterus  is  stretched  with  thinning 
or  hypertrophy  of  the  wall  (Beckmann,  Terillon).  Occlusion  of  the  uterine 
canal  may  lead  to  retention  of  serous,  bloody,  or  purulent  fluids.  In  one  case 
Terillon  withdrew  15  liters  of  bloody  fluid.  A  thin  uterine  wall  may  suffer 
inversion  (Williams).  The  original  mucosa  may  remain  intact;  but  is  grad- 
ually altered  by  the  growth  of  the  tumor,  by  interstitial  endometritis,  or  by 
erosion  and  replacement  by  granulation  tissue. 

The  tumor  is  at  first  sharply  separated  from  the  muscularis,  but  soon 
invasion  of  the  wall  occurs  and  extension  follows  to  the  parametrium,  perito- 


FIG.  85. — Myosarcoma  of 
uterus.  A  rare  type.  The  small 
cell  groups  surround  minute  ves- 
sels. 


CLINICAL  TYPES  OF  SARCOMA  267 

neum  and  vagina.  Metastases  are  observed  in  the  regional  nodes,  lungs,  and 
elsewhere  (Gessner). 

Secondary  changes  are  common  in  both  forms  of  sarcoma  of  the  endo- 
metrium.  The  superficial  portions  early  become  eroded,  infected,  and  ne- 
crotic.  Hemorrhages,  edema,  myxomatous  softening,  wide  areas  of  caseation, 
and  fibrinous  exudate  combine  to  give  a  varied  appearance. 

The  polypoid  form  is  most  pronounced  in  the  cervix,  where  it  is  not  readily 
distinguished  from  polypoid  mural  sarcoma  and  certain  malignant  teratoid 
growths.  The  teratoid  tumors  include  the  malignant  myxosarcoma  of  Spiegel- 
berg  which  is  the  most  important  cervical  sarcoma  and  is  to  be  sharply  dis- 
tinguished from  the  present  group.  Many  reported  polypoid  sarcomas  of 
the  cervix  refer  to  cellular  polyps  chiefly  of  inflammatory  origin  and  it  appears 
doubtful  if  the  cervical  mucosa  is  the  seat  of  any  true  sarcomas  apart  from 
the  two  above  types. 

The  structure  of  endometrial  sarcoma  is  quite  varied.  Ruge  describes 
4  varieties:  (i)  Large  round  and  spindle-cells;  (2)  decidua-like  cells;  (3) 
giant-cells  with  small  round  cells  and  spindle-cells,  and  (4)  small  round 
cells.  It  is  probable  that  all  these  forms  represent  variations  of  one  original 
cell  type.  Thus  Meyer  found  round  cells  in  the  superficial  layers,  spindle- 
cells  in  the  deeper  portions  of  a  polypoid  tumor.  He  interprets  the  decidual 
cells  as  transitory  effects  of  the  menstrual  influence,  and  the  giant-cells  as 
regressive  forms.  In  my  own  cases  the  chief  features  have  been  the  diffuse 
arrangement  of  large  and  small  rounded  cells  with  hyperchromatic  nuclei. 
The  long  spindles,  parallel  intertwining  columns,  and  vasoformative  tenden- 
cies of  myosarcoma  are  wanting.  The  liability  to  necrosis  is  much  more 
pronounced. 

The  diffuse  distribution  of  many  endometrial  sarcomas  is  strong  evidence 
that  the  tumor  arises  form  the  stroma-cells.  Some  have  traced  the  earliest 
stages  to  the  periacinar  stroma.  Wolgren  describes  as  "fibroma tosis  uteri" 
a  tumor-like  thickening  of  the  endometrium  due  to  overgrowth  of  stroma- 
cells  most  marked  about  cystic  glands,  and  Fellander  places  in  an  intermediate 
group  between  inflammatory  and  neoplastic  processes  his  case  of  benign 
"elephantiasis  fibrosarcomatosa"  in  which  many  giant-cells  were  mingled 
with  short  spindles.  The  occurrence  of  such  intermediate  forms  of  hyperplasia 
renders  it  probable  that  highly  malignant  tumors  also  arise  from  the  stroma- 
cells.  That  some  of  the  supposed  sarcomas  of  the  mucosa  are  advanced 
stages  of  mural  myosarcoma  is  nevertheless  probable.  Ruge  states  that 
sarcoma  follows  periacinar  interstitial  endometritis  and  that  the  tumor  proc- 
ess first  affects  groups  of  glands  about  which  the  stroma-cells  increase  in  size 
and  number. 

For  the  endometrium  a  special  factor  in  the  genesis  of  sarcoma  which 
should  not  be  overlooked  is  the  influence  of  gestation.  Yet  the  varieties  of 
sarcoma  are  well  represented  in  children  and  virgins.  Highly  malignant 
lymphosarcomas  are  said  to  have  existed  in  rare  cases,  but  their  exact  nature 
is  uncertain  (Wilischamin,  Wagner,  Gow).  Melanosarcomas  result  from  im- 
bibition of  blood.  Alveolar  and  angiosarcomas  illustrate  occasional  second- 
ary structural  features. 

Carcinosarcoma  of  Uterus. — In  a  series  of  cases  carcinoma  and  sarcoma 
have  been  found  in  the  same  uterus,  and  the  interpretation  of  these  cases  has 
given  rise  to  much  discussion  (Gessner,  Meyer,  Herxheimer,  H.  Albrecht). 

i.  Simultaneous  occurrence  of  two  separate  tumors  has  been  observed  in 
10  cases  and  constitutes  the  most  frequent  and  least  notable  form  of  the 
combination.  Usually  a  polypoid  sarcoma  is  associated  with  diffuse  adeno- 
carcinoma  of  the  body  (Niebergall). 


268  NEOPLASTIC  DISEASES 

2.  Two  tumors  arise  separately,  but  later  one  invades  the  other  (Nebesky, 
Schaller). 

3.  At  the  point  where  a  submucous  or  mural  sarcoma  meets  the  glandular 
layer  carcinoma  develops  secondarily.    This  event  seems  to  be  not  infrequent 
and  is  illustrated  in  Albrecht's  case  where  carcinoma  developed  in  the  mucosa 
of  a  uterus  inverted  by  a  sarcomatous  polyp.    It  may  indicate  a  stimulating 
influence  of  sarcoma-cells  upon  epithelium  or,  more  probably,  the  ordinary 
effects  of  the  hyperemia  and  irritation  to  which  the  mucosa  becomes  exposed. 
I  have  seen  it  in  connection  with  a  benign  submucous  fibromyoma,  and  near 
a  calcific  myoma. 

4.  The  glands  included  in  sarcomatous  polyps  or  in  inflammatory  polyps 
or  in  adenomyoma  may  become  carcinomatous.     In   Gebhard's  case  the 
glands  surrounded  by  round-cell  sarcoma  of  the  mucosa  appeared  to  become 
carcinomatous.     Amann's  case  has  usually  been  interpreted  as  an  adeno- 
sarcoma  in  which  the  glands  became  carcinomatous  and  appeared  alone  in 
the  recurrences.    Ballin  assumed  a  simultaneous  process  in  both  stroma  and 
glands. 

5.  The  sarcomatous  transformation  of  the  stroma  of  a  cervical  carcinoma 
was  assumed  to  have  occurred  in  a  case  of  Lindemann's,  but  the  gross  appear- 
ance of  his  specimen  strongly  suggests  an  ordinary  cervical  carcinoma  with 
vesical  fistula  and  with  marked  inflammatory  cell  changes. 

6.  Spurious  cases  are  undoubtedly  recorded  in  which  atypical  proliferation 
of  glands  was  interpreted  as  carcinoma  (Klein),  or  endothelial  proliferation 
was  so  mistaken  (Riederer),  or  in  which  carcinoma,  becoming  diffuse  and  its 
cells  assuming  a  spindle  form,  bore  a  certain  resemblance  to  sarcoma. 

There  is  little  doubt  that  many  so-called  carcinosarcomas  result  from 
the  atypical  growth  of  epithelial  cells.  Gessner  refers  all  such  tumors  to 
this  origin,  pointing  out  that  their  metastases  are  usually  carcinomatous. 
The  exudation  and  inflammation  accompanying  tumors  of  the  endometrium 
greatly  favor  atypical  cell-growth,  the  scope  of  which  is,  I  believe,  under- 
estimated. I  have  studied  several  tumors  which  appeared  to  exhibit  sarco- 
matous and  carcinomatous  structure,  but  have  regarded  them  as  unfavorable 
material  for  accurate  observations  on  histogenesis.  R.  Meyer  holds  that 
sarcomatous  transformation  of  the  stroma  of  a  carcinoma  has  not  yet  been 
demonstrated. 


CHAPTER  XIX 
SARCOMAS  OF  BONE  AND  BONE-MARROW 

The  malignant  tumors  of  bone  constitute  one  of  the  most  important 
departments  of  oncology.  Their  very  frequent  occurrence,  local  destructive 
tendencies  resulting  in  loss  of  limbs,  rapid  extension  with  loss  of  life,  and 
the  difficulties  in  establishing  the  prognosis  render  them  a  complex  surgical 
problem.  Arising  from  cells  whose  natural  function  is  to  produce  the  most 
stable  of  tissues,  these  tumors  rank  with  the  most  rapidly  growing  of  neo- 
plasms. Although  often  most  clearly  connected  with  a  traumatic  origin 
the  mode  of  action  of  the  trauma  remains  highly  obscure,  and  while  the  neo- 
plastic  nature  is  usually  most  obvious,  the  general  etiology  of  some  of  the 
growths  reveals  complex  relations  with  normal  growth  of  bone  and  physio- 
logical regeneration  and  with  nutritional,  inflammatory,  and  infectious 
processes. 

Finally,  the  histological  structure  of  this  group  of  tumors  while  often 
highly  characteristic  is  subject  to  wide  variations,  so  that  many  problems 
of  histogenesis  remain  unsolved. 

Historical. — Although  Astley  Cooper  recognized  a  distinction  between 
periosteal  and  medullary  tumors  of  bone,  the  older  clinicians  separated  im- 
perfectly between  primary  sarcoma,  secondary  carcinoma,  and  chronic  inflam- 
mations of  bone.  Boyer  first  employed  the  term  "osteosarcoma"  and  applied 
it  to  certain  malignant  bone-tumors.  The  microscopical  distinctions  be- 
tween sarcoma  and  carcinoma  of  bone  were  established  by  Lebert  in  1845. 
Virchow  very  fully  described  the  morphology  of  these  tumors,  but  did  not 
separate  them  sharply  from  cancer.  In  1849  Robin  described  two  types  of 
marrow-cells  which  he  believed  gave  origin  to  bone-tumors.  One  of  these, 
the  myeloplaque,  was  described  as  a  large  giant-cell  with  6  to  10  nuclei,  each 
with  nucleoli,  and  found  chiefly  in  young  mammals  in  the  spongy  tissue  and 
between  the  marrow  and  the  inner  wall  of  the  bone.  These  cells  appeared 
abundantly  in  some  tumors.  The  other  type  of  cells,  the  medullocelles,  were 
large  round-cells  with  single  nuclei  and  often  made  up  the  majority  of  marrow- 
cells.  They  also  were  found  in  tumors.  It  is  clear  that  Robin  did  not  fully 
distinguish  bone-forming  from  blood-forming  cells  in  the  marrow.  Kolliker 
identified  the  myeloplaques  with  osteoclasts  and  the  medullocelles  with 
osteoblasts. 

In  1853  Paget  also  recognized  a  variety  of  tumors  containing  large  giant- 
cells  which  he  identified  with  the  giant-cells  of  marrow,  and  Gray  described 
these  cells  as  forming  a  well-defined  layer  where  the  marrow  comes  in  con- 
tact with  the  bone  in  subjects  under  20  years  of  age.  In  1860  Nelaton  con- 
tributed an  important  monograph  in  which  he  emphasized  the  importance  of 
Robin's  cell  groups  and  sharply  distinguished  between  the  malignant  tumeur 
A  medullocelles  and  the  benign  tumeur  a  myeloplacques.  In  1879  Gross  re- 
viewed the  history  and  morphology  of  giant-cell  sarcoma,  emphasizing,  against 
Billroth's  opinion,  the  benign  prognostic  importance  of  the  giant-cell  struc- 
ture and  showing  in  4  fatal  cases  that  this  tumor  might  become  malignant. 

Gross's  description  of  the  origin,  structure,  clinical  characters,  and  treat- 
ment of  bone-sarcoma  stands  today  as  the  classic  contribution  on  this  subject. 

269 


270  NEOPLASTIC  DISEASES 

Robin's  derivation  of  the  giant-cells  from  bone-forming  cells  of  the  marrow 
did  not  receive  complete  endorsement.  Rindfleisch,  Virchow,  Wyss,  Ziegler, 
and  Hulke  derived  the  giant-cells  from  hypertrophied  bone-cells  liberated 
during  the  absorption  of  bone  (Gross).  Wegner  in  Germany  and  Malassez 
and  Monod  in  France  and  many  later  writers  have  claimed  that  these  cells 
are  vasoformative  in  nature  and  of  endothelial  origin.  Many  observers  have 
shown  that  they  are  present  in  many  forms  of  inflammation  of  bone  (Rustizky, 
Fehr,  Barrie). 

In  recent  years  studies  in  this  field  have  dealt  with  the  origin  of  the 
giant-cells,  the  relation  of  giant-cell  sarcoma  to  inflammation,  and  the  general 
etiology,  prognosis,  and  treatment  of  these  tumors. 

Classification. — Tumors  occurring  primarily  in  bone  include  those  arising 
from  bone-cells  or  osteogenic  tissue  and  those  arising  from  bone-marrow. 
Bone-cells  give  origin  to  tumors  which  retain  more  or  less  of  the  function 
of  bone  production  and  are  properly  called  osteogenic,  while  the  marrow- 
cells  give  origin  to  a  very  different  class  of  tumors  which  are  called  myelomas. 
Malignant  tumors  of  bone-cells,  although  differing  markedly  in  many  features, 
are  essentially  one  and  the  same  disease,  which  may  be  designated  as  osteo- 
genic sarcoma.  The  anatomic  varieties  of  osteogenic  sarcoma  result  from 
exaggeration  of  bone  production,  as  in  sclerosing  osteogenic  sarcoma,  or  over- 
growth of  blood-vessels  as  in  the  telangiectatic  type,  or  from  the  predominance 
of  fibrocellular  tissue  as  in  the  so-called  periosteal  sarcoma.  Many  osteogenic 
sarcomas  combine  all  three  of  these  features.  The  location  of  the  growth  is  of 
minor  importance,  and  yet  periosteal  tumors  are  usually  fibrocellular,  telan- 
giectatic tumors  either  originate  in  the  medullary  portion  of  the  shaft  or  soon 
involve  the  marrow  cavity,  and  sclerosing  sarcoma  fills  the  marrow  cavity  with 
dense  bone.  In  rare  instances  osteogenic  sarcoma  arises  in  two  or  more  bones. 
The  attempt  to  classify  these  tumors  as  periosteal  or  medullary  is,  therefore, 
unsatisfactory,  since  most  of  them  involve  marrow  cavity,  shaft,  and  peri- 
osteum. 

The  benign  giant-cell  sarcoma  of  epulis  type  is  not  osteogenic,  but  is 
essentially  connected  with  the  absorption  of  bone,  and  usually  of  cancellous 
bone.  Its  position  is  usually  medullary.  Its  structure  may  arise  as  a  sec- 
ondary process  in  osteogenic  sarcoma. 

A  peculiar  and  somewhat  rare  tumor  of  bone  presents  the  structure  of 
angio-endothelioma.  It  is  not  osteogenic,  although  it  may  arise  from  the 
blood-vessels  of  bone,  or,  more  probably,  from  the  vessels  of  the  marrow. 
It  is  described  as  an  endothelioma. 

The  myelomas,  although  destroying  bone,  have  no  relation  to  osteogenic 
sarcoma. 

The  entire  group  of  primary  sarcomatous  tumors  of  bone  and  bone-marrow 
may  be  best  classified  as  follows: 

Primary  sarcomatous  tumors  occurring  in  bone. 

1.  Osteogenic  sarcoma: 

a.  Fibrocellular,  chiefly  periosteal. 

b.  Telangiectatic,  involving  marrow  cavity,  shaft,  and  periosteum. 

c.  Sclerosing,  affecting  marrow  cavity,  shaft,  and  periosteum. 

2.  Benign  giant-cell  sarcoma  of  epulis  type. 

3.  Myeloma,  arising  from  bone-marrow  cells. 

4.  Endothelioma,   or   angio-endothelioma,   arising   from   blood-vessels   of 
bone  or  marrow.     (Described  under  Endothelioma.) 

Osteogenic  Sarcoma. — (a)  Periosteal  Sarcoma. — The  ends  of  the  long 
bones,  femur,  tibia,  and  humerus  are  the  chief  seats,  but  the  small  bones  of 
hands,  feet  and  skull,  and  many  other  portions  of  the  skeleton  are  involved. 


SARCOMAS  OF  BONE  AND  BONE-MARROW  271 

The  site  of  origin  of  osteogenic  sarcomas  is  nearly  always  at  the  ends  of  the 
shaft.  A  location  in  the  middle  third  of  the  shaft  is  strong  evidence  against 
an  osteogenic  tumor.  The  main  gross  feature  of  the  periosteal  sarcoma  is  the 
production  of  a  tumor  arising  in  the  inner  layers  of  the  periosteum,  extending 
along  and  inclosing  the  shaft,  with  a  sharply  marked  border,  causing  a  rela- 
tively bulky  rounded  fusiform  or  lobulated  tumor  lying  outside  the  shaft  which 
long  remains  intact.  This  position  favors  a  bulky  growth  so  that  periosteal 


FIG.  86.— Periosteal  sarcoma  completely  traversing  shaft  as  a  telangiectatic  structure. 

sarcomas  commonly  reach  a  large  size,  some  of  them  attaining  very  large  di- 
mensions after  a  long  period.  The  integrity  of  the  shaft  is  usual,  but  not  con- 
stant, for  the  more  cellular  growths  early  penetrate  and  destroy  the  compact 
bone  and  lead  to  spontaneous  fractures.  Even  thus  the  extramedullary  tumor 
is  usually  more  bulky  than  with  corresponding  central  telangiectatic  sarcoma. 
According  to  the  consistence  periosteal  sarcomas  are:  (i)  soft,  cellular, 
and  highly  malignant,  or  (2)  firm  and  fibrous,  or  (3)  irregularly  ossified.  En- 


272  NEOPLASTIC  DISEASES 

capsulation  by  the  periosteum  is  maintained  for  periods  varying  with  the 
character  of  the  growth,  but  the  more  malignant  tumors  invade  not  only  the 
shaft  but  the  surrounding  muscles,  fasciae,  vessels,  and  eventually  the  skin. 
Tendon  insertions  offer  considerable  resistance  to  progress  of  the  growth. 
The  general  appearance  of  these  tumors  supports  the  view  that  the  peri- 
osteum is  not  passively  displaced  by  an  underlying  growth,  but,  as  Marullaz 
finds,  that  the  periosteum  contributes  to  the  growth  and  undergoes  sarco- 


FIG.  87. — Periosteal  sarcoma,  combined  with  diffuse  central  sclerosing  sarcoma. 

matous  transformation.     A  thin,  bony  capsule  may  be  laid  down  by  the 
periosteum. 

Incision  reveals  a  solid  tumor  mass  in  which  the  shaft  is  fused  with  ossi- 
fying tumors  or  eroded  by  cellular  growths.  An  expansion  of  the  shaft  as 
noted  with  benign  central  giant-cell  sarcoma  is  missing.  Fatty  and  mucoid 
degenerations,  hemorrhage,  and  necrosis  may  greatly  alter  the  appearance. 
Maceration  by  removing  the  soft  parts  may  leave  bony  trabeculae  radiating 
out  from  the  shaft,  or  a  globular  mass  resembling  an  exostosis,  or  isolated  bony 


SARCOMAS  OF  BONE  AND  BONE-MARROW 


273 


areas  may  be  removed  entirely.  Many  of  the  large  tumors,  especially  of 
the  spindle-cell  variety,  contain  cysts  filled  with  serous  fluid,  or  semifluid 
detritus,  or  blood.  Although  sometimes  quite  vascular,  periosteal  sarcomas 
do  not  pulsate. 

All  the  histological  varieties  of  bone-sarcoma  originate  in  the  periosteum, 
but  the  spindle-cell  type  is  most  frequent.  Giant-cells  are  absent  in  many 
cases,  and  always  less  numerous  than  in  benign  central  sarcomas,  being  found 
usually  in  areas  of  dissolving  bone.  The  tendency  to  calcification  and  ossi- 
fication may  be  very  prominent.  In  one  group,  in  which  the  cells  are  usually 
large  and  polyhedral,  the  matrix 
is  chiefly  cartilaginous.  Some  of 
the  most  malignant  bone-tumors 
are  of  this  type,  and  at  times 
the  large  polyhedral  cells  grow  dif- 
fusely, while  the  cartilaginous  ma- 
trix is  missing  or  reduced  to  hyaline 
traces. 

(V)  Telangiectatic  Bone-sarcoma. 
— A  considerable  proportion  of  bone- 
sarcomas  present  an  extensive  de- 
velopment of  blood-vessels  supported 
by  more  or  less  cellular  osteogenic 
tumor-tissue,  they  early  destroy  the 
shaft,  penetrate  the  marrow  cavity 
for  a  short  distance,  and  ruptur- 
ing the  periosteum  extend  widely 
through  fasciae  and  muscle.  The 
exact  origin  of  these  tumors  is  not 
satisfactorily  located,  but  they  seem 
to  arise  from  the  blood-vessels  and 
bony  tissue  of  the  shafts  of  long 
bones.  They  are  sometimes  called 
central  osteogenic  sarcoma,  but  the 
majority  of  central  tumors  are  not 
of  this  type.  They  are  often  con- 
fused with  benign  giant-cell  sarcoma, 
which  is  a  central  medullary  tumor, 
but  is  not  osteogenic  or  malignant. 
The  structure  of  this  telangiectatic 
sarcoma  is  occasionally  seen  over  an 
entire  tumor,  but  more  often  it  is 
associated  with  other  structural 
types,  so  that  it  is  best  interpreted 
as  an  exaggeration  of  the  blood- 
vessel element  in  osteogenic  bone- 
sarcoma.  .  ,  ., 

The  absorption  of  bone  occurs  rapidly,  and  the  line  of  absorption  while 
ragged  is  rather  sharp,  suggesting  that  the  growth  has  originated  in  the  marrow, 
but  the  same  type  of  absorption  occurs  in  vascular  portions  of  tumors  which  are 
chiefly  periosteal.  Spontaneous  fracture  quickly  results  in  many  cases  and 
may  be  the  first  symptom  of  the  disease  to  be  detected. 

Telangiectatic  sarcomas  of  bone  are  osteogenic,  but  the  production  of 
bone  and  even  of  tumor-tissue  may  be  slight.     The  more  solid  portions  of 
such  tumors  usually  present  irregularly  ossified  or  only  calcified    brands, 
18 


FIG.  88. — Telangiectatic,  periosteal, 
spindle-  and  giant-cell  sarcoma  of  femur. 
Perforation  of  shaft. 


274 


NEOPLASTIC  DISEASES 


plates,  or  spicules  of  imperfectly  formed  bone.  In  some  cases  the  periosteum 
is  displaced  outward  and  succeeds  in  laying  down  a  thin  shell  of  bone  which 
crepitates  on  pressure. 

In  the  malignant  bone  aneurysm  the  vessels  are  widely  dilated  into  ir- 
regular sinuses  and  the  tumor-tissue  is  correspondingly  reduced,  or  limited 
to  an  irregular  layer  disposed  along  the  periphery.  Formation  of  bony  or 
osteoid  tissue  is  also  reduced  and  may  be  missing.  The  tumors  may  pulsate 
and  yield  a  bruit. 

The  head  of  the  humerus,  upper  end  of  tibia,  and  lower  end  of  femur  are 
the  chief  seats  of  malignant  bone  aneurysms.  As  a  rule  the  tumor  proves 
highly  malignant  and  recurs  locally  or  in  the  lungs  after  amputation. 


FIG.   89. — Malignant   central   sclerosing  osteogenic   sarcoma   of   lower  end   of   femur. 
Note  partial  limitation  at  epiphyseal  line. 


The  relation  of  the  malignant  bone  aneurysm  to  cavernous  angioma, 
benign  giant-cell  sarcoma,  and  simple  blood-cysts  of  bone  has  been  much 
discussed.  The  opinion  expressed  by  Nelaton,  Volkmann,  Lucke,  and  Gross, 
that  the  great  majority  of  bone  aneurysms  are  forms  of  sarcoma,  has  been 
supported  by  recent  observers  (Gaylord,  Nakayama,  Bloodgood). 

It  is  not  always  easy  but  yet  highly  important  to  distinguish  between 
malignant  bone  aneurysm  and  very  vascular  forms  of  benign  giant-cell  sar- 
coma. The  malignant  disease  is  almost  never  found  until  it  has  destroyed 
much  of  the  shaft  of  the  bone,  whereas  the  benign  process  long  spares  the 
shaft  and  expands  so  slowly  that  the  periosteum  is  able  to  lay  down  a  firm 


SARCOMAS  OF  BONE  AND  BONE-MARROW  275 

bone  capsule  about  the  expanding  tumor.  The  great  majority  of  simple  bone- 
cysts  are  not  connected  with  tumors. 

(c)  Sclerosing  Osteogenic  Sarcoma. — The  production  of  much  dense  solid 
bone  occurs  in  portions  of  many  bone-sarcomas,  but  occasionally  it  forms  the 
bulk  of  the  tumor  or  is  exclusively  present,  and  since  it  is  associated  with  a 
prolonged  clinical  course,  there  are  both  anatomic  and  clinical  grounds  for 
recognizing  it  as  a  specific  form  of  osteogenic  sarcoma.  These  tumors  were 
once  the  subject  of  much  debate  (cf.  Gross),  being  regarded  by  many  authors 
as  bone  cancers,  until  Volkmann  and  Virchow  established  their  true  nature 
and  termed  them  "sclerosing  osteoid  sarcoma." 

In  typical  cases  a  large  portion  of  the  end  of  a  long  bone  is  converted  into 
a  solid  mass  of  dense  almost  ivory-like  bone,  which  obliterates  marrow  cavity 
and  shaft  and  produces  a  fusiform  swelling  of  considerable  dimensions.  Blood- 
vessels are  very  scanty  except  about  the  periphery  or  over  a  small  area  of  the 
tumor,  yet  metastases  form  in  a  high  proportion  of  cases,  so  that  this  slowly 
advancing  tumor  has  long  been  known  to  be  fully  as  malignant  as  the  others. 
They  show  comparatively  little  tendency  to  invade  surrounding  soft  parts. 

Areas  of  sclerosing  sarcoma  occur  frequently  with  periosteal  growths 
in  which  they  show  all  grades  of  bone  formation  up  to  the  very  dense  ivory- 
like  type. 

Capsular  and  Parosteal  Sarcoma. — Osteogenic  tumors  not  infrequently 
involve  the  capsules  of  joints  or  appear  in  the  soft  tissues  about  joints  or 
along  the  shafts  of  bones.  This  group  of  cases  is  important  not  only  for  their 
clinical  interest  but  also  for  their  bearing  on  the  origin  of  bony  tumors  and 
of  certain  neoplasms  not  always  recognized  as  related  to  bone.  The  capsule 
of  the  knee-joint  is  the  chief  seat  of  capsular  sarcoma,  and  here  the  tumors 
illustrate  most  of  the  clinical  and  histological  features  of  bone-sarcoma 
(Rydygier,  Lit.).  They  are  distinguished  chiefly  by  the  failure  to  involve 
the  joint-cavity  or  the  bone,  and  their  malignancy  is  distinctly  less  than 
that  of  corresponding  tumors  of  periosteum  or  medulla.  Yet  malignant 
cases  occur  which  are  rapidly  fatal  after  resection  or  amputation.  Some 
produce  a  fusiform  swelling  of  the  joint,  and  being  accompanied  by  fever  the 
case  resembles  tuberculosis  (Garre).  Or  a  localized  tumor  appears  at  one 
point  in  the  capsule  (Marsh). 

Pedunculated  giant-  and  spindle-cell  sarcomas  have  been  described  by 
Weir  and  by  Dowd.  The  structural  variations  cover  most  of  the  scope  of 
bone-sarcoma  with  corresponding  prognosis. 

Capsular  sarcomas  of  the  ankle  exhibit  much  the  same  characters  as  in 
the  knee  (Moser,  Lit.).  The  tendon-sheaths  are  a  common  seat  of  sarcoma 
which  usually  takes  the  form  of  a  giant-cell  tumor  of  slight  malignancy. 
The  deep  fasciae  may  be  the  seat  of  sarcomas  of  various  osteogenic  varieties 
which  have  no  definite  connection  with  the  periosteum  and  the  true  nature 
of  which  may,  therefore,  be  overlooked.  They  include  giant-,  spindle-,  and 
round-cell  types,  and  may  belong  in  the  group  of  chondrosarcoma  or  its 
derivative,  myxochondrosarcoma. 

Along  the  cranial  sutures,  base  of  skull,  pharynx,  nares,  vertebrae,  and 
pelvis  occur  many  tumors  of  pronounced  osteogenic  character  which  belong 
in  this  group,  and  not  a  few  in  which  the  derivation  from  bone  is  only  vaguely 
indicated  by  the  structure. 

The  course  of  osteogenic  sarcoma  varies  greatly  and  accords  in  general 
with  the  histological  structure.  As  a  rule  they  are  malignant  tumors  appear- 
ing before  the  3oth  year,  recurring  after  incision  or  amputation  and  producing 
pain,  fever,  metastases,  and  cachexia.  Coley  reports  4  bone-sarcomas  occurring 
in  subjects  aged  17  months  to  9  years.  Goebel  has  collected  a  series  of  con- 


276  NEOPLASTIC  DISEASES 

genital  sarcomas  of  bone  and  other  tissues,  and  recorded  a  successful  result 
with  periosteal  sarcoma  by  local  extirpation  and  x-ray  treatment.  The  spindle- 
cell  tumors  grow  rather  slowly,  but  nevertheless  tend  to  recur  and  cause  death 
by  local  growth  and  internal  metastasis.  Jackson  recorded  an  unusual  case 
in  which  a  small  growth  on1  the  under  side  of  the  knee  increased  very  slowly 
for  32  years,  when  after  trauma  it  grew  rapidly  and  produced  a  large  medullary 
tumor.  The  highly  osteoid  tumors  may  also  pursue  a  very  chronic  course,  as 
with  cases  of  Paget  and  Holmes,  which  proved  fatal  with  metastases  after  21 
and  25  years. 

Metastases  are  frequent  with  osteogenic  periosteal  sarcoma,  in  the  ad- 
vanced stages  of  all  types  and  very  early  with  soft  and  cellular  varieties. 
A  period  of  months  or  years  may  intervene  between  the  appearance  of  the 
primary  and  the  secondary  tumors  or  there  may  be  almost  simultaneous 
involvement  of  several  bones  (LeDentu,  Zahn,  Poncet).  That  these  tumors 
are  not  myelomas  is  attested  by  Poncet's  case.  The  lungs  are  chiefly  in- 
volved by  emboli  through  the  blood-vessels  and  other  widely  distant  organs 
may  be  reached  by  the  same  route.  Neighboring  or  distant  lymph-nodes  are 
also  occasionally  invaded  through  lymphatics,  but  swollen  lymph-nodes 
usually  prove  to  be  purely  inflammatory.  The  occurrence  of  pulmonary 
tumors  secondary  to  periosteal  sarcomas  was  noted  by  Virchow,1  but  the 
frequency  and  extent  of  such  metastatic  tumors  has  lately  been  emphasized 
by  LeCount  (Lit.).  In  malignant  cellular  and  vascular  tumors  pulmonary 
metastases  often  occur  quite  early  in  the  disease,  so  that  operation  in  these 
cases  should  not  be  considered  until  the  condition  of  the  lungs  is  determined 
by  #-ray  photograph. 

These  tumors  appear  as  multiple  nodules,  or  as  superficial  pleural  growths, 
or  as  bulky  pleural  or  pulmonary  tumors.  Extensive  diffuse  pleural  growths 
are  reported  by  Virchow,  Pitts,  LeCount,  and  others,  and  pedunculated  pleural 
tumors  by  Virchow  and  Cocks  and  Wilks.  Massive  intrapulmonary  growths 
have  been  observed  by  Birch-Hirschfeld,  Kuster,  Allin,  Meakin  and  others. 
In  structure  the  tumors  have  been  soft  and  cellular  or  cartilaginous  and 
bony,  or  encased  in  a  bony  shell.  In  a  remarkable  case  described  by  Bosch, 
the  pulmonary  metastases  of  an  osteoid  sarcoma  of  the  femur  exhibited  lamellar 
structure  as  in  the  long  bones,  and  enclosed  groups  of  cells  resembling  lymphoid 
marrow.  Pleural  effusion  may  be  absent  and  pulmonary  symptoms  may  be 
slight,  but  bloody  effusions,  dyspnea,  and  hemoptysis  frequently  occur  and 
suggest  tuberculosis. 

In  a  few  cases  extensive  intravascular  growths  have  been  observed. 
Hektoen  found  bony  masses  from  a  tibial  sarcoma,  which  nearly  filled  the 
right  ventricle  and  produced  secondary  growths  in  the  lungs.  Feistmantel 
found  cylindrical  bone  masses  in  one  lung  and  large  nodules  in  the  opposite 
lung  which  probably  resulted  from  metastases  in  the  pulmonary  artery  from 
a  femoral  sarcoma.  Pulmonary  metastases  appear  to  have  occurred,  while 
the  primary  tumors,  of  foot  and  wrist,  were  quite  small  in  the  cases  of  Pitts 
and  of  West.  Usually  they  appear  a  few  months  after  operation  on  the  pri- 
mary growth,  while  in  Jenckel's  case  death  from  a  pulmonary  growth  occurred 
15  years  after  amputation  of  the  femur. 

That  metastases  are  often  produced  by  the  trauma  of  operation  is  indicated 
by  McAuliffe's  observation  of  tumor-cell  emboli  in  many  organs  after  death 
from  resection  of  a  sacral  sarcoma. 

Structure  of  Osteogenic  Sarcoma. — The  three  main  anatomical  varieties 
of  osteogenic  sarcoma  are  marked  by  distinctive  histological  features,  but  the 
frequent  occurrence  of  different  structures  in  the  same  tumor  indicates  that 
the  disease  is  essentially  one  and  the  same.  This  fact  does  not,  however, 


SARCOMAS  OF  BONE  AND  BONE-MARROW  277 

assure  that  with  the  progress  of  knowledge  it  may  not  be  possible  to  separate 
certain  types  of  bone  sarcoma  with  peculiar  histological  structure  and  which 
arise  under  peculiar  conditions. 

i.  Spindle-cell  tumors  are  the  most  frequent,  and  this  is  the  usual  form  of 
periosteal  growth.  The  cells  have  a  short  spindle  form,  or  they  appear  larger 
and  almost  polyhedral,  and  in  very  anaplastic  processes  they  are  small  and 
appear  almost  round,  although  never  assuming  lymphoid  characters.  Osteo- 
genic  sarcoma  is  never  a  round -cell  tumor.  All  round-cell  growths  of  bone 
arise  from  bone-marrow  cells  and  should  be  sharply  separated  from  tumors  of 
bone-cells. 

The  spindle-  or  polyhedral  or  rounded  cells  of  osteogenic  sarcoma  present 
many  variations  in  size  and  chromatin  content  which  are  of  importance  in 


FIG.  90. — Myxosarcoma-like  structure  in  benign  central  sarcoma. 

prognosis.  Intercellular  substance  may  be  considerable  in  the  slowly  growing 
fibrosarcomas,  but  it  is  reduced  to  a  scant  trace  in  more  rapidly  growing  tu- 
mors, and  may  be  entirely  absent  in  the  most  malignant  cases.  It  may  appear 
in  fibrillar,  hyaline,  or  osteoid  form,  and  when  this  tendency  becomes  marked 
the  growth  passes  into  the  ossifying  group.  The  more  leisurely  the  growth, 
the  more  prominent,  as  a  rule,  is  the  production  of  bony  stroma. 

The  slowly  growing  tumors  are  poor  in  vessels,  but  the  malignant  cellular 
forms  may  be  quite  vascular  and  yield  early  metastases.  The  walls  of  the 
larger  vessels  are  often  infiltrated  with  lymphocytes,  occasionally  they  appear 
sarcomatous,  and  sometimes  they  are  found  distended  with  tumor  tissue 
(Bristowe)  (Fig.  90).  In  vascular  tumors  a  close  relation  of  the  tumor-cells 


278 


N  EOF  LAST  1C  DISEASES 


to  the  blood-vessels  is  common,  and  the  structure  of  perithelioma  may  be 
simulated.    A  pseudo-alveolar  structure  is  sometimes  observed. 

While  usually  well  circumscribed,  spindle-cell  osteogenic  sarcoma  may 
extend  widely  along  the  periosteum,  so  that  very  extensive  areas  of  the  bone 
surface  may  be  involved  in  a  comparatively  flat  tumor.  I  have  found  the 
upper  third  of  the  femur  and  almost  the  entire  surface  of  the  pelvic  bones 
invaaed  by  a  rather  flat  growth  of  small  spindle-cells.  Similar  tendencies  may 
appear  in  the  metastases  of  this  tumor. 

2.  Telangiectatic  sarcoma  usually  presents  a  complex  histological  picture. 
The  dilated  sinuses  are  lined  by  very  cellular  tumor-tissue  in  which  many 

foreign  body  giant-cells  may  appear  and 
lead  to  an  erroneous  diagnosis  of  a  be- 
nign process.  Yet  the  intervening  walls 
and  septa  are  composed  of  large  poly- 
hedral or  spindle-cells  with  hyperchro- 
matic  nuclei  wrhich  fully  attest  the  malig- 
nant character  of  the  disease.  Imperfect 
bone  trabeculae  are  often  found  in  por- 
tions of  these  growths.  In  malignant 
bone  aneurysm  the  tumor  tissue  may  be 
greatly  reduced  by  the  distended  sin- 
uses. In  solid  portions  which  usually 
accompany  the  vascular  tumors  the 
cells  are  very  abundant,  the  stroma 
scanty,  and  the  vessels  small.  The  sur- 
rounding muscles  and  fascise  are  in- 
vaded along  the  septa  and  by  the  blood- 
vessels. Rapidly  advancing  tumors  of 
this  type  may  cause  separation  of  a  large 
portion  of  the  diaphysis,  which  lies  loose 
in  the  center  of  the  mass.  In  and  about 
the  tumor  old  or  new  bone  in  process  of 
absorption  may  yield  very  complex  pic- 
tures often  marked  by  foreign  body  giant- 
cells  and  irregular  calcific  deposits. 

3.  Sclerosing  (Ossifying)  Osteogenic 
Sarcoma. — The  formation  of  dense  bone 
tissue  is  a  feature  of  the  more  slowly  pro- 
gressive bone  tumors,  in  which  the  rate  of 
proliferation  of  the  cells  is  sufficiently  re- 
strained to  permit  them  to  exhibit  their 
natural  function.  Cellular  bone-free 
sarcomas,  under  #-ray  treatment,  may 
cease  to  grow  and  begin  to  lay  down 
bone. 

In  periosteal  tumors  the  bone  usually  appears  in  stalactite  form  radiating 
from  the  shaft  and  giving  a  characteristic  appearance  by  the  x-ray.  The  struc- 
ture shows  well-formed  trabeculae  of  variable  size  surrounded  by  and  including 
many  hyperchromatic  osteblasts.  In  portions  of  such  tumors  much  cartilage 
or  osteoid  tissue  may  appear  and  show  gradual  transformation  into  bone. 
Tumors  composed  chiefly  of  cartilage,  osteochondrosarcoma,  contain  many 
large  polyhedral  cells,  in  compact  groups  or  separated  by  hyaline  stroma, 
and  these  are  among  the  most  malignant  of  osteogenic  sarcomas. 

In  sclerosing  central  sarcoma  the  very  dense  bone,  filling  the  marrow 


FIG.  91. — Osteogenic  sarcoma,  perios- 
teal and  central. 


SARCOMAS  OF  BONE  AND  BONE-MARROW 


279 


cavity  and  distending  the  shaft,  presents  solid  masses  and  irregular  trabeculas 
of  bone  between  which  lie  compressed  tumor-cells.  More  cellular  foci  often 
appear  along  the  edges  of  the  tumor  or  scattered  through  it.  About  many 
sclerosing  sarcomas  very  cellular  tumor  tissue  may  infiltrate  the  muscle  and 
invade  the  veins  (Fig.  94). 

In  most  ossifying  sarcomas  the  production  of  bone  is  accompanied  by  its 
absorption  in  other  portions  of  the  growth,  or  the  two  processes  may  be  found 


FIG.  92. — Malignant  periosteal  and  central  osteogenic  sarcoma. 


closely  associated.  When  bone  is  absorbed  the  solid  trabeculae  first  exhibit 
interfibrillary  clefts  from  decalcification,  then  canals  are  formed  by  advancing 
blood-vessels  or  groups  of  tumor-cells,  or  giant-cells  form  in  lacunas.  In  most 
cases  where  bone,  normal  or  neoplastic,  is  being  absorbed,  the  giant-cells  tend 
to  assume  the  foreign-body  type  of  benign  sarcoma. 

When  ossifying  sarcoma  invades  the  muscle  the  histological  picture  may 
closely  resemble  myositis  ossificans. 


280 


NEOPLASTIC  DISEASES 


Benign  Giant-cell  Sarcoma  (Epulis  Type).— This  peculiar  condition  was 
first  fully  described  as  a  benign  process  in  bone  by  Nelaton,  who  emphasized 
the  reddish  jelly-like  appearance  of  the  tumor-tissue,  noted  its  capacity  to 
absorb  bone  and  widen  the  marrow  cavity,  and  fully  established  its  benign 
course  and  the  wisdom  of  conservative  treatment.  All  of  these  features  have 
been  fully  recognized  by  most  later  observers,  but  not  by  all,  so  that  many 
limbs  have  been  needlessly  sacrificed  because  of  the  failure  to  distinguish  be- 
tween this  benign  process  and  the  malignant  central  telangiectatic  sarcoma. 

The  disease  appears  at  the  ends  of  the  long  bones,  but  it  very  frequently 
arises  in  the  maxillae,  leading  to  the  extraction  of  teeth,  so  that  it  is  often  called 


FIG.  93. — Benign  central  giant-cell  sarcoma.    Epulis  type.    Note  limiting  shell  of  bone 

and  multicystic  appearance. 

the  epulis  type  of  sarcoma.  Very  often  the  first  symptom  noted  is  a  spontaneous 
fracture  at  the  point  where  the  process  has  absorbed  the  shaft.  It  has  fre- 
quently appeared  as  a  multiple  tumor,  and  one  of  the  most  remarkable  of  these 
cases  is  that  of  Martland  in  which  tumors  appeared  in  widely  distant  parts  of 
the  body  over  a  long  period  without  showing  any  evidence  of  local  malignancy. 

Very  similar  tumors  occur  in  the  capsules  of  the  joint,  and  along  the 
tendon  sheaths  and  bursae. 

In  the  long  bones  the  tumors  produce  reddish  jelly-like  tumor  masses 
resembling  granulation  tissue  and  replacing  the  cancellous  portions  of  the 
bone.  They  may  also  slowly  absorb  the  shaft  while  the  periosteum  lays 


SARCOMAS  OF  BONE  AND  BONE-MARROW 


281 


down  an  advancing  shell  of  new  bone.  Eventually  this  shell  may  become  thin 
and  allow  passage  of  the  tumor-tissue,  but  there  is  seldom  any  tendency  toward 
invasion  of  soft  parts.  Likewise  the  cartilaginous  surfaces  of  the  joint  may  be 
reached  and  absorbed  and  the  joint  surfaces  may  collapse,  from  simple  absorp- 
tion, but  without  infiltration  (Gross,  Stimson). 

In  more  cellular  tumors  the  jelly-like  appearance  is  replaced  by  a  more 
opaque  and  firmer  texture,  which  occupies  the  periphery  of  the  growth  while 
the  central  portion  is  soft  or  cystic  and  infiltrated  with  blood. 

Occasionally  these  tumors  present  a  golden-yellow  xanthomatous  appear- 
ance, which  is  associated  with  the  presence  of  many  large  cells  distended  with 
lipoid  granules.  Such  tumors  may  be  bulky,  but  they  are  not,  as  a  rule,  espe- 
cially aggressive. 


:rx 


;$ 

"•* 


FIG.  94.— Periosteal  sarcoma.    Vein  lined  with  tumor-cells.    This  structure  explains  the 
ready  metastases  of  these  tumors. 

Finally,  the  tumor  may  exhibit  the  features  of  a  myxoma  or  myxosarcoma, 
being  more  or  less  translucent  and  elastic.  It  seems  probable  that  the  so- 
called  myxomas  of  the  marrow  cavity  have  mainly  this  origin.  The  charac- 
teristic giant-cells  of  epulis  type  may  be  found  in  many  portions  of  the  growth. 

There  is  considerable  variation  in  the  rate  of  growth  and  bone  absorption 
by  benign  giant-cell  sarcoma.  As  the  spindle-cells  of  the  stroma  become 
more  active  and  abundant,  the  giant-cells  diminish,  the  tumor  shows  less 
resemblance  to  granulation  tissue,  but  becomes  firmer  and  like  spindle-cell 
sarcoma.  Such  growths  recur  locally  and  may  destroy  bone  and  infiltrate 
the  soft  tissues,  but  I  have  never  known  them  to  yield  metastases.  Iney 
regularly  fail  to  produce  bone. 

The  earliest  stages  of  this  disease  have  been  traced  to  the  walls  of  small 
cysts  forming  in  osteitis  fibrosa  cystica.  Here  the  process  may  be  interpreted 


282 


NEOPLASTIC  DISEASES 


as  a  form  of  bone  absorption  or,  as  some  prefer,  rarefying  osteitis  or  osteo- 
myelitis, with  the  formation  of  cysts. 

In  some  cases  the  process  appears  to  subside,  leaving  cysts  with  smooth 
lining  and  serous  contents.  In  most  cases  it  is  progressive  and  acquires  the 
characters  of  a  mild  tumor  process,  and  rarely  it  develops  greater  momentum, 
actively  destroys  bone,  and  exhibits  certain  clinically  malignant  tendencies. 

While  many  of  these  tumors  are  successfully  dealt  with  by  curettage,  there 
are  several  hazards  in  their  surgical  treatment.  The  growth  may  promptly 
recur  after  curettage  and  exhibit  increased  growth  capacity,  while  the  curetted 
bone  is  thinned  and  offers  less  resistance.  The  large  cavity  remaining  after 

curettage  may  fail  to  heal  and  a  difficult 
surgical  problem  remains,  which  some- 
times calls  for  amputation.  Infection 
of  various  types  is  a  sequel  which  may 
prove  very  difficult  to  control,  since 
both  the  tumor-tissue  and  the  exposed 
bone-marrow  are  particularly  suscep- 
tible to  bacterial  invasion.  All  of  these 
complications  may  greatly  alter  the 
natural  gross  appearance  of  giant-cell 
sarcoma. 

Structure  of  Giant-cell  Sarcoma. — 
The  typical  benign  giant-cell  sarcoma 
presents  a  very  characteristic  picture 
which  is  chiefly  marked  by  the  abund- 
ance of  large  giant-cells  containing 

_.-£.W  "j* -js  fi£g£*\t*$'<^  SV\         many  small  separate  oval  nuclei.    This 
'•• »  v»  ,.,v  .  ^k  *  peculiar  structure  indicates  the  presence 

^  -  of  a  peculiar  disease,  and  it  is,  therefore, 
highly  desirable  to  restrict  the  term 
"giant-cell  sarcoma  of  bone"  to  this 
relatively  benign  process.  Similar  cells 
are  sometimes  seen  in  portions  of 
malignant  tumors.  These  cells  are  of 
large  size,  the  cytoplasm  is  opaque  and 
acidophile,  and  the  nuclei  are  numer- 
ous, separate,  oval,  and  usually  grouped 
in  the  center  of  the  cell.  They  often 
contain  vacuoles,  fatty  detritus,  homo- 
geneous material,  red  blood-cells,  and 

occasionally  spicules  of  bone.     They  have  the  general  characters  of  foreign 
body  giant-cells  (Fig.  96). 

The  bulk  of  these  growths  is  composed  of  loosely  packed  spindle-cells 
surrounding  many  vessels,  capillaries,  and  sinuses.  There  is  much  variation 
in  the  vascularity  of  these  tumors  and  in  the  number,  size,  and  nuclear  chro- 
matin  of  the  spindle-cells,  and  there  is  a  corresponding  difference  in  their 
powers  of  growth. 

Osteogenic  sarcoma  may  contain  giant-cells  of  the  above  type,  especially 
where  the  tumor  comes  in  contact  with  absorbing  bone,  but  both  periosteal 
and  central  sarcomas  may  exhibit  giant-cells  of  distinctly  different  type  and 
significance.  These  cells  may  be  large  or  small,  the  cytoplasm  stains  poorly, 
the  nuclei  are  large  and  vesicular  and  composed  of  many  lobes  which  may 
become  detached.  As  a  rule  these  cells  belong  to  malignant  tumors.  While  the 
two  types  of  giant-cells  are  usually  distinct,  it  must  be  admitted  that  transitional 


»* i--      «  *  t     • 


FIG.    95. — Malignant     chondrosarcoma 
of  femur. 


SARCOMAS  OF  BONE  AND  BONE-MARROW 


283 


forms  seem  to  occur,  especially  when  malignant  tumors  undergo  regressive 
changes,  erode  bone,  or  become  inflamed  (Fig.  97). 

The  existence  of  different  types  of  giant-cells  in  bone-sarcoma  has  been  recognized 
by  several  observers.  Poncet  describes  true  and  false  myeloplaques.  The  former  are 
as  large  as  3  to  4  ordinary  tumor-cells  and  contain  5  to  6  nuclei;  the  latter  are  as  large 
as  4  to  5  ordinary  cells  and  contain  12  to  20  nuclei,  and  correspond  to  the  common  giant- 
cell  of  the  epulis.  Borst  states  that  the  giant-cells  of  medullary  sarcoma  are  more 
delicate  than  those  of  periosteal  origin,  in  which  the  cytoplasm  is  more  compact,  often 
free  from  granules,  and  more  sharply  denned,  and  the  cell  processes  are  longer  than  in 
medullary  tumors.  Mallory  distinguishes  between  true  tumor  giant-cells  and  the  foreign 
body  giant-cells  of  osteogenic  and  other  sarcomas.  The  tumor  giant-cells  differ  from 
other  tumor-cells  chiefly  in  size  and  number  of  nuclei  which  may  multiply  by  mitosis. 
They  produce  specific  fibrils.  The  foreign  body  giant-cells  are  of  endothelial  origin, 
and  correspond  in  type  to  those  of  the  epulis. 


.  xv* 


•'-&.  v^V"*5  * 

v"^V*j3'r*  *  *i  j»  _•£*•*,  s.    .  -  '  .  ** 


pIG    96.— Benign  giant-cell  sarcoma  of  head  of  tibia.     Epulis  type  of  medullary  sar- 
coma.    Giant-cells  forming  about  blood  masses  and  hpoid  material. 

The  origin  of  the  giant-cells  of  the  epulis  type  has  been  the  subject  of  much  discussion. 
Virchow  and  Rindfleisch  believed  that  they  were  hypertrophied  bone-cells  set  free  by  the 
absorption  of  the  bone  matrix  and  that  they  are  identical  with  the  osteoblasts  of  Kolliker. 
Robin  and  Nelaton,  in  describing  the  giant-cell  sarcoma  of  bone  (tumeur  a  myeloplaxes), 
accepted  the  identity  of  the  giant-cells  with  Kolliker's  osteoblasts.  This  view  is  favored 
by  the  very  frequent  presence  of  giant-cells  in  many  lesions  of  bone  and  has  been  widely 
accepted.  The  direct  transformaton  of  bone-cells  into  giant-cells  of  sarcoma  has  been 
traced  by  Wyss,  Ziegler,  and  others,  but  it  is  not  clear  that  the  giant-cells  observed  in 
the  malignant  tumors  of  those  authors  were  identified  with  those  of  the  epulis.  Ziegler 
found  that  giant-cells  are  by  no  means  constant  in  the  absorption  of  bone  and  suspected 
that  osteoclasts  might  have  a  variable  origin. 

Wegner,  Malassez,  and  many  later  observers  have  been  led  to  conclude  that  the 
giant-cells  of  the  epulis  are  derived  from  modified  endothehum  or  angioblastic  cells,  and 


284 


NEOPLASTIC  DISEASES 


Malassez  classified  this  tumor  with  the  angioblastic  sarcomas.  Very  similar  results 
were  reached  by  Ritter,  who  traced  the  cells  in  Howship's  lacunae  to  proliferating  endo- 
thelium,  and  he  further  concluded  that  these  cells  may  take  on  the  function  of  bone-cells. 
Borst  recognizes  the  multiple  origin  of  the  giant-cells  of  sarcomas,  but  clings  to  the 
view  that  in  the  epulis  they  stand  as  evidence  of  the  bony  origin  of  the  tumor  matrix. 
Mallory  holds  that  the  giant-cells  of  epulis  are  transformed  wandering  endothelial 
leukocytes  and  do  not  belong  to  the  tumor  process. 

Thus,  both  in  morphology  and  in  origin  it  is  necessary  to  recognize  two  types 
of  giant-cells  in  bone-sarcoma.  One  occurs  chiefly  in  the  benign  epulis,  is 
chiefly  of  endothelial  origin,  and  belongs  among  the  foreign  body  giant-cells, 
although  participating  in  the  tumor  process.  The  other  occurs  chiefly  in 
malignant  periosteal  tumors  and  is  derived  from  tumor-cells. 


FIG.  97. — Periosteal  sarcoma.     Malignant  giant-cell  structure. 


The  giant-cells  of  bone  sarcoma  are,  therefore,  contributed  both  by  the 
bone-cells  and  by  proliferating  angioblastic  cells.  Apparently  the  growing 
endothelium  feels  the  influence  of  the  mother  tissue  and  may  take  on  some 
of  the  form  and  function  of  bone-cells,  giving  the  specific  structure  of  the 
benign  epulis  which  is  rarely  observed  except  in  connection  with  bone. 

On  account  of  their  chiefly  angioblastic  origin  and  benign  course  many 
have  suggested  that  bone-tumors  of  the  epulis  type  should  be  excluded  from 
the  class  of  sarcomas  or  even  of  true  tumors.  Yet  these  cases  show  many  feat- 
ures of  neoplasms,  not  a  few  are  moderately  malignant,  and  many  transi- 
tional forms  up  to  the  malignant  tumors  are  observed. 

Prognosis  of  Bone  Sarcoma. — The  widest  extremes  are  represented  in 
the  prognosis  of  different  sarcomas  of  bone,  and  it  becomes  a  matter  of  first 
importance  to  determine  the  prognosis  in  the  light  of  all  the  data,  clinical 
and  pathological. 


SARCOMAS  OF  BONE  AND  BONE-MARROW  285 

The  age  of  the  patient,  the  duration  of  the  disease,  its  rate  of  progress, 
the  particular  bone  affected,  the  completeness  of  the  operation,  and,  above  all, 
the  structure  and  essential  malignancy  of  the  tumor,  must  all  be  considered. 
Subjects  under  20  years  withstand  the  progress  of  malignant  tumors  poorly. 

The  duration  of  the  disease  must  be  considered  from  several  standpoints. 
A  tumor  which  grows  very  slowly  is  for  that  reason  probably  less  malignant, 
yet  there  are  numerous  records  of  long  existing  tumors  suddenly  assuming 
active  growth  after  trauma  (Jackson).  Certain  slowly  growing  but  malig- 
nant osteoid  tumors  appear  not  formidable  in  themselves,  but  early  produce 
metastases  (Le  Count).  The  local  damage  to  tissues  occurring  in  the  ad- 
vanced stages  of  otherwise  comparatively  benign  tumors  is  an  important 
element  in  prognosis,  chiefly  because  it  complicates  the  operation,  but  also 
because  it  favors  invasion  of  veins  and  metastasis.  Kramer  states  that  en- 
capsulation is  the  most  important  factor  in  the  prognosis  of  most  bone 
sarcomas. 

The  rapidity  of  growth  is  a  very  reliable  clinical  sign  of  malignancy  and 
should  always  control  the  deductions  drawn  from  histological  structure. 
Rapidly  growing  tumors  are  nearly  always  malignant  and  eventually  fatal. 
A  highly  anaplastic,  small  spindle-cell,  traumatic  sarcoma  of  patella  sub- 
mitted to  me  by  Dr.  John  Rogers  proved  fatal  6  weeks  after  the  trauma,  with 
very  extensive  local  recurrence  and  metastases.  Many  would  have  described 
this  growth  as  of  round-cell  structure. 

Yet  the  essential  capacity  for  growth  cannot  always  be  estimated  clin- 
ically, encapsulation  restrains  growth,  and  it  is  possible  for  a  tumor  to  change 
its  rate  of  growth.  A  central  tumor  which  long  remains  confined  by  the  peri- 
osteum usually  has  a  limited  growth  capacity,  for  very  malignant  tumors 
early  perforate  the  shaft.  Yet  in  one  of  Bloodgood's  fatal  cases  symptoms 
had  existed  for  25  years. 

It  is  an  established  rule  that  periosteal  growths  are  much  more  malignant 
than  central  tumors,  but  this  rule  has  little  practical  value.  Gross  found  the 
average  duration  of  life  with  round-cell,  spindle-cell,  and  osteoid  periosteal 
tumors  with  operation  at  18,  20,  and  92.7  months  respectively.  While  ampu- 
tation in  the  early  stages  of  spindle-cell  or  osteoid  sarcoma  of  the  extremities 
may  be  followed  by  complete  recovery,  the  prognosis  of  any  variety  of  peri- 
osteal sarcoma  located  in  or  near  the  trunk  is  very  grave.  The  great  majority 
of  cases  which  seem  to  recover  after  operation  eventually  suffer  from  local 
recurrence  or  internal  metastasis.  Gross  concluded  that  practically  all  cases 
of  round-cell  or  spindle-cell  periosteal  sarcoma  eventually  die  of  the  disease, 
while  with  osteoid  sarcoma  65.62  per  cent,  of  the  cases  prove  fatal.  More 
recent  statistics  show  slightly  better  results  and  some  dependence  of  the  out- 
come upon  the  particular  bone  affected. 

Kocher  collected  48  cases  of  sarcoma  of  long  bones  which  were  regarded 
as  cured.  Of  these,  the  radius  was  the  seat  of  the  growth  in  4,  ulna  i,  humerus 
10,  femur  23,  tibia  12.  Coley  collected  57  cases  of  apparent  cures,  30  of 
the  "myelogenous"  type,  15  periosteal,  12  undetermined.  Butlui  collected 
1 8  cases  of  periosteal  sarcoma  of  humerus  which  survived  operation,  but 
only  one  remained  well  after  3  years.  Of  68  cases  of  periosteal  sarcoma  of 
femur  only  one  doubtful  case  remained  well  3  years.  Yet  McCosh  had  3 
recoveries  of  spindle-cell  sarcoma  of  the  femur  among  7  cases.  Bloodgood 
reports  26  medullary  giant-cell  sarcomas  all  living;  18  inoperable  malignant 
sarcomas;  34  high  amputations  without  a  single  cure;  and  6  permanent  cures 
(periosteal  osteosarcoma,  3;  myxochondrosarcoma,  2;  fibrosarcoma,  i). 

Rheinhardt  reported  7  permanent  cures  (8  to  12  years)  out  of  54  cases, 
including  4  round-cell  tumors,  of  tibia  2,  and  humerus  2.  Coley  collected 


286  NEOPLASTIC  DISEASES 

62  cases  of  sarcoma  of  clavicle,  of  which  6  recovered,  but  in  many  the  result 
was  not  known.  Nancrede  could  find  no  cases  of  recovery  from  sarcoma  of 
the  scapula.  The  interscapulothoracic  amputation,  while  comparatively 
effective  for  benign  tumors  of  the  humerus,  appears  to  have  succeeded  in 
curing  only  i  advanced  malignant  tumor  of  the  humerus  (Berger's  case) 
(Jeanbreau,  Riche). 

From  a  general  survey  it  appears  that  recovery  has  occasionally  followed 
operation  for  almost  every  variety  of  sarcoma  of  the  long  bones,  but  in  none 


FIG.  98. — Rapidly  growing  telangiectatic  osteogenic  sarcoma  of  femur.     A  malignant 
bone  aneurysm.    Sequestration  of  end  of  diaphysis.     Total  duration  6  months. 

of  the  statistical  reports  of  Nasse,  Reinhardt,  Koeber,  Butlin,  Coley  has 
adequate  attention  been  given  to  the  dependence  of  prognosis  upon  the  loca- 
tion, origin,  and  structural  type  of  the  tumor. 

Although  Billroth  asserted  that  the  histological  structure  is  of  no  aid 
in  prognosis,  this  opinion  cannot  apply  to  the  more  malignant  tumors,  most  of 
which  prove  fatal  and  among  which  recovery  is  determined  by  the  location 
and  stage  of  growth  of  the  tumor.  Contrary  to  the  above  opinion,  histo- 
logical studies  have  established  the  benign  nature  of  the  central  giant-cell  sar- 


SARCOMAS  OF  BONE  AND  BONE-MARROW  287 

coma,  the  greater  malignancy  of  other  types  of  giant-cell  tumors,  and  the 
very  unfavorable  prognosis  of  the  small  spindle-round-cell  growths.  The 
chief  source  of  difficulty  and  confusion  in  this  field  has  arisen  from  the  as- 
sumption that  the  tumors  fall  into  a  few  sharply  defined  categories,  as  giant-, 
spindle-,  and  round-cell,  whereas  there  are  different  grades  of  potential  malig- 
nancy in  each  of  these  groups.  When  this  factor  is  considered  I  believe  it 
will  be  found  in  bone-sarcoma  as  with  other  groups  of  tumors  that  there  is  a 
definite  relation  between  prognosis  and  structure. 

1.  The  benign  nature  of  central  giant-cell  sarcoma  of  the  epulis  type 
was  early  pointed  out  by  Nelaton,  later  by  Gross,  Haberer,  and  others,  and 
is  now  generally  recognized.     Bloodgood  finds  that  practically  all  of  these 
tumors  respond  to  conservative  operations,  and  that  considerable  invasion  of 
the  soft  parts  is  no  bar  to  conservative  treatment.    This  treatment  consists  of 
curettage,  or  resection,  followed  by  application  to  the  wound  of  pure  carbolic 
acid,  and  alcohol,  or  chlorid  of   zinc.     Implantation   of   bone  is  employed 
when  necessary.    Among  26  cases  curetted,  Bloodgood  records  5  recurrences, 
all  of  which  were  cured  by  a  second  curettage  or  by  resection  or  by  amputa- 
tion.   Kramer  and  Hinds  report  successful  curettage  when  both  condyles  of 
the  femur  were  involved.    Most  of  these  tumors  respond  well  to  radium. 

It  was  early  shown  that  certain  giant-cell  sarcomas  of  bone  are  very  malig- 
nant (Ziegler,  Wyss,  Gross),  and  this  fact  has  stood  against  the  general  recog- 
nition of  the  benign  nature  of  the  epulis  type.  Yet  the  giant-cells  of  the 
malignant  tumor  are  quite  different  in  appearance  from  those  of  the  epulis 
and  present  single  multilobed  hyperchromatic  nuclei,  while  the  chief  spindle- 
cells  of  the  tumor  also  show  the  features  of  malignancy,  mitoses,  and  hyper- 
chromatic  nuclei.  Gross  found  that  the  malignant  giant-cell  sarcomas  exhibit 
calcific  deposits  and  bony  trabeculae,  but  these  features  are  wanting  in  the 
sarcomas  of  the  epulis  type. 

2.  The  telangiectatic  sarcoma  and  the  bone  aneurysm  usually  contain 
many  giant-cells,  but  the  prognosis  of  these  tumors  varies  extremely,  some 
proving  highly  malignant.     Here  I  have  several  times  observed  that  the 
character  of  the  giant-cells  is  not  a  safe  guide,  but  that  in  the  malignant  cases 
the  chief  or  spindle-cells  present  unmistakable  features  of  malignancy.    My 
experience  leads  me  to  conclude  that  telangiectatic  bone  sarcoma  tends  to 
prove  malignant  when  it  occurs  near  the  trunk,  when  round  or  spindle-cells 
with  hyperchromatic  nuclei  predominate  over  giant-cells,  and  when  perfora- 
tion and  destruction  of  the  shaft  occur  early.    In  the  malignant  cases  reported 
by  Nakayama  and  Bloodgood  the  scanty  tumor  tissue  was  composed  chiefly 
of  round-  and  spindle-cell  tissue. 

3.  A  source  of  error  arises  when  one  portion  of  the  tumor  differs  from 
another.     When   ulceration  and  necrosis  occur  the  superficial  portions  of 
the  tumor  may  lose  their  original  structure  and  giant-cells  assume  the  benign 
foreign-body  type.     I  have  made  an  erroneous  prognosis  of  benign  sarcoma 
from  the  fungating  tissue  about  a  sinus  leading  to  a  malignant,  sclerosing, 
central  and  periosteal  tumor. 

4.  With   spindle-cell  growths   considerable   differences   in   structure   and 
malignancy  exist  which  are  constantly  revealed  by  the  minute  characters 
of  the  cells.     Comparatively  adult  types  of  spindle-cells  with  much  fibrous 
or  osteoid  tissue  belong  to  the  slowly  growing  tumors  which,  however,  recur 
locally  and  in  advanced  stages  metastasize.     Here  the  prognosis  depends 
upon  the  location,  extent,  and  complications  of  the  tumor.     At -the  other 
extreme  stand  the  very  malignant  rapidly  growing  small  spindle-cell  tumors, 
often  called  round-cell  sarcoma,  for  which  a  fatal  prognosis  must  be  given 
at  all  stages.     Tumors  of  large  polyhedral  or  rounded  cells  occur  in  bone 


288 


NEOPLASTIC  DISEASES 


which  in  general  exhibit  marked  malignancy.  The  exact  grade  may  be  esti- 
mated by  the  minute  characters  of  the  cells,  especially  by  the  activity  of 
cell  division  and  by  nuclear  hyper chromatism.  Fibrosarcoma  and  cellular 
chondromas  are  comparatively  benign.  Myxochondrosarcoma  is  also  as  a 
rule  not  very  malignant,  and  if,  as  is  often  the  case,  such  tumors  are  parosteal 
and  encapsulated,  the  condition  invites  conservative  treatment. 

5.  It  should  be  emphasized  that  the  histological  structure  indicates  only 
the  potential  malignancy  of  a  tumor,  or  its  rate  and  capacity  of  growth.  This 
factor  is  only  one  of  many  which  determine  the  actual  course  of  the  tumor, 


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FIG.  99. — Malignant  telangiectatic  central  sarcoma  of  head  of  humerus  in  a  child. 
Malignant  bone  aneurysm.  The  giant-cells  are  of  the  epulis  type,  but  the  malignancy 
is  indicated  by  the  spindle-cells  with  very  hyperchromatic  nuclei. 

which  forms  the  clinical  conception  of  malignancy.  In  the  field  of  bone 
sarcoma  when  the  clinical  course  does  not  accord  with  the  structural  char- 
acters the  discrepancy  should  be  attributed  to  lack  of  information  regarding 
the  gross  and  clinical  features  of  the  case. 

Treatment. — The  surgical  treatment  of  bone  tumors  is  highly  unsatis- 
factory. Statistics  show  that  nearly  all  osteogenic  sarcomas  eventually  prove 
fatal,  and  while  recovery  seems  to  have  occurred  in  rare  cases  in  several  loca- 
tions, this  fortunate  outcome  is  the  meager  fruit  of  large  numbers  of  useless 
amputations.  Moreover,  it  must  be  recognized  that  the  difficulty  of  separating 
the  benign  from  the  malignant  conditions  results  in  the  needless  sacrifice  of 


SARCOMAS  OF  BONE  AND  BONE-MARROW 


289 


many  limbs,  and  raises  a  reasonable  doubt  about  the  nature  of  some  of  the 
reported  surgical  successes.  Under  these  circumstances  the  demonstration 
that  radium  and  ac-rays,  energetically  employed,  have  a  pronounced  influence 
on  the  cellular  tumors  of  bone  and  bone-marrow  is  a  matter  of  first  impor- 
tance. Applied  to  the  limit  of  skin  tolerance,  these  agents,  especially  radium 
in  large  doses  heavily  filtered,  seem  to  cause  regression  of  the  benign  giant-cell 
sarcoma  with  gradual  restoration  of  the  shafts,  produce  rapid  absorption  of 
the  cellular  myelomas,  and  to  have  considerable  restraining  influence  on  cer- 
tain malignant  osteogenic  sarcomas  which  in  some  cases  has  resulted  in  a 
clinical  cure.  If  these  results  withstand  the  test  of  time,  and  some  of  those 
obtained  at  the  Memorial  Hospital  are  already  of  considerable  duration,  then 
the  treatment  of  choice  of  all  tumors  of  bone  and  bone-marrow  is  by  means  of 


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FIG.  TOO.— Central  sarcoma  of  bone.     Epulis  type.     This  particular  tumor  is  more 
cellular  than  usual,  and  is  not  entirely  benign. 

these  physical  agents.  Not  even  incision  for  diagnosis  can  be  recommended. 
Such  incision  may  lead  to  infection,  it  often  fails  to  yield  material  on  which 
a  positive  diagnosis  can  be  based,  and  it  interferes  with  subsequent  treatment. 
On  the  other  hand,  the  clinical  history,  physical  signs,  *-ray  findings,  and  re- 
sults of  treatment  should  permit  a  reasonably  accurate  estimate  of  the  true 
nature  of  the  case. 

Etiology.— The  etiology  of  bone  sarcoma  is  highly  obscure.  While 
trauma  must  be  accepted  as  a  very  common  exciting  factor,  little  is  known 
about  the  growth  or  structure  of  bone  which  can  explain  the  mode  of  action  of 
the  trauma  A  study  of  the  healing  process  in  fractures  is  yet  very  sug- 
gestive of  the  mode  of  origin  of  traumatic  sarcoma.  In  the  average  specimen 
of  callus  the  proliferative  activity  of  fibroblasts,  osteoblasts,  and  endothehum 
is  quite  remarkable  and  often  presents  a  picture  which  is  difficult  to  separate 
19 


290  NEOPLASTIC  DISEASES 

from  sarcoma.  Especially  in  certain  foci  the  cells  may  be  quite  as  abundant 
as  in  sarcoma,  but  their  arrangement  is  more  orderly  and  the  nuclei  are  not 
hyperchromatic  (Fig.  66).  The  organization  of  considerable  masses  of  blood 
provides  conditions  favorable  for  very  free  growth  of  atypical  cells.  Some 
organizing  blood-clots  after  fracture  I  have  found  quite  difficult  to  separate 
from  sarcoma.  Formation  of  progressive  traumatic  angiomas  which  gradually 
extend  beneath  the  periosteum,  often  inclosed  by  a  shell  of  new  bone,  may 
apparently  precede  the  late  development  of  traumatic  sarcoma. 

As  a  rule  the  trauma  is  moderately  severe  and  may  result  in  fracture  or 
splintering,  or  in  local  hemorrhage,  and  the  tumor  seems  to  represent  an 
exaggeration  and  perversion  of  the  healing  process.  Klebs  describes  a  very 
early  medullary  sarcoma  in  which  the  adventitial  cells  of  the  blood-vessels 
seemed  to  be  chiefly  concerned.  There  is  some  evidence  that  the  presence  of 


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FIG.  101. — Structure  of  malignant  chondrosarcoma  of  bone. 


blood  exerts  a  peculiar  stimulating  influence  on  the  regeneration  of  bone. 
Both  these  factors  are  present  in  the  healing  of  fractures  and  other  traumatic 
conditions. 

All  varieties  of  sarcoma  have  been  attributed  to  trauma,  but  it  is  evident 
that  the  injury  is  only  one  of  several  essential  factors,  since  many  or  most 
cases  fail  to  give  a  history  of  trauma,  many  tumors  arise  in  bones  protected 
from  injury,  and  occasionally  bone-sarcomas  are  multiple.  The  traumatic 
origin  applies  chiefly  to  periosteal  sarcoma.  The  fact  that  central  sarcomas 
arise  in  the  diaphysis,  usually  near  the  epiphyseal  line,  indicates  that  disorders 
in  the  growth  of  bone  at  this  point  are  involved  in  their  origin.  Borst  reports 
a  remarkable  case  of  periosteal  ossifying  sarcoma  which  contained  islands  of 
lymphoid  cells  and  hematoblasts,  and  he  suggests  that  the  tumor  arose  in 
part  from  an  aberrant  portion  of  marrow  tissue.  For  the  common  epulis  of 
the  alveolar  border  injury  to  the  periosteum  and  bone  from  extraction  of  teeth 


SARCOMAS  OF  BONE  AND  BONE-MARROW 


291 


may  be  responsible.  Yet  primary  tumors  of  this  type  are  common  in  the  jaw 
bones,  and  they  may  precede  and  call  for  the  extraction  of  teeth. 

The  origin  of  parosteal  sarcoma  must  be  referred  to  misplaced  islands 
of  bone-forming  tissue.  An  imperfect  differentiation  of  tissues  neighboring 
to  bone  such  as  has  been  assumed  to  exist  in  myositis  ossificans  may  also 
be  included  as  an  etiologic  factor.  The  observed  facts  do  not  seem  to  require 
the  theory  of  a  metaplastic  development  of  any  recognized  type  of  bone- 
sarcoma. 

Simple  chronic  inflammation  of  various  types  may  be  concerned  with 
some  of  the  capsular  sarcomas.  Syphilis  and  tuberculosis  may  be  suggested 
as  probable  factors  in  certain  of  the  round-cell  and  diffuse  sarcomas,  but 
the  grounds  for  such  an  assumption  are  quite  indefinite.  The  Wassermann 
reaction  has  been  present  in  some  of  my  cases  of  extensive  bone-sarcoma. 


FIG.  1 02. — Excessive  callus  developing  in  2  weeks  about  a  comminuted  fracture  of  inner 
end  of  clavicle.     Clinically  resembling  sarcoma. 

The  idea  that  trauma  or  any  other  factor  may  lead  to  the  development  of 
sarcoma  at  the  ends  of  long  bones  which  are  previously  entirely  normal  is, 
I  think,  without  satisfactory  foundation.  There  is,  however,  abundant 
evidence  that  developmental  disturbances,  chiefly  at  the  epiphyseal  lines, 
form  an  essential  factor.  The  routine  examination  of  the  ends  of  bones  in 
infants  shows  not  a  few  irregularities  in  growth  resulting  in  the  displacement 
of  islands  of  cartilage  in  marrow  cavity  or  periosteum.  These  irregularities 
I  find  especially  frequent  after  rickets.  Many  osteogenic  sarcomas  are  sharply 
separated  from  the  marrow  cavity  by  a  septum  of  bony  or  osteoid  tissue, 
indicating  that  the  tissue  of  origin  was  also  separated.  After  rickets  definite 
masses  of  imperfectly  ossified  cartilage  are  often  found  in  the  marrow  cavity. 
It  is  reasonable  to  assume  that  mild  forms  of  bone  dyscrasiae  exist  which  are 
not  recognized  clinically,  but  which  are  capable  of  causing  abnormalities  in  the 
formation  of  the  ends  of  the  bones  with  a  tissue  predisposition  to  tumor  growth. 


292  NEOPLASTIC  DISEASES 

The  elements  of  tissue  predisposition  and  constitutional  tendency  become 
most  apparent  in  connection  with  the  disease  osteitis  fibrosa. 

Osteitis  Fibrosa. — This  interesting  malady,  first  fully  described  in  1891, 
has  important  bearing  on  the  etiology  and  significance  of  giant-cell  sarcoma  of 
bone  of  the  epulis  type  (Haberer,  Bloodgood,  Lit.)-  It  occurs  chiefly  in  chil- 
dren and  has  been  termed  "osteodystrophia  juvenilis"  (Monckberg,  Tietze, 
Konig).  Barrie  emphasizes  the  importance  of  abnormal  bone  formation  and 
defective  calcium  metabolism  (A.  S.,  71,581).  It  also  occurs  in  elderly  sub- 
jects where  its  relation  to  osteomalacia  is  apparent.  It  pursues  a  long  course, 
but  often  ends  fatally  from  cachexia  or  intercurrent  disease.  It  is  charac- 
terized by  defective  calcification  of  the  bones  which  leads  to  thickening,  weak- 
ening and  deformity  of  one  or  many  bones  of  the  limbs,  jaws,  skull,  or  trunk. 
The  bone  tissue  is  replaced  by  cellular  fibrous  tissue  which  may  invade  the 
marrow  cavity  replacing  the  red  marrow.  From  this  stage  the  disease  takes  one 
of  two  courses,  the  cellular  tissue  softening  and  producing  multiple  bone  cysts 
lined  by  fibrous  tissue  and  filled  with  clear  fluid,  or  in  the  wralls  of  the  cysts  or 
with  cyst  formation  giant-cell  sarcoma  develops.  There  has  been  much  con- 
troversy regarding  the  relation  of  the  different  stages  of  this  process,  some 
holding  that  the  cysts  always  follow  the  sarcomatous  process,  others  finding 
that  the  sarcoma  develops  in  the  cysts.  Both  events  seem  to  occur.  A  history 
of  trauma  and  the  presence  of  hemorrhage  and  pigmentation  in  the  walls  of 
cysts  seem  to  show  that  the  presence  of  blood  coagulum  influences  the  develop- 
ment both  of  cysts  and  of  sarcoma.  In  some  cases  fibrous  cysts  are  chiefly 
observed  (Monckberg,  Heinecker),  in  others  cystic  sarcomas  (Haberer),  or 
again  solid  sarcomas  (Rehn).  The  long  duration,  9  years  (Rehn),  and  rela- 
tively benign  quality  of  the  sarcomatous  process  are  notable  features.  Arising 
in  the  course  of  a  nutritional  disturbance  ,of  bone  and  being  associated  with 
inflammatory  changes  Rehn  concludes  that  the  entire  process  is  inflammatory. 
Cystic  softening  of  the  tumors,  transformation  into  fibrous  tissue,  and  spon- 
taneous disappearance  have  several  times  been  observed.  Lubarsch  points 
out  that  very  similar  processes  giving  rise  to  a  diagnosis  of  sarcoma  occur  at 
the  points  of  fractures  in  cases  of  osteitis  fibrosa  and  he  inclines  to  the  opinion 
that  the  process  is  not  a  true  sarcoma  (Gaugele). 

A  remarkable  case  reported  by  Martland  of  multiple  giant-cell  sarcomas 
involving  many  of  the  bones  of  the  body  probably  belongs  in  this  category 
and  illustrates  a  universal  tissue  predisposition  to  the  disease.  Knaggs  and 
Gruner  describe  an  atypical  case  of  fibrous  osteitis  affecting  femur,  tibia,  and 
fibula,  and  ending  in  malignant  sarcoma. 

Kolisko  identifies  osteitis  fibrosa  with  Paget's  osteitis  deformans  arid  finds 
that  in  both  the  transformation  of  bone-marrow  into  fibrosa  tissue  may  be 
followed  by  regressive  changes  leading  to  bone  cysts  or  to  progressive  changes 
giving  rise  to  giant-cell  sarcoma  of  slight  malignancy. 

MULTIPLE  MYELOMA 

Multiple  myeloma  is  a  specific  malignant  tumor  of  the  bone-marrow 
arising  probably  from  a  single  cell  type,  and  characterized  chiefly  by  multiple 
foci  of  origin,  a  uniform  and  specific  structure  composed  of  plasma-cells  or 
their  derivatives,  rare  metastases,  albumosuria,  and  a  fatal  termination. 
This  orthodox  definition  of  the  classic  picture  of  the  disease  is,  however, 
subject  to  extensive  modifications,  as  will  appear  in  the  context. 

The  disease  was  first  described  by  Mclntyre  in  1850  under  the  term  "mol- 
lities  ossium,"  and  has  been  variously  interpreted  by  subsequent  observers 
as  senile  osteomalacia  (Marchand);  myelogenous  pseudoleukemia  (Zahn); 


SARCOMAS  OF  BONE  AND  BONE-MARROW  293 

primary  multiple  sarcoma  of  bone-marrow  (Buch).  The  general  clinical 
characters  were  early  recognized,  Mclntyre  reporting  the  presence  of  Bence- 
Jones  albumose  in  the  urine,  while  the  tendency  of  the  disease  to  limit  itself 
to  the  bone-marrow  and  the  resemblance  to  an  infectious  granuloma  have 
been  repeatedly  noted.  Rusticky  (1873)  seems  to  have  first  recognized  the 
disease  as  a  specific  affection  of  the  bone-marrow  and  employed  the  term 
"myeloma."  Kahler  (1889)  demonstrated  the  nearly  constant  occurrence  of 
the  albuminuria  and  the  peculiar  nature  of  the  protein  involved.  The  identity 
of  the  tumor-cells  in  many  cases  with  plasma-cells  was  pointed  out  by  Wright 
in  1900.  The  etiology,  pathogenesis,  origin  of  the  albumosuria,  and  the 
relation  to  other  tumors  and  pathological  processes  in  bone-marrow  still  re- 
main obscure. 

Gross  Anatomy. — The  ribs  and  sternum  are  the  chief  original  seats  of  the 
tumors,  while  the  vertebrae,  skull,  femur,  pelvis,  and  humerus  are  less  fre- 
quently involved,  and  in  the  order  named.  In  3  cases  the  ilium  appears  to 
have  been  the  primary  seat  (Hoffmann).  The  tumors  form  small  nodules, 
multiple  and  as  large  as  a  bean,  or  bulky  growths  as  large  as  an  orange,  asso- 
ciated with  many  smaller  tumors.  Twenty-eight  separate  tumors  have 
been  observed  in  the  skull  (Winkler),  and  the  diffusion  of  the  process  is  often 
wide-spread,  involving  many  bones  and  revealing  a  certain  systemic  quality 
which,  however,  is  nearly  always  much  less  marked  than  that  of  leukemia. 
Yet  the  process  occasionally  appears  in  diffuse  form  and  circumscribed  tumors 
are  missing  (Winkler,  Jochmann,  Schumm,  Abrickassoff,  Hirschfeld,  Lit.). 

The  tumors  are  soft  or  firm,  translucent  or  opaque,  and  whitish,  gray,  or 
deep  red  according  to  vascularity.  Hemorrhage,  infarction,  blood  cysts,  and 
necrotic  areas  may  be  present.  The  bone  tissue  suffers  active  absorption 
and  the  shafts  become  very  thin,  or  multiple  perforations  result,  or  fractures 
occur.  After  passing  the  periosteum  the  surrounding  tissues  are  diffusely 
invaded. 

Many  cases  terminate  without  metastases  in  the  organs,  but  distant  second- 
ary growths  have  been  found  in  liver,  spleen,  kidney,  lung,  and  ovary,  while  in 
certain  very  malignant  cases  that  probably  belong  in  this  category  nearly 
every  organ  in  the  body  may  be  involved. 

The  clinical  course  of  multiple  myeloma  is  that  of  a  progressive  malignant 
tumor  with  gradual  and  often  very  extensive  invasion  of  the  bone-marrow, 
pronounced  lesions  in  the  other  organs,  a  somewhat  specific  cachexia,  and  an 
invariably  fatal  termination.  These  same  general  clinical  features  are  ob- 
served in  all  types  of  myeloma,  in  so-called  myelosarcoma,  and  in  endothe- 
lioma  of  bone,  and  were  closely  simulated  by  a  case  of  chondrosarcoma  re- 
ported by  Seegelken. 

The  disease  arises  chiefly  in  males,  in  the  4th  and  5th  decades  (24  to  69 
years)  and  continues  a  few  months  or  several  years.  The  tumors  are  usually 
first  detected  from  the  pain  they  produce  from  erosion  of  periosteum,  pres- 
sure on  adjacent  nerves,  and  from  general  toxemia,  and  continuous  or  parox- 
ysmal pain  usually  persists.  Recurring  fever  has  been  observed,  but  the 
temperature  is  usually  subnormal.  Fractures  and  extensive  deformities  of 
the  skeleton  mark  the  later  stages.  Prolonged  cases  may  resemble  osteo- 
malacia  (Marchand).  Anemia  may  become  very  severe  and  exhibit  perni- 
cious features  (Grawitz),  but  in  many  cases  the  blood  shows  no  pronounced 
changes.  Rarely  there  is  an  increase  of  myelocytes  in  the  blood,  in  one  case 
up  to  21.8  per  cent.  (Saltykow,  Sternberg).  In  the  blood  of  Aschoffs  case 
Schridde  found  plasma-cells.  Albumosuria  has  been  noted  first  in  the  nth 
week  or  5th  year  of  the  disease.  Its  occurrence  may  be  continuous  or  periodic, 
and  the  quantity  of  albumose  may  be  scanty  or  large,  up  to  6.9  per  cent. 


294 


NEOPLASTIC  DISEASES 


It  has  been  found  in  less  than  half  the  cases,  and  occurs  in  myxedema,  leu- 
kemia, carcinoma  of  bone,  etc. 

Neither  the  exact  nature,  position,  nor  origin  of  the  urinary  protein  are 
fully  understood.  It  bears  some  relation  to  a  severe,  but  non-specific  nephri- 
tis which  commonly  marks  the  disease,  and  other  proteins  may  occur  in  the 
urine.  The  peculiar  qualities  of  this  protein  have  been  fully  studied  by  Mag- 


FIG.  103. — Diffuse  myeloma  of  the  humerus. 

nus-Levy,  Jochmann  and  Schumm,  and  others.  It  precipitates  at  55°  C.,  the 
precipitate  becomes  most  abundant  at  65°  C.,  and  gradually  dissolves  at  85° 
C.,  and  reappears  on  cooling.  Williams  finds  that  its  physical  properties  may 
change  from  day  to  day,  that  it  contains  a  carbohydrate  radicle,  no  phos- 
phorus, and  falls  in  the  group  of  mucins.  According  to  Geis  the  albumose  is 
derived  from  the  elastin  of  bone  tissue  absorbed  bv  the  tumors. 


SARCOMAS  OF  BONE  AND  BONE-MARROW 


295 


The  spleen  is  often  moderately  enlarged,  at  times  partly  in  compensation 
for  the  loss  of  bone-marrow,  or  from  the  general  toxemia,  and  from  metas- 
tases.  The  lymph-nodes  are  rarely  hyperplastic  (Weber,  Scheele,  Ewald). 
Extensive  amyloid  degeneration  of  the  muscles  of  thorax  and  intestine  was 
observed  by  Hueter.  The  termination  of  the  disease  is  marked  by  anemia, 
emaciation,  diarrhea,  dyspnea,  paralysis,  and  coma. 

Structure. — While  in  some  cases  the  cells  of  myeloma  exhibit  the  features 
of  plasma-cells,  large  or  small,  with  single  or  multiple  nuclei,  yet  in  the  entire 
scope  of  tumors  which  probably  belong  in  this  class  the  cells  vary  widely 
in  size  and  character.  In  some  cases  the  entire  tumor  is  composed  of  loosely 
packed  typical  plasma-cells,  8  to  12 fj,  in  diameter,  round,  oval,  or  polygonal, 
and  with  opaque,  amphophile,  non-granular  cytoplasm.  The  single  or  mul- 
tuple  nuclei  are  relatively  small,  eccentric,  or  protruding  from  the  cytoplasm, 


FIG.   104. — Structure  of  a  diffuse  lymphocytic  myeloma  involving  whole  shaft  of  hu- 
merus.     (Same  tumor  as  in  Fig.  .103) 

surrounded  by  a  clear  zone,  and  presenting  blocks  of  chromatin  arranged 
along  the  nuclear  membrane.  Mitotic  figures  are  observed  in  many  cases, 
but  are  less  numerous  when  the  cells  are  typical  plasma-cells.  Certain  cyto- 
plasmic  bodies  have  been  interpreted  as  centrosomes  (Christian).  The  clear 
zone  about  the  nucleus  has  been  described  as  a  vacuolated  secretory  product. 
In  rare  cases  the  round  cells  are  mingled  with  spindle-cells  which  probably 
result  from  pressure  (Wieland). 

In  a  second  group  of  cases  the  cells  are  larger,  giant-cells  with  multilobed 
nuclei  appear,  multiple  and  vesicular  nuclei  are  more  prominent,  nucleoli  are 
large  and  acidophile,  the  resemblance  to  plasma-cells  is  not  striking,  the 
tumors  are  more  malignant  and  metastases  occur.  Here  one  finds  a  structure 
which  recalls  lymphosarcoma  with  large  cells. 

In  this  group  are  rare  cases  of  very  malignant  large  cell  sarcoma  of  the 


296 


NEOPLASTIC  DISEASES 


bone-marrow  with  universal  involvement  of  this  tissue  and  very  extensive 
growths  in  lymph-nodes,  spleen  and  other  organs,  and  in  which  the  cells  are 
uniformly  round,  large,  granular,  and  with  single  or  multiple  vesicular  and 
hyperchromatic  nuclei.  An  extreme  case  of  this  group  has  been  fully  de- 
scribed by  Norris.  It  seems  probable  that  these  tumors  are  a  very  malig- 
nant form  of  neoplasm  derived  from  bone-marrow.  The  relation  to  myeloma 
is  especially  indicated  by  the  fact  that  the  tumors  in  certain  regions  may 
exhibit  a  structure  closely  resembling  ordinary  myeloma. 

The  arrangement  of  the  cells  in  myeloma  is  diffuse,  but  there  is  often  a 
scanty  stroma  separating  groups  of  cells.  Occasionally  the  cells  are  embedded 
in  a  hyaline  acidophilic  material,  and  in  malignant  forms  the  tumors  are 


FIG.  105. — Structure  of  plasma-cell  type  of  multiple  myeloma. 

very  edematous.  As  the  tumor  progresses  the  other  elements  of  the  marrow 
disappear,  but  on  the  edges  tumor  and  marrow-cells  are  intermingled.  Bone 
trabeculae  undergo  simple  absorption  or  in  the  case  of  compact  bone  osteo- 
blasts  are  found  in  lacunae.  The  tumor  never  produces  bone.  An  inflam- 
matory reaction  with  exudate  of  lymphocytes  and  plasma-cells  may  mark 
the  advance  in  bone-marrow,  periosteum,  or  other  tissues.  Some  of  the 
tumors  are  oversupplied  with  small  blood-vessels,  and  in  Rusticky's  case 
a  frontal  tumor  pulsated.  The  larger  vessels  possess  well-formed  walls,  but 
many  small  sinuses  occur  without  definite  walls,  as  in  bone-marrow.  Hemor- 
rhage is  frequent  in  the  central  growths  and  leads  to  softening,  forms  blood 
cysts,  and  leaves  pigmentation.  Extensive  areas  of  necrosis  occur  and  here 


SARCOMAS  OF  BONE  AND  BONE-MARROW  297 

the  cells  undergo  the  usual  forms  of  degeneration.  Similar  degenerative 
changes  overtake  single  cells  in  well-nourished  tumors  and  have  been  used  by 
Hoffmann  as  a  basis  of  classification  of  cell  types.  Extensive  fibrosis  seems 
to  be  the  natural  termination  of  the  process  in  many  areas  of  typical  my- 
eloma. 

Histogenesis. — The  origin  of  the  cells  of  multiple  myeloma  has  been  the 
subject  of  much  discussion  which  necessarily  invades  the  extensive  fields  of 
literature  on  the  relations  of  bone-marrow  cells  and  on  the  origin  of  plasma- 
cells  (Hirschfeld,  Lit.).  That  the  tumor-cells  in  one  group  of  cases  represent 
various  forms  of  plasma-cells  is  strongly  attested  by  the  comparison  made  by 
Christian.  In  one  group  of  cases  the  identity  with  plasma-cells  is  so  striking 
as  to  suggest  that  those  writers  who  doubt  this  identity  have  never  seen  such 
a  case.  Assuming  that  the  plasma-cells  are  derived  from  adventitial  cells 
of  the  vessels  the  myeloma  must  be  derived  from  the  supporting  tissue  of  the 
blood-vessels  of  the  marrow  and  not  from  blood-forming  cells.  Although  the 
earliest  stages  of  formation  of  myeloma  from  adventitial  cells  have  not  been 
traced,  this  theory  of  origin  accords  with  certain  important  clinical  features  of 
the  disease,  such  as  its  relatively  benign  character,  and  partial  resemblance  to 
a  granuloma  and  serves  to  maintain  the  complete  separation  of  the  malady 
from  leukemia.  It  also  serves  to  explain  in  some  degree  the  capacity  of  the 
tumor  to  destroy  bone  tissue.  The  origin  from  adventitial  cells  nearly  related 
to  endothelium  is  further  supported  by  the  occurrence  of  multiple  perforating 
tumors  of  bone  clinically  resembling  myeloma,  but  composed  of  cells  with 
striking  endothelial  characters.  Such  cases  have  been  recorded  by  Kahler 
and  Marckwald,  and  observed  once  by  the  writer,  and,  in  fact,  if  solitary  mar- 
row tumors  are  included  they  are  not  infrequent. 

In  another  group  of  cases  the  cells  lack  close  resemblance  to  plasma-cells 
and  their  form  and  arrangement  strongly  suggest  an  origin  from  the  blood- 
forming  cells  of  the  marrow.  Both  the  red-  and  the  white-cell  progenitors 
have  been  included  in  the  scope  of  this  origin.  Sternberg,  Lubarsch,  Herz, 
and  Charles  were  able  to  demonstrate  a  few  neutrophile  granules  in  the  cells 
of  their  cases,  and  this  evidence  is  believed  by  some  to  demonstrate  an  origin 
from  the  granular  leukocyte  series  (leukocytoma).  Since  these  granules 
are  demonstrated  with  difficulty  in  tissues  from  leukemia  and  since  they  may 
well  be  absent  in  neoplastic  cells,  many,  after  careful  study,  admit  the  absence 
of  granules,  but  still  claim  the  identity  of  the  tumor-cells  with  immature 
myelocytes,  basing  their  conclusion  on  the  other  features  of  the  cells  (Menne, 
Lit.). 

Against  this  view  stands  especially  the  fact  that  other  tumor-like  processes 
affecting  myelocytes,  as  in  leukemia,  pursue  a  wholly  different  course  from 
myeloma.  The  so-called  myelocytomas  being  as  a  rule  more  active  than  the 
plasmomas,  it  may  be  urged  that  a  greater  degree  of  anaplasia  may  transform 
plasma-cells  into  cells  resembling  myelocytes. 

Opinions  regarding  the  scope  of  the  disease,  multiple  myeloma,  have  been 
based  not  only  on  the  histological  structure  of  the  tumors  but  also  upon  the 
clinical  features.  Many  observers  would  adhere  narrowly  to  certain  general 
clinical  characters  which  they  assume  to  be  essential  and  would  eliminate 
from  the  group  all  cases  which  do  not  present  these  features.  Thus  Winkler 
insists  upon  the  strict  limitation  of  the  process  to  the  bone-marrow,  the  absence 
of  metastases,  the  importance  of  albuminuria,  and  the  perfectly  uniform  size 
and  character  of  the  cells.  Yet  it  is  clear,  as  Lubarsch  pointed  out,  that  the 
occurrence  of  metastases  is  more  or  less  accidental,  that  albumosuria  may  be 
absent,  and  the  size  and  form  of  the  cells  may  vary  considerably,  in  cases 
which  in  generaly  strongly  impress  themselves  as  essentially  the  same  disease. 


298  NEOPLASTIC  DISEASES 

On  structure  chiefly  Kaufmann  separates  from  multiple  myeloma  a  group 
of  malignant  lymphosarcomas  of  bone-marrow.  In  these  the  cells  are  larger 
than  plasma-cells,  giant-cells  occur,  a  reticular  matrix  is  present,  and  metas- 
tases  occur.  They  correspond  to  the  writer's  group  of  more  malignant  my- 
elomas. Yet  the  cases  of  Wieland  to  which  Kaufmann  refers  present  the 
main  characteristics  of  malignant  myeloma  and  it  is  clear  that  many  authors 
have  accepted  such  cases  as  true  myeloma,  so  that  the  grounds  for  their 
separation  seem  inadequate.  Both  are  multiple  primary  tumors  of  bone- 
marrow,  perforating  the  compact  tissue,  sparing  lymph-nodes,  producing  al- 
bumosuria,  and  following  the  same  general  clinical  course,  while  variations  in 
the  cells  seem  to  indicate  only  different  grades  of  anaplasia. 

A  distinctly  different  condition  from  myeloma  appears  to  have  existed  in 
the  case  described  by  Hammer  in  which  severe  recurrent  fever,  invasion  of 
lymph-nodes,  metastatic  growths  in  the  dura,  and  extensive  thickening  of 
many  bones  without  albumosuria  were  associated  with  diffuse  lymphoid 
hyperplasia  without  circumscribed  tumors  of  the  bone-marrow.  Such  a 
picture  suggests  a  true  pseudoleukemic  process  and  differs  essentially  from 
multiple  myeloma.  Very  similar  cases  of  myelogenous  pseudoleukemia  have 
been  described  by  Baumgarten  and  by  Rubinstein.  Hodgkin's  granuloma 
affects  the  bone-marrow,  but  its  structure  is  specific  and  quite  different  from 
that  of  multiple  myeloma. 

An  erythroblastic  origin  of  certain  cases  of  myeloma  is  indicated  by  the 
observation  of  Ribbert,  who  found  hemoglobin  in  the  cells  of  his  case.  Norris 
has  also  encountered  such  a  case.  In  a  recent  case  of  multiple  perforating 
bone-tumors  with  enlarged  regional  lymph-nodes,  I  found  most  of  the  cells 
smaller  than  lymphocytes  with  pyknotic  nuclei  and  strongly  acidophile  homo- 
geneous cytoplasm. 

Finally,  in  certain  cases  the  tumor-cells  seemed  to  the  observers  to  lack  the 
specific  features  of  any  of  the  adult  marrow-cells  and  either  to  belong  to  the 
lymphocyte  class  or  to  represent  an  indifferent  blood  metrocyte.  It  is  nota- 
ble that  certain  of  these  cases  have  been  very  rapid  and  malignant  forms  of 
myeloma  (Scheele,  Herxheimer,  Jellinek,  Vignard,  Norris). 

Thus  if  one  classifies  myeloma  according  to  the  views  of  different  observers 
concerning  the  origin  of  the  tumor-cells  the  following  groups  appear:  (i) 
Plasmocytoma,  (2)  erythroblastoma,  (3)  myelocytoma,  adult  and  embryonal, 
(4)  lymphocytoma.  Whether  such  varied  interests  are  actually  represented 
in  the  scope  of  multiple  myeloma  or  whether  we  have  to  deal  with  varying 
grades  of  anaplasia  in  a  single  cell  or  origin  remains  to  be  determined.  At 
present  the  data  seem  to  favor  the  former  alternative. 

Regarding  the  etiology  of  multiple  myeloma  little  can  be  said.  It  is  a 
disease  of  middle  life,  occurring  chiefly  in  males  (19  to  7)  of  the  middle 
classes.  Multiple  tumors  can  hardly  be  closely  connected  with  trauma,  yet 
3  cases  were  referred  to  injury  (Marchand,  Ewald,  Winkler),  and  Winkler 
discusses  at  length  its  mode  of  action.  Grawitz  observed  a  case  which  followed 
typhoid  fever.  Stokvis  found  2  cases  in  brothers.  An  infectious  origin  has 
frequently  been  suggested  from  the  clinical  features,  the  general  significance 
of  plasma-cells,  and  the  relatively  slow  course  of  many  cases.  As  a  late  and 
indirect  sequel  of  an  infectious  process  acting  in  subjects  with  tissue  pre- 
disposition the  disease  is  perhaps  well  conceived.  Yet  several  cases  have 
indicated  a  dependence  on  nutritional  disorders  of  the  bone  itself  which  in 
other  subjects  leads  to  osteitis  or  osteomalacia. 


CHAPTER  XX 
ENDOTHELIOMA 

The  term  "endothelioma"  is  applied  to  an  extensive  group  of  tumors  which 
are  believed  to  be  derived  from  the  lining  cells  of  blood-vessels,  lymph-vessels 
and  spaces,  subdural  spaces,  and  serous  cavities. 

The  scope  of  endothelioma  has  suffered  wide  fluctuations  because  of  the 
uncertainty  surrounding  the  embryological  relations  of  different  classes  of 
endothelial  cells,  the  peculiar  position  occupied  by  these  cells  as  intermediate 
between  epithelium  and  fibroblasts,  and  the  difficulty  of  determining  the  origin 
of  many  tumors  supposed  to  belong  in  this  class.  Thus  some  authors  find 
the  group  extremely  numerous  and  complex,  while  others  insisting  upon 
more  rigid  data  describe  a  very  restricted  class  of  tumors  as  endothelioma. 

Origin  and  Functions  of  Endothelial  Cells. — The  embryological  relations 
of  the  flat  internal  lining  cells  of  the  body  deserve  first  consideration  in  the 
study  of  endothelioma  both  for  the  sake  of  accurate  classification  and  for 
the  bearing  on  many  peculiarities  of  these  tumors. 

Although  our  knowledge  in  this  field  is  still  incomplete  two  main  facts  seem 
to  be  sufficiently  attested:  (i)  The  lining  cells  of  the  great  body  cavities, 
pleura,  pericardium,  and  peritoneum,  arise  from  cells  lining  the  celomic  cavity 
which  forms  early  by  the  splitting  of  two  layers  of  mesoderm;  (2)  the  lining  cells 
of  the  blood-  and  lymph-vessels,  as  well  as  the  subdural  membranes  are  derived 
from  mesenchymal  cells  and  are  very  closely  related  to  connective  tissue. 

Through  the  researches  of  Huxley,  Balfour,  Lancaster,  and  the  Hertwigs 
it  has  been  shown  that  the  mesoderm  owes  its  origin  in  vertebrates  to  a  sepa- 
ration of  cells  derived  from  both  ectoderm  and  endoderm  near  the  primitive 
groove.  The  definite  layer  thus  produced  splits  into  two  lamellae  uniting  with 
the  ectoderm  on  the  one  hand  to  form  the  somatopleura,  and  with  the  endo- 
derm to  form  the  splanchnopleura,  and  inclosing  the  celomic  cavity  between 
them.  In  addition  to  the  processes  which  gives  rise  to  a  definite  middle  germ 
layer,  an  entirely  different  process  gives  origin  to  the  sustentative  tissues  of 
the  body  which  spread  out  into  the  various  ramifications  of  the  main  germ 
layers.  O.  and  R.  Her  twig  (1881)  and  others  have  shown  that  the  sustentative 
tissues  are  derived  from  the  middle  germ  layer  by  the  splitting  off  of  many 
ameboid  cells  which  spread  out  between  the  epithelial  germ  layers  and  form 
the  mesenchyme.  From  this  embryonal  tissue  it  is  now  generally  agreed  that 
the  connective  tissues  and  the  lining  cells  of  the  vessels,  blood-cells,  lymphoid 
organs,  the  smooth  involuntary  muscles,  heart  muscle,  and  in  some  cases  the 
striated  muscles  are  derived.  Concerning  the  exact  mode  of  origin  of  the  blood 
and  vessels,  opinions  are  still  at  variance,  but  the  data  are  becoming  more 
definite.  According  to  Ziegler  the  fundaments  of  the  blood-  and  lymph- 
vessels  are  derived  from  the  interstitial  spaces  of  the  primitive  body  cavity 
which  persists  as  lacunae  and  interstices  in  the  advancing  mesenchyme  and 
become  confluent  in  that  tissue.  A  very  similar  process  is  described  by  others 
who  assume  that  the  first  vessels  arise  from  mesenchymal  cells,  which  arrange 
themselves  in  rows  and  become  canalized,  forming  the  vessels.  Finally,  there 
are  those  who  assume  an  entirely  different  origin  for  connective  tissues  and 
vascular  endothelium,  attributing  the  former  to  migrating  cells  from  the  meso- 
derm and  the  latter  to  cells  of  the  endoderm  which  are  constricted  off  as  an 
independent  tissue  and  give  origin  to  the  whole  vascular  system  (Uskow, 

299 


300  NEOPLASTIC  DISEASES 

Gegenbauer,  Ruckert).  Thus,  embryological  data  do  not  warrant  fundamental 
distinctions  between  the  various  cells  now  commonly  grouped  as  endothelium, 
since  all  are  of  mesodermal  origin.  Although  the  celomic  lining  cells  which 
give  origin  to  the  serous  endothelium  maintain  a  lining  character  throughout, 
that  fact  does  not  warrant  their  identification  with  any  forms  of  epithelium 
such  as  is  derived  from  ectoderm  or  endoderm. 

The  vascular  endothelium  being  of  mesenchymal  origin  is  closely  related 
to  the  connective  tissues,  and  this  fact  may  serve  to  explain  the  resemblance 
of  certain  endotheliomas  to  connective-tissue  tumors,  while  the  difference 
in  the  embryological  history  of  serous  and  vascular  endothelium  seems  to 
find  some  expression  in  the  morphology  of  tumors  derived  from  these  two  types 
of  cells.  Tumors  of  the  serous  cells  show  certain  cacrinomatous  rather  than 
sarcomatous  tendencies.  From  the  embryologic  standpoint  one  might  assume 
a  certain  relation  between  endothelioma  and  tumors  of  lymphoid  or  smooth 
muscle-tissue,  but  observation  does  not  indicate  that  this  relation  is  impor- 
tant. In  the  field  of  endothelioma  as  elsewhere  the  adult  characters  of  the 
cells  seem  to  be  of  more  importance  than  their  embryological  history. 

The  physiology  of  endothelial  cells  establishes  their  position  as  inter- 
mediate between  epithelium  and  connective  tissue.  They  enjoy  certain  func- 
tions recalling  those  of  epithelium,  but  less  specialized.  In  the  formation  of 
lymph  Heidenhain  and  Hamburger  have  shown  that  the  lymphatic  endo- 
thelium exerts  a  secretory  action.  The  secretion  of  a  mucinous  lubricant  is 
a  constant  property  of  serous  endothelium.  Thoma  attributed  to  a  secretory 
process  the  appearance  of  blood  fluids  in  the  closed  cell  layers  of  the  area 
vasculosa  of  the  chick.  Metabolic  functions  are  evidenced  by  the  occurrence 
of  fat  droplets  in  the  normal  endothelium  of  the  pleura  (Thoma).  Phago- 
cytosis by  vascular  and  serous  endothelium  is  often  extremely  active,  espe- 
cially in  the  spleen  and  liver. 

Considerable  light  has  been  thrown  on  the  origin  of  endothelium  and 
blood-cells  by  Stockard's  study  of  fundulus  embryos  without  a  circulation. 
Here  the  serous  endothelium  secretes  large  amounts  of  fluid  distending  the 
pericardium  until  it  deforms  the  embryo.  Vascular  endothelium  forms  locally 
throughout  the  mesenchyme  from  wandering  mesenchymal  cells.  Similar 
wandering  mesenchymal  cells  also  produce  chromatophores.  The  vascular 
endothelium  never  produces  red  or  white  blood-cells.  The  red  blood-cells 
arise  from  a  specialized  portion  of  mesenchyme  or  intermediate  cell  mass, 
derived  from  the  posterior  region  of  the  embryo.  Some  of  these  cells  wander 
out  on  the  yolk-sac,  producing  the  blood  islands  of  Pander.  Leukocyte  pro- 
duction is  largely  limited  to  mesenchymal  cells  in  the  anterior  portion  of  the 
embryo,  but  later  occurs  throughout  the  mesenchyme,  always  from  extra- 
vascular  mesenchymal  cells  and  not  from  endothelial  cells. 

According  to  these  data  vascular  endothelium,  leukocytes,  and  red  blood- 
cells  are  separate  cell  series  derived  from  different  mesenchymal  anlagen. 
Closely  related  to  them  in  origin  is  a  series  of  wandering  chromatophores. 

This  study  is  in  accord  with  others  which  indicate  that  lymphocytes 
are  not  derived  from  the  reticulum  cells  of  lymph-nodes.  The  results  are 
probably  not  irreconcilable  with  the  opinions  of  Councilman,  Mallory,  and 
others  that  lymphatic  endothelium  is  a  source  of  some  large  mononuclear 
cells  of  the  blood. 

The  general  pathology  of  endothelium  most  clearly  illustrates  the  dual 
tendencies  of  these  cells,  revealing,  on  the  one  hand,  the  assumption  of  epithe- 
lial qualities  and  on  the  other  the  possession  of  certain  potencies  of  con- 
nective-tissue cells.  In  the  course  of  inflammation  of  serous  surfaces  endo- 
thelial cells  multiply  readily,  and  form  giant-cells  and  concentric  endothelial 


ENDOTHELIOMA 


301 


pearls.  In  granulation  tissue  they  become  ameboid  and  phagocytic.  Pial 
tubercles  may  be  composed  exclusively  of  aggregations  of  proliferating  en- 
do  thelial  cells.  Birch-Hirschfeld  found  serous  endothelium  closely  related  to 
fibroblasts,  observing  that  they  participated  largely  in  chronic  thickenings 
of  the  peritoneum.  In  artificial  adhesions  of  serous  membranes  Graser 
and  Roloff  traced  the  change  of  serous  cells  into  fibroblasts,  while  fibroblasts 
in  turn  produced  serous  endothelium  on  new  surfaces.  Borst  saw  serous 
cells  assume  star  and  spindle  shapes,  and  Lubarsch  and  Marchand  have 
described  the  formation  of  intercellular  substance  and  fibrils  from  these  cells. 
Yet  Ribbert,  Ziegler,  and  others  do  not  accept  these  observations  as  proving 
the  transformation  of  serous  cells  into  genuine  fibroblasts,  and  it  seems  highly 
probable  that  the  new  tissues  produced  by  proliferating  endothelium  have 


FlG.  1 06. — Angio-endothelioma  arising  in  a  thrombosed  vein. 

not  the  permanence  of  true  connective  tissue,  but  early  undergo  hyalinosis 
and  atrophy. 

Vascular  endothelium  also  proliferates  readily  in  inflammation  and  forms 
collections  of  cells  which  may  resemble  the  groups  of  endothelioma  or  car- 
cinoma. In  endarteritis  the  endothelial  cells  may  contribute  largely  to  the 
new  tissue,  especially  in  syphilis.  In  tuberculous  endarteritis  very  extensive 
new  growth  of  endothelium  is  observed  in  the  intima.  In  the  organization 
of  thrombi  the  endothelial  cells  are  very  active,  wandering  out  into  the  blood- 
clot,  acting  as  phagocytes,  replacing  the  thrombus  with  strands  of  spmdle- 
or  masses  of  flat  cells,  and  conducting  new  capillaries.  The  subsequent 
cicatrization  of  the  organized  thrombus  illustrates  the  usual  fate  of  new  tissues 
produced  by  proliferating  endothelium.  Many  authors  have  described  the 


302  NEOPLASTIC  DISEASES 

alveolar  structures  produced  by  the  reversion  to  the  cubical  type  by  endo- 
thelium  of  tissue  spaces  in  chronic  inflammation.  In  many  cases  of  chronic 
inflammation  of  serous  membranes  groups  of  endothelial  cells  become  in- 
carcerated by  adhesions  and  transformed  into  cubical  or  cylindrical  cells 
producing  structures  resembling  gland  alveoli  (Ribbert,  Renngli,  Meyer, 
Menetrier).  In  most  tissues  the  endothelial  cells  are  the  chief  source  of  the 
epithelioid  elements  in  miliary  tubercles. 

In  lymph-nodes  some  remarkable  grades  of  endothelial  proliferation 
are  observed.  In  chronic  lymphadenitis,  probably  of  tuberculous  origin, 
several  types  of  large  cell  hyperplasia  occur,  some  of  which  closely  resemble 
or  actually  merge  into  neoplasms.  In  scrofulous  lymphadenitis  the  entire 
node  may  be  replaced  by  masses  of  poorly  staining  endothelium.  In  chronic 
congestion  of  the  spleen  the  sinuses  may  appear  lined  by  cubical  endothelium. 
These  and  many  other  details,  which  have  been  extensively  discussed  by 
Borst,  illustrate  the  behavior  of  endothelial  cells  under  abnormal  conditions, 
and  they  may  serve  as  a  standard  of  comparison  in  the  interpretation  of  neo- 
plastic  processes  in  these  cells. 

History  of  Endothelioma. — The  history  of  endothelioma  has  passed 
through  many  stages.  Arising  from  a  well-characterized  cell  type,  these 
tumors  are  of  such  wide  distribution  and  exhibit  so  many  of  the  varied  qual- 
ities and  relations  of  the  originating  cells  that  much  change  and  conflict  of 
opinion  have  always  existed  regarding  their  scope  and  classification. 

Koster  first  clearly  maintained  the  opinion  that  the  endothelium  of  lymph 
spaces  and  vessels  gave  origin  to  many  tumors,  which,  however,  he  regarded  as 
carcinomas.  His  demonstration  that  endothelium  may  give  rise  to  tumors 
closely  resembling  carcinoma  strengthened  the  old  doctrine  of  Virchow  that 
all  cancers  arise  from  the  matrix  of  connective  tissue.  When  Thiersch  and 
Waldeyer  established  the  epithelial  origin  of  carcinoma  and  Carmalt  showed 
that  cancer-cells  could  be  washed  out  of  the  invaded  lymph-vessels,  leaving 
the  endothelial  cells  intact,  the  way  was  opened  for  the  recognition  of  a  special 
group  of  tumors  derived  from  endothelium.  Waldeyer's  authority  encour- 
aged the  interpretation  of  certain  tumors  in  various  organs  as  of  endothelial 
origin. 

In  1869  Golgi  introduced  the  term  "endothelioma,"  applying  it  especially 
to  psammoma  of  the  dura  mater,  which  has  always  stood  as  a  standard  type 
of  the  growth.  The  use  of  this  term  became  established  slowly,  many  authors 
classifying  endothelial  tumors  with  sarcoma.  Thus  Waldeyer  described  the 
perivascular  growths  as  angiosarcoma,  and  Kolaczek  in  an  extensive  study 
classified  all  the  tumors  of  the  endothelium  of  blood-  and  lymph-vessels  as 
angiosarcoma.  The  mixed  tumors  of  the  salivary  glands  previously  regarded 
as  carcinomas  were  placed  by  Kaufmann  among  sarcomas  until  Wartmann 
in  1879  first  maintained  that  the  polyhedral  cells  of  these  growths  are  derived 
from  endothelium.  Yet  the  endothelial  origin  of  salivary  gland  tumors  has 
never  been  universally  accepted,  and  while  Ribbert  and  many  others  have 
firmly  maintained  their  epithelial  nature,  Kaufmann,  Borst,  and  others  accept 
in  part  the  endothelial  theory. 

As  early  as  1866  Lucke  described  a  pulsating  tumor  following  a  fracture 
of  the  forearm,  the  adenoid  structure  of  which  he  referred  to  a  growth  from 
indifferent  cells  of  the  connective  tissue.  Kocher  (1868)  and  Billroth  (1869) 
derived  somewhat  similar  tumors  of  bone  from  the  walls  of  blood-vessels. 
Tillmanns  (1873)  and  Joppe  trace  these  tumors  to  the  endothelial  or  peri- 
thelial  cells.  Schweninger  (1876)  clearly  traced  the  development  of  an  ade- 
noid bone  tumor  to  the  endothelial  cells  of  blood-  and  lymph-vessels  and 
lymph  spaces. 


ENDOTHELIOMA  303 

In  the  orbit  Pagenstecher  first  described  a  tumor  removed  by  Knapp, 
which  by  exclusion  he  was  compelled  to  refer  to  proliferating  endothelium 
of  lymph  spaces,  and  this  view  was  endorsed  by  Knapp  (1872)  in  the  descrip- 
tion of  later  cases.  Yet  it  now  appears  probable  that  most  of  these  tumors 
were  derivatives  of  the  lacrimal  gland  and  that  endothelioma  of  the  orbit 
arises  chiefly  from  the  optic  nerve  sheath. 

In  1879  a  group  of  ovarian  endotheliomas  was  brought  forward  by  March- 
and,  although  Leopold  had  previously  regarded  certain  large  solid  tumors  of 
the  ovary  as  of  endothelial  origin.  In  1870  Wagner  recognized  the  endo- 
thelial  origin  of  certain  pleural  tumors  and  his  view  was  strongly  supported 
by  Neelsen's  study.  In  1867  Massey  and  in  1879  Hubl  described  endothelial 
tumors  of  the  peritoneal  serosa. 

In  the  skin  Kaposi  described  under  the  term  lymphangioma  tuberosum 
a  tumor  which  Jarisch  later  grouped  among  the  hemangio-endotheliomas, 
but  it  has  long  been  known  that  this  tumor  is  derived  from  the  epithelial 
structures  of  the  skin. 

The  lymph-nodes  were  drawn  into  the  sources  of  endothelioma  by  Zahn 
in  1874  under  the  title  of  sarcoma  epithelioides,  while  in  1881  Hoffmann 
and  Schottelius  described  a  similar  tumor  as  endothelioma.  Most  of  these 
tumors  appear  to  have  been  classed  as  carcinomas,  angiosar comas,  and  al- 
veolar sarcomas.  The  writer  in  1914  finds  that  tumors  derived  from  the 
endothelium  and  reticulum  cells  of  lymph-nodes  form  separate  well-defined 
and  rather  frequent  groups  of  tumors. 

In  the  stomach  Hansemann  maintained  that  many  of  the  so-called  scirrhous 
cancers  are  derived  from  endothelial  cells  of  the  lymph  spaces,  a  view  which 
Borst  accepts.  Yet  this  interpretation  is  open  to  question  and  the  existence 
of  a  true  endothelioma  of  the  gastro-intestinal  tract  remains  unproved,  if  not 
improbable.  Likewise  the  existence  of  an  endothelioma  of  the  cervix  uteri  is 
claimed  by  Amann,  Hurdon,  Kirschgessner,  and  denied  by  Sperber,  R.  Meyer, 
and  others. 

In  the  kidney  a  group  of  vascular  tumors  became  generally  recognized  as 
probable  endotheliomas.  The  common  angiosarcoma  of  this  organ  was 
interpreted  by  de  Paoli  as  a  derivative  of  perithelial  cells,  but  the  exact  nature 
of  these  tumors  and  their  common  origin  has  not  yet  been  determined.  Most 
of  them  are  probably  derived  from  adrenal  rests  or  represent  renal  adenomas. 
In  1896  Hansemann  claimed  to  have  traced  the  origin  of  a  vascular  renal  tumor 
to  the  lining  endothelium  of  a  small  and  originally  angiomatous  growth,  but  it 
has  remained  practically  impossible  to  separate  from  the  numerous  renal 
tumors  any  which  may  safely  be  referred  to  this  origin. 

From  time  to  time  specific  terms  have  been  introduced  to  designate  struc- 
tural types  of  endothelioma  or  of  tumors  so  interpreted.  In  1856  Billroth 
described  under  the  term  cylindroma  a  tumor  composed  of  glassy  translucent 
cylinders  of  hyaline  connective  tissue  between  which  ran  a  network  of  tumor- 
cells.  This  structure,  which  is  regarded  by  some  authors  as  a  form  of  inter- 
fascicular  endothelioma,  is  still  often  designated  as  cylindroma. 

v.  Ohlen  in  1893  pointed  out  that  many  authors  had  been  recognizing  a 
second  form  of  cylindroma  arising  by  degeneration  of  groups  of  cells  in  en- 
dothelial masses  and  the  formation  of  cylinders  of  mucinous  material.  This 
structure  likewise  often  received  the  designation  of  cylindroma,  but  it  is  doubt- 
ful if  it  is  ever  produced  by  endothelioma. 

For  many  years  the  term  "angiosarcoma"  was  loosely  applied  to  certain 
endotheliomas.  This  term  was  first  employed  by  Waldeyer  and  Kolaczek 
to  designate  all  tumors  originating  from  blood-  and  lymph-vessels,  and  thus 
it  came  to  include  those  developing  from  endothelial  cells  lining  the  vessels. 


304  NEOPLASTIC  DISEASES 

With  the  recognition  that  Eberth's  perithelial  cells,  described  originally  for 
the  cerebral  vessels,  exist  also  in  many  other  organs,  as  testicle,  adrenal, 
breast,  and  salivary  glands  (Arnold,  Paltauf,  Luschka,  v.  Brunn),  and  that 
tumors  probably  arise  from  these  cells,  a  specific  variety  of  angiosarcoma 
was  admitted  under  the  term  "perithelioma."  This  term  was  especially 
recommended  by  Hildebrandt.  It  has  remained  firmly  established  in  the 
nomenclature,  but  its  relation  to  endothelioma  has  not  yet  been  finally  de- 
termined. According  to  Borrmann,  perithelial  cells  are  modified  endothelial 
cells  of  adventitial  lymph  spaces.  Many  vessels  possess  not  merely  lymph 
spaces  and  perithelium,  but  also  a  definite  plexus  of  lymph-vessels  from 
which  Borrmann  believes  tumors  arise.  He  would,  therefore,  distinguish 
between  perithelioma  and  peri-endothelioma,  the  cells  of  the  former  radiating 
from,  those  of  the  latter  encircling  the  vessel.  In  any  case  perithelioma  ex- 
hibits sarcomatous,  not  endotheliomatous  characters,  and  in  the  writer's 
opinion  this  tumor  should  be  grouped  with  the  sarcomas  (Earth,  Hippel). 
Thus  the  old  class  of  angiosarcomas  is  today  resolved  into  perithelioma, 
periendothelioma,  and  the  various  forms  of  endotheliomas  arising  from  blood- 
and  lymph-vessels.  The  present  tendency  is  to  limit  the  term  "angiosarcoma" 
to  cellular  angiomas  in  which  the  unit  is  the  vessel  and  not  the  endothelial  cell. 

The  scope  of  the  group  of  endothelioma  as  commonly  accepted,  especially 
in  Germany,  reached  its  acme  with  the  appearance  of  Volkmann's  study  in 
which  he  endeavored  to  establish  the  endothelial  origin  of  the  mixed  tumors 
of  the  salivary  glands.  In  1897  Borst  reviewed  in  great  detail  the  behavior 
of  endothelial  cells  under  physiological  and  pathological  conditions  with  a 
result  favorable  on  the  whole  to  the  probable  wide  extent  of  endothelial 
tumors.  In  French  the  tendency  to  recognize  endothelioma  as  of  frequent 
occurrence  was  much  less  pronounced  (Malassez,  Berget,  Collet).  In  recent 
years  a  rigid  critique  has  emphasized  the  fact  that  comparatively  few  of  the 
recognized  groups  are  supported  by  satisfactory  data.  In  1899  Hinsberg 
actively  contested  the  endothelial  origin  of  the  salivary  tumors  and  he  has 
been  supported  by  Ribbert,  Marchand,  and  others,  so  that  the  fibro-epithelial 
nature  of  this  group  has  become  generally  accepted.  Lubarsch  also  has 
demolished  the  diagnosis  of  endothelioma  in  several  types  of  tumors,  includ- 
ing Mulert's  multiple  endothelioma  of  scalp,  a  so-called  endothelioma  of  the 
orbit  which  he  derived  from  the  lacrimal  gland,  and  a  cylindromatous  epi- 
thelioma  of  the  nasal  mucosa.  Ribbert  does  not  accept  the  endothelial  origin 
of  various  cutaneous  growths,  cylindromas,  and  tumors  of  parotid.  The 
so-called  renal  endothelioma  he  thinks  is  of  epithelial  origin,  while  the  endo- 
thelial origin  of  bone-tumors,  as  in  Sternberg's  case,  is  not  proved.  No  tumor 
of  perithelial  cells,  he  believes,  has  yet  been  demonstrated. 

Thus  while  the  existence  of  certain  distinct  classes  and  many  well-defined 
forms  of  endothelioma  was  early  demonstrated,  the  attempt  to  enlarge  the 
scope  to  this  group  of  tumors  by  assuming  an  endothelial  origin  for  many 
growths  of  uncertain  nature  has  met  with  only  partial  success.  The  studies 
of  recent  years  have  served  chiefly  to  emphasize  the  difficulty  of  separating 
true  endothelioma  from  many  typical  sarcomas,  lymphosarcomas,  carcinomas, 
and  certain  embryonal  tumors. 

In  this  dilemma  one  may  follow  Ribbert's  plan  of  discriminating  rigidly 
against  the  tendency  to  discover  endothelial  qualities  in  many  tumors  of 
uncertain  origin.  In  that  case  the  discussion  of  endothelioma  becomes  com- 
paratively brief.  Or  one  may  accept  Borst's  conception  that  the  scope  of 
endothelioma  is  probably  very  wide,  and  one  may  thus  give  full  expression 
to  the  views  of  many  who  favor  the  endothelial  origin  of  a  very  wide  variety 
of  tumors  whose  exact  nature  has  not  been  determined.  While  fully  admit- 


ENDOTHELIOMA  305 

ting  the  deficiencies  of  present  knowledge,  my  own  experience  in  this  field 
inclines  me  to  pursue  the  latter  course. 

Classification  and  Nomenclature. — Various  plans  of  classification  of 
endotheliomas  have  been  suggested.  Hansemann  at  one  time  recommended 
the  elimination  of  the  term  "endothelioma"  and  the  designation  of  these  tu- 
mors as  endothelial  sarcoma,  carcinoma,  adenoma,  etc.  Ackermann  classified 
the  tumors  according  to  their  origin  as  intra vascular,  lymphangiomatous, 
and  interfascicular  (from  lymph  spaces).  Many  recognize  perithelioma  as 
a  separate  variety  derived  from  blood-vessels. 

Borrmann  has  constructed  an  ideal  histogenetic  scheme  including 
hemangio-endothelioma,  lymphangio-endothelioma,  capillary  endothelioma, 
perithelioma,  and  peri-endothelioma.  Of  capillary  endothelioma,  with  pro- 
liferating capillaries  filled  with  endothelial  cells,  he  finds  only  3  recorded 
cases  (Langhans,  Limacher  (Case  II),  Borrmann).  Peri-endothelioma  refers 
to  a  growth  of  cells  of  perivascular  lymph-vessels  concentrically  about  the 
vessel  wall.  In  a  case  described  by  Perthes  he  detects  a  combination  of 
perithelioma  and  peri-endothelioma.  However  desirable  such  histogenetic 
distinctions  may  be,  the  practical  difficulty  of  unraveling  them  has  stood 
in  the  way  of  general  adoption  of  this  scheme.  Borrmann's  capillary  endo- 
thelioma is  generally,  and  I  think,  better  designated  as  an  angioma. 

The  writer  agrees  with  Borst  that  the  most  serviceable  grouping  of  endo- 
theliomas is  based  on  their  morphology  and  he  has  long  employed  the  follow- 
ing plan : 

Histological  Types  of  Endothelioma. — i.  Interfascicular. — The  cells 
grow  in  thin  layers  between  strands  of  connective  tissue.  When  these 
strands  are  swollen  and  hyaline  the  tumor  may  be  designated  as  cylindroma. 

2.  Alveolar. — The  cells  grow  in  small  or  large  groups,  as  in  adenoma. 
When  appearing  in  long  sections  the  groups  may  be  tubular.    When  mutin- 
ous degeneration  occurs  in  these  cell  groups  a  variety  of  cylindroma  is  pro- 
duced, but  the  use  of  this  term  for  such  structures  leads  to  confusion  and  is 
inadvisable. 

3.  Plexiform. — The  cells  grow  in  convoluted  columns  often  surrounding 
vascular  paths.     Papillary  projections  may  arise  from  these  columns  sug- 
gesting the  term  "papillary  endothelioma."    This  structure  is  represented  by 
several  tumors  of  doubtful  origin. 

4.  Perivascular. — The  cells  surround  definite  vascular  paths  usually  in 
concentric  fashion,  as  in  the  dura  mater.    Psammoma,  or  sand  tumor,  applies 
to  this  growth  when  the  units  are  calcified.    Osteo-endothelioma  forms  rarely 
in  the  same  manner  (Perthes). 

5.  Diffiise.—The   cells   grow   diffusely   or   without   definite   arrangement 
in  uniform  relations. 

6.  Miscellaneous  changes  in  the  stroma,  progressive  and  regressive,  are 
readily  indicated  by  appropriate  terms,  as  osteo-,  myxo-,  fibro-,  cysto-,  etc.  ^ 

Perithelioma,  whatever  its  origin,  is  a  highly  characteristic  structure  which 
exhibits  the  qualities  of  sarcoma  or  carcinoma,  with  which  groups  it  should 
be  classed. 

Origin  and  Growth. — The  exact  origin  of  endotheliomas  must  be  referred 
in  general  to  the  various  endothelial  cells,  but  the  earliest  stages  of  growth  are 
rarely  observed.  While  the  absence  of  blood  in  any  of  the  tumor  spaces 
distinctly  favors  a  lymphatic  origin,  its  presence  is  of  less  significance,  since 
abnormal  communications  form  between  the  channels  of  tumors  and  the 
blood-vessels. 

According  to  Borrmann,  true  hemendothelioma  is  extremely  rare  and  he 
accepts  only  a  few  cases,  some  of  which  were  traced  to  capillary  endothelium. 
20 


306  NEOPLASTIC  DISEASES 

The  endotheliomas  of  pleura  and  pericardium  have  been  referred  both  to  the 
lining  cells  and  to  the  cells  of  superficial  lymphatics.  It  seems  probable 
that  both  elements  give  rise  to  tumors  which  differ  somewhat  in  structure. 

The  rare  and  doubtful  ovarian  endotheliomas  have  been  referred  to  the 
perivascular  lymphatics.  While  Rosthorn  traced  capillary  blood-vessels 
into  the  masses  of  tumor-cells,  he  was  uncertain  to  what  extent  the  lining 
cells  of  the  vessels  participated  in  the  process.  For  the  perivascular  tumors 
an  origin  from  the  lymphatic  endothelium  lying  outside  of  the  lining  cells 
must  be  assumed.  Endothelioma  of  lymph-nodes  arises  from  the  lining 
cells  of  lymph  and  cavernous  sinuses. 

Thus  in  the  great  majority  of  cases  it  is  the  endothelium  of  small  vessels 
or  lymph  spaces  which  gives  origin  to  endothelioma.  Many  authors  have 
claimed  that  they  could  trace  tumors  to  more  than  one  form  of  endothelial 
structure,  as  lymph  spaces  and  lymph-vessels,  or  serous  lining  cells  and  endo- 
thelium of  lymphatics  (Volkmann),  lymph  spaces,  and  lining  cells  of  blood- 
vessels (v.  Ohlen,  Franke).  I  do  not  find  that  the  data  presented  by  these 
authors  is  at  all  adequate  for  their  conclusions,  while  some  of  them  were 
probably  not  dealing  with  genuine  endothelioma. 

From  this  chief  source  the  growth  proceeds  either  by  extension  of  the 
cells  derived  from  the  original  territory  or  by  the  continuous  transformation 
of  adjoining  normal  cells  into  tumor-cells.  Ribbert  and  Borrmann  maintain 
that  endotheliomas  grow  exclusively  from  their  own  resources.  In  various 
endotheliomas  Borrmann  finds  that  the  proliferating  cells  of  lymph  capil- 
laries and  spaces  distend  and  enlarge  these  structures  and  eventually  break 
into  other  spaces,  but  they  do  not  produce  new  capillaries  and  "contact  in- 
fection" does  not  occur.  On  the  other  hand,  Best  and  others  describe  the 
gradual  involvement  of  normal  endothelium  in  the  extension  of  the  tumor 
process.  He  finds  this  evidence  chiefly  along  the  growing  edges  of  larger 
tumors,  while  in  the  very  early  stages  of  small  growths  the  increase  seems  to 
be  exclusively  in  the  tumor-cells.  The  multiplicity  of  many  endotheliomas 
renders  the  decision  in  this  question  unusually  difficult.  In  certain  tumors 
of  the  peritoneum  Neelson  and  Glockner  find  a  progressive  involvement 
of  neighboring  lymphatics,  the  lining  cells  of  which  actively  proliferate,  pro- 
ducing a  condition  described  as  lymphangitis  carcinomatosa  (Schottelius) 
or  prolifera  (Schweninger).  Lubarsch  saw  this  process  extend  from  the 
peritoneum  into  the  liver.  It  has  been  held  that  secondary  tumors  may 
arise  in  this  way  without  the  transportation  of  any  tumor-cells  (Schulz, 
Neelson). 

In  many  instances  endothelioma  appears  to  invade  the  tissues  chiefly 
or  exclusively  through  preexisting  channels,  as  lymph-vessels  and  spaces, 
and  fails  to  split  up  the  tissues  as  do  carcinoma  and  epithelioma.  This  feature 
was  especially  notable  in  an  endothelioma  of  the  peritoneum  studied  by 
Wichern. 

The  growth  of  endotheliomas  is  usually  slow  but  progressive^  and  in  this 
resjiect  they  arejcomparatively  benigri.  Especially  m'TOmparison  witrTthe 
forms  of  carcinoma  and  sarcoma  which  they  resemble  histologically,  the 
course  of  endotheliomas  is  relatively  favorable.  When  undisturbed  by  the 
knife  the  growth  capacities  of  some  of  these  tumors  seem  to  be  confined  within 
certain  limits  which  do  not  apply  to  carcinoma  and  sarcoma.  In  the  dura 
very  slow  growth  characterizes  most  of  the  perivascular  tumors  and  pres- 
sure symptoms  are  often  long  delayed.  On  account  probably  of  their  infil- 
trating character  thorough  extirpation  is  often  difficult,  so  that  endothe- 
liomas are  notable  for  persistent  local  recurrence.  Each  recurrence  is  apt 
to  show  increasing  capacity  for  growth  and  changes  in  structure.  This  fact 


ENDOTHELIOMA 


307 


encourages  complete  removal  of  the  organ  involved  and  not  merely  extirpa- 
tion of  the  tumor. 

Extension  to  the  neighboring  lymph-nodes  is  also  late  or  entirely  missing. 
Yet  pleurarendothelioma  has  invaded  the  lung  and  pulmonary  nodes.  As 
an  exception  to  the  rule  certain  endotheliomas  of  lymph-nodes  described 
by  Zahn,  Volkmann,  and  the  writer  were  rather  malignant. 

Hemangio-endothelioma. — Many  authors  have  endeavored  to  emphasize 
and  define  a  distinct  group  of  tumors  which  they  designate  as  above  (Borr- 
mann,  Limacher,  Borst). 

Among  the  tumors  commonly  included  in  this  group  are  certain  growths 
of  the  type  of  angioma,  but  exhibiting  an  excess  of  endothelial  cells,  and  cer- 
tain well-known  cases  are  specifically  included  in  the  group  by  the  above 
authors  (Borrmann,  Lit.).  Yet  Nauwerck's  case  was  designated  by  the 
authors  as  a  simple  hyperplastic  telangiectasis.  Langhans  described  a  multiple 


FIG.  107. — Angioendothelioma  about  tendon  sheath.     A  small,  slowly  growing  tumor 

pulsating  cavernous  angioma  of  the  spleen.  Borrmann's  case  seems  to  fall  in 
the  group  of  simple  angiomas  with  moderate  excess  of  cells,  while  Steudener 
describes  a  rapidly  growing  ulcerating  tumor  of  the  forehead  which  he  thought 
resembled  carcinoma.  None  of  these  tumors  seems  to  deserve  a  special  classi- 
fication apart  from  angioma  or  perithelioma. 

A  second  group  includes  the  rare  and  somewhat  obscure  intravascular 
endothelioma  of  corpus  cavernosum  which  cannot  be  classed  with  angioma. 
In  several  small  encapsulated  slowly  growing  subcutaneous  tumors  I  have 
been  able  to  trace  the  abundant  cells  to  proliferating  endothelium  of  dilated 
varicose  veins.  The  circulation  appeared  to  have  been  previously  obstructed. 
The  endothelium  grows  first  in  broad  papillary  masses  which  later  become 
fused  and  enlarged,  distending  the  vessel  wall.  The  endothelial  characters 
of  the  cells  were  maintained,  but  the  nuclei  became  enlarged  and  hyper- 
chromatic.  Schlagenhaufer  has  described  such  tumors  arising  in  hemor- 
rhoidal  veins. 


308 


NEOPLAST1C  DISEASES 


In  the  bones,  while  Narath's  pulsating  tumor  of  the  tibia  belongs  with 
cellular  angiomas,  Marckwald's  remarkable  multiple  tumor  of  the  bones 
may  well  be  designated  as  an  endothelioma  of  vascular  origin. 

In  the  testis  many  authors  have  described  as  intravascular  endothelioma 
tumors  which  in  all  probability  are  derivatives  of  teratomas  and  do  not  merit 
classification  with  any  form  of  endothelioma.  Of  the  old  angiosarcomas  most 
authors  are  agreed  that  none  can  be  regarded  as  hemangio-endothelioma, 
and  Borst  would  discard  the  term  "angiosarcoma"  as  misleading. 

Thus  on  analysis  it  appears  that  the  various  tumors  which  at  one  time 
or  another  have  led  various  authors  to  employ  the  term  "hemangio-endothe- 
lioma" fall  readily  into  other  groups  and  that  this  term  has  a  very  limited 
application  and  would  include  certain  rare  tumors  as  follows:  (i)  The  doubt- 
ful endothelioma  of  corpus  cavernosum;  (2)  Marckwald's  multiple  endo- 


FlG.  108. — A  type  of  papillary  proliferation  of  endothelium  arising  in  long  distended 

lymphatics. 

thelioma  of  bones;  (3)  a  fibrocellular  tumor  of  the  thyroid  described  by 
Limacher  in  which  the  vessels  were  too  scanty  and  the  cells  too  numerous 
for  angioma  and  in  which  many  endothelial  cells  had  become  disseminated 
from  the  vessels  (in  the  ovary  somewhat  similar  endotheliomas  may  possibly 
occur) ;  (4)  a  slowly  growing  tumor  of  the  skin  in  which  a  moderate  number 
of  blood-vessels  are  lined  by  many  layers  of  endothelium;  (5)  an  intravascular 
endothelioma  arising  in  hemorrhoidal  and  other  dilated  veins. 

Gross  Anatomy. — The  gross  appearances  of  endotheliomas  are  quite 
as  varied  as  their  other  characters.  Solid  circumscribed  slowly  growing 
tumors  occur  regularly  in  the  dura.  In  the  serous  membranes  the  growth 
begins  as  multiple  flat  or  nodular  outgrowths,  which  coalesce  and  extend 
gradually  over  a  wide  area  of  the  membrane,  producing  thickenings  and 
adhesions.  In  the  pleura  the  entire  surface  of  both  sides  may  be  diffusely 


ENDOTHELIOMA 


309 


thickened  and  the  cavities  obliterated.  In_the Jhones  endothelioma  tends  to 
replace  preexisting  tissues  with  little  or  no  increase  in  the  size  of  the  bone, 
but  with  perforations.  In_the  skin  endothelioma  is  said  to  take  the  form 
of  large  single  tumors.  In  the  ovary  cystic  endothelioma  is  said  to  occur. 

In  the  lymph-nodes  endothelioma  produces  solid  tumors  which  may 
reach  considerable  dimensions.  They  usually  involve  more  than  one  node 
and  some  become  systemic.  They  are  often  mistaken  for  tuberculous  nodes 
at  first,  later  for  carcinoma.  Rarely  they  are  cystic. 


FIG.  109. — Extensive  endothelioma  of  pleura  with  hydrothorax. 

The  various  forms  of  secondary  changes  may  chiefly  determine  the  gross 
appearance  of  the  tumor. 

Multiplicity  is  one  of  the  most  constant  characters  of  endothelioma. 
In  the  dura  therelmay  be  a  score  of  separate  nodules.  In  the  serous  mem- 
branes the  tumors  begin  as  multiple  coalescing  nodules.  ^  In  the  spleen 
Weichselbaum  observed  a  notable  form  of  multiple  endothelioma  or  cellular 
angioma.  In  the  bones  many  have  classed  multiple  myeloma  with  endothe- 
lioma (Zahn)  and  a  remarkable  case  of  multiple  endothelioma  involving 
nearly  all  the  bones  is  recorded  by  Marckwald. 


310  NEOPLASTIC  DISEASES 

Structure  of  Endothelioma. — The  endothelial  cell  in  tumors  usually 
retains  some  of  its  distinguishing  features  on  which  alone  the  recognition 
of  the  nature  of  the  growth  may  often  be  based.  The  form  is  polyhedral, 
often  pavement  in  type,  and  occasionally  cylindrical.  Under  pressure  it 
assumes  a  spindle  form  and  in  edematous  tissues  it  swells  to  spheroidal  form 
and  considerable  dimensions. 

A  well-defined  cell-membrane,  relatively  clear  cytoplasm,  small  pale 
vesicular  nucleus  with  minute  multiple  nucleoli  are  features  so  frequently 
exhibited  as  to  render  them  valuable  diagnostic  aids  which  are  too  often 
neglected.  Especially  in  separating  endothelioma  from  epithelioma  these 
characters  are  of  value,  since  the  epithelial  cell  usually  exhibits  a  granular 
opaque  cytoplasm,  prominent  nuclei,  and  bulky  acidophile  nucleoli.  Yet 
in  some  malignant  tumors  the  endothelial  characters  of  the  cells  are  lost  and 
embryonal  epithelium  resembles  endothelium.  In  certain  endotheliomas 
the  cells  tend  to  become  flattened  and  spindle  shaped  and  to  form  compact 
masses  in  which  hyaline  intercellular  substance  appears  in  increasing  amount 
until  finally  the  tumor  is  largely  transformed  into  hyaline  fibrous  tissue. 
This  process  reveals  the  natural  termination  of  old  endotheliomas  of  the 
dura.  It  is  sometimes  assumed  that  we  have  to  deal  with  the  production 
of  intercellular  fibrils  by  endothelial  cells  and  with  the  conversion  of  endothe- 
lial tissue  into  connective.  Yet  it  appears  more  probable  that  the  fibrils 
represent  elongated  and  hyaline  cell  bodies  and  that  the  resulting  hyaline 
mass  represents  the  gradual  conversion  of  the  compressed  cells  into  homo- 
geneous material.  Definite  formation  of  intercellular  fibrils  I  have  been 
unable  to  detect  in  endothelioma.  In  dural  endothelioma  their  absence  is 
conspicuous. 

In  various  tissues  normal  endothelial  cells  show  morphological  differences 
which  dominate  the  tumors  arising  in  these  tissues.  Serous  endothelium 
is  notably  flat,  bulky,  and  pavement  in  type,  and  these  features  long  persist 
in  tumors  of  the  peritoneum  and  pleura.  Giant-cells  of  many  forms  have 
been  encountered  in  various  endotheliomas,  but  their  occurrence  is  compara- 
tively rare  (Glockner,  Lit.). 

Syncytial  masses  with  scattered  nuclei  were  observed  in  cylindroma  by 
Sattler.  In  4  pleural  or  peritoneal  endotheliomas  Glockner  found  mono- 
nuclear  and  polynuclear  giant-cells,  in  one  case  so  numerous  as  to  dominate 
the  picture.  In  an  abdominal  endothelioma  which  he  derived  from  the 
lymph-nodes  Glockner  found  very  large  giant-cells  measuring  up  to  176 
micra.  In  an  endothelioma  of  the  pleura  Brosch  describes  giant-cells  re- 
sembling the  Langhans  type  in  tubercle,  and  I  have  seen  such  cells  in  an 
endothelioma  of  the  scalp.  In  dural  tumors  multinuclear  giant-cells  are 
not  infrequent. 

Retained  secretion  affects  the  appearance  of  endothelioma,  and  endo- 
thelial tumors  of  lymph-nodes  may  be  cystic.  Extensive  pigmentation 
occurred  in  a  peculiar  tumor  with  numerous  metastases  which  Rindfleisch 
interpreted  as  an  endothelial  myeloma.  In  an  endothelial  tumor  of  the  sole 
of  the  foot  attached  to  the  bone  I  found  considerable  pigment  evidently 
derived  from  extravasated  blood.  Secondary  changes  in  the  cells  and  stroma 
greatly  alter  or  dominate  the  appearance  of  many  of  these  tumors.  Fatty 
degeneration  is  not  prominent,  but  in  a  case  of  Ritter's  it  was  quite  pro- 
nounced. Glycogenic  degeneration  has  been  noted  in  many  cases  of  actively 
growing  endothelioma  (Driessen,  Volkmann).  Accordingly  to  Best  its  abun- 
dance may  distinguish  endothelioma  as  a  class  from  sarcoma. 

Hyaline  degeneration  frequently  affects  the  cells,  stroma,  and  vessels 
of  endothelioma.  Involving  the  stroma  of  interfascicular  growths  it  pro- 


ENDOTHELIOMA  311 

duces  the  appearance  of  cylindroma.  In  psammoma  it  is  associated  with 
calcification  of  the  concentric  groups  of  cells  and  produces  the  sand  grains. 
Other  dural  tumors  may  be  rendered  quiescent  by  nearly  complete  hyalino- 
sis.  In  a  slowly  growing  angio-endothelioma  of  dura  I  found  the  walls  of  all 
vessels  thick  and  hyaline  and  many  occluded  by  hyaline  material,  while  the 
cells  were  intact. 

In  the  true  endothelioma  mucinous  degeneration  is  of  rare  occurrence,  but 
is  observed  in  certain  tumors  of  serous  membranes,  and  in  the  group  of  ova- 
rian endothelioma,  in  both  of  which  it  may  become  extensive,  with  the  forma- 
tion of  mucinous  cysts. 

Calcification  overtakes  many  slowly  growing  endotheliomas,  especially 
the  perivascular  and  psammomatous  tumors  of  the  dura.  The  deposits 
appear  in  the  cells,  stroma,  and  walls  of  blood-vessels.  In  a  subcutaneous 
tumor  of  the  foot  Perthes  found  extensive  calcification  leading  eventually 
to  ossification.  In  a  remarkable  form  of  endothelioma  of  the  orbit  I  found 
very  extensive  deposits  of  calcific  nodules  producing  a  form  of  osteoid 
tissue. 

The  various  arrangements  of  the  cells  in  endbtheliomas  yield  characteristic 
structures  which  form  the  basis  of  the  plan  of  classification  previously  given. 
These  classes  by  no  means  exhaust  the  architectural  peculiarities  and,  as  in 
carcinoma,  combinations  of  several  types  may  occur  in  the  same  tumor. 
Likewise,  epithelioma  may  be  simulated  not  only  by  the  morphology  of  the 
cells,  but  by  the  formation  of  pearls  with  hyaline  centers.  Prickle  cells  and 
keratohyalin  granules,  however,  are  absent  in  the  endothelial  structures. 
The  structure  of  sarcoma  is  simulated  by  many  spindle-cell  endotheliomas 
and  ih  this  group  it  becomes  desirable  to  recognize  as  types  of  sarcoma  cer- 
tain tumors  whose  cells  of  origin  may  be  ultimately  of  endothelial  nature, 
although  modified  by  location  and  function. 

Vascular  endothelioma  tends  to  remain  of  smaller  size  and  to  assume 
cuboidal  or  cylindrical  rather  than  pavement  types.  From  the  lymph  spaces 
develop  tumors  of  more  embryonal  type  with  cells  lacking  the  above-men- 
tioned adult  endothelial  characters.  These  cells  are  small  with  opaque 
granular  cytoplasm  and  very  intimate  connections  with  the  tissue  stroma. 
From  certain  specialized  derivatives  of  endothelial  cells,  as  perithelium, 
and  the  germ  center  cells  of  lymph-nodes,  the  tumors  are  almost  wholly 
lacking  in  endothelial  qualities  and  constitute  subvarieties  of  sarcoma. 

An  intimate  relation  to  the  supporting  stroma  is  an  important  structural 
peculiarity  which  distinguishes  many  endotheliomas  from  epithelial  tumors. 
The  cells  cling  to  the  walls  of  spaces  in  spite  of  the  shrinkage  of  hardening 
and  the  cell  bodies  may  seem  to  pass  insensibly  into  the  substance  of  the 
stroma.  Small  fibroblasts  and  fine  fibrils  may  ramify  between  the  endothe- 
lial cells.  Yet  it  has  repeatedly  been  shown  that  these  same  peculiarities 
may  be  present  in  basal  cell  epithelioma  and  that  they  alone  do  not  warrant 
the  diagnosis  of  endothelioma. 

Combination  of  Endothelioma  and  Sarcoma. — In  some  spindle-cell 
sarcomas  there  is  evidence  that  endothelial  cells  are  commingled  with  the 
main  tumor  element,  but  they  lose  their  endothelial  characters  among  the 
derivatives  of  fibroblasts.  Borst  mentions  the  occurrence  of  large  spindle- 
cell  sarcomas  in  which  are  well-defined  groups  of  neoplastic  endothelial  cells 
which  may  resemble  carcinomatous  alveoli  except  for  the  intimate  relation 
with  the  sarcoma-cells.  I  have  seen  such  appearances  in  teratomas.  He 
also  describes  angiomatous  spindle-cell  sarcomas  in  which  the  numerous 
vessels  are  lined  by  proliferating  cubical  endothelium  recalling  gland  alveoli. 
In  lymphangio-endothelioma  the  stroma  may  be  very  cellular,  or  one  part 


312  NEOPLASTIC  DISEASES 

of  an  angioma  may  be  very  vascular  and  another  part  chiefly  composed  of 
cellular  stroma. 

Differential  Diagnosis  of  Endothelioma. — Although  there  have  been 
numerous  attempts  to  establish  differential  diagnostic  signs  between  endothe- 
lioma  and  other  tumors,  it  must  be  admitted  with  Lubarsch  that  reliable 
criteria  of  general  application  are  lacking.  On  this  account  the  personal 
impressions  of  the  individual  observer  have  figured  too  prominently  in  the 
steady  expansion  of  this  group  of  tumors. 

The  most  reliable  sign  of  endothelioma  is  found  in  the  minute  characters 
of  the  cells  as  above  described,  but  these  characters  are  lost  in  many  actively 
growing  tumors  and  in  recurrences.  Yet  a  thorough  search  for  the  translu- 
cent polyhedral  cells  with  pale  nuclei  devoid  of  acidophile  nucleoli  is  often 
rewarded  in  tumors  the  bulk  of  which  fails  to  show  such  cell  types.  Espe- 
cially in  edematous  foci  the  pavement  characters  reassert  themselves. 

The  concentric  perivascular  arrangement  is  a  convincing  appearance, 
but  is  limited  chiefly  to  dural  growths.  All  other  arrangements  of  the  cells 
exhibited  by  endothelioma  are  duplicated  by  other  tumors. 

The  occurrence  of  endothelial  pearls  with  hyaline  or  calcified  centers,  but 
without  prickle  cells  and  keratohyalin  granules,  as  emphasized  by  many, 
stands  in  the  opinion  of  Lubarsch  and  Ribbert  a  strong  indication  against 
endothelioma.  Prickle  cells  and  specific  granules  are  often  absent  in  epithe- 
lioma,  and  with  the  exception  of  psammoma  I  have  never  seen  definite  pearl 
formation  in  any  undoubted  endothelioma. 

The  relation  of  tumor-cells  directly  walling  circulatory  paths  is  a  con- 
vincing feature  of  some  endotheliomas,  but  it  rarely  exists  unless  the  charac- 
ters of  the  cells  are  even  more  indicative  of  endothelioma.  The  identification 
of  lymph,  paths  is  usually  difficult,  while  endothelioma  of  blood-vessels  is 
rare.  It  must  be  recognized  also  that  the  presence  of  a  column  of  blood  in 
immediate  contact  with  tumor-cells  is  not  a  certain  criterion  of  endothe- 
lioma. Hemorrhage  often  fills  the  alveoli  of  carcinoma,  and  in  epithelioma 
of  the  skin  blood  sinuses  invade  the  epithelial  cell  groups,  lose  their  endothe- 
lial lining,  and  the  blood  lies  in  immediate  contact  with  cuboidal  epithelial 
cells. 

The  intimate  relation  of  the  cells  to  the  supporting  stroma  is  regarded 
by  Borst  and  many  others  as  a  most  important  criterion.  In  soft  tissues 
the  endothelial  cells  are  said  to  grow  out  like  young  capillaries.  Yet  this 
sign  led  to  error  in  the  case  of  the  spurious  endotheliomas  of  the  parotid. 

The  desmoplastic  properties  of  many  endotheliomas  assist  in  their  recog- 
nition, and  a  peculiar  form  of  hyalinosis  may  sharpen  this  feature,  as  in  cyl- 
indroma.  On  the  edges  of  endothelioma  the  tumor-cells  may  fade  in  the 
advancing  fibrosis  in  a  manner  quite  foreign  to  carcinoma.  Fine  fibroblasts 
and  even  capillaries  may  grow  out  between  the  cells  of  alveoli  both  in  endo- 
thelioma and  carcinoma.  The  structure  of  cylindroma,  especially  that  form 
resulting  from  mucous  degeneration  in  cellular  alveoli,  is  not  distinctive 
of  endothelioma,  since  hyaline  and  mucous  degeneration  of  cell  groups,  stroma, 
and  vessels  often  occurs  in  carcinomas  (Lubarsch,  Schmidt). 

On  the  growing  edges  the  tumor-cells  are  said  to  pass  insensibly  into  the 
endothelium  of  lymph  spaces  (Volkmann,  Hansemann),  but  this  appearance 
occurs  also  in  carcinoma  (Ribbert,  Borst).  Proliferation  of  endothelium 
of  vessels  invaded  by  tumor-cells  occurs  both  in  endothelioma  and  carcinoma, 
but  rather  more  in  the  former. 

The  location  of  the  tumor  may  furnish  important  evidence,  as  when 
multiple  endothelioma  develops  in  lymph-nodes,  bone-marrow,  or  in  any 
tissue  not  containing  epithelium.  Yet  unless  the  sources  of  primary  tumors 


ENDOTHELIOMA  313 

are  carefully  eliminated  this  evidence  is  worthless,  and  there  remains  the 
possibility  of  aberrant  tissue  rests. 

Finally,  it  should  be  urged  that  the  diagnosis  of  endothelioma  should  be 
accepted  only  when  the  evidence  is  clear  and  conclusive.  Otherwise  this 
group  will  continue  to  represent  the  resting  place  of  miscellaneous  tumors 
on  which  the  data  and  study  have  been  inadequate. 

Etiology. — In  the  etiology  of  endothelioma  the  influence  of  chronic 
irritation  or  trauma  and  low  grades  of  inflammation  must  be  given  a  promi- 
nent place.  In  a  few  instances  it  has  been  possible  clinically  to  establish 
the  existence  of  such  factors.  Endothelioma  of  lymph-nodes  appears  to 
follow  forms  of  chronic  lymphadenitis.  In  the  skin  chronic  trauma  is 
abundantly  provided,  especially  in  the  sole  of  the  foot.  In  the  serous  mem- 
branes endothelioma  in  some  cases  appears  to  be  connected  with  tubercu- 
losis. As  a  rule,  however,  the  tumor  appears  to  develop  spontaneously. 
On  the  other  hand,  it  is  necessary  to  assume  a  local  predisposition  to  tumor 
growth,  and  in  certain  cases  efforts  have  been  made  to  establish  a  relation 
with  definite  embryogenic  disturbances.  It  cannot  be  said  that  much  suc- 
cess has  attended  these  efforts.  Many  endotheliomas  first  appear  in  small 
encapsulated  areas  suggesting  an  embryonal  isolation  of  the  originating 
tissue.  Eberth  and  Spude  have  described  a  small  teratoid  endothelioma 
of  the  dura  mater.  Ribbert  suggests  that  endothelioma  of  the  dura  arises 
from  groups  of  cells  misplaced  during  the  separation  of  the  original  membrane 
into  pia  and  dura.  Schmidt  has  described  such  collections  of  superfluous 
endothelial  cells  in  the  normal  dura.  I  have  observed  a  small  perfectly  iso- 
lated endothelioma  embedded  in  the  tissues  of  the  spermatic  cord.  Yet 
the  great  majority  of  endotheliomas  fail  to  give  any  tangible  evidence  of  a 
relation  to  embryogenic  disturbance. 

The  multiple  origin  of  tumors  appearing  successively  over  many  years 
(Marckwald),  the  genesis  from  minute  lymph  spaces  and  vessels,  and  the 
slow  growth,  all  indicate  that  these  tumors  usually  develop  from  adult  endo- 
thelium  under  the  influence  of  chronic  irritation. 

CLINICAL  TYPES  OF  ENDOTHELIOMA 

A.  Tumor-like  Hyperplasia  of  Endothelium. — Under  certain  conditions 
endothelium  exhibits  a  grade  of  hyperplasia  which  is  intermediate  between 
inflammatory  and  neoplastic  overgrowth. 

1.  In  chronic  lymphadenitis  a  peculiar  form  of  endothelial  hyperplasia 
may  occur  which  exhibits  some  of  the  morphological  and  clinical  features  of 
a  neoplasm.    These  cases  occur  in  the  group  of  chronic  enlargements  of  the 
lymph-nodes  of  uncertain  origin  and  they  pursue  the  course  of  Hodgkin's 
disease,  but  specific  Hodgkin's  structure  and  specific  signs  of  tuberculosis 
are  missing. 

Microscopically  one  finds  irregular  foci  and  broad  sheets  of  large  flat 
endothelial  cells,  obliterating  the  normal  structure,  grading  insensibly  into 
lymphoid  tissues,  and  apparently  originating  in  the  sinus  endothelium. 
The  cells  are  slightly  granular,  clearly  outlined,  polyhedral  or  elongated, 
with  large  vesicular  hyperchromatic  nuclei.  The  appearance  is  quite 
different  from  that  of  the  large  cell  hyperplasia  of  tuberculosis  or  of  the  com- 
mon Hodgkin's  structure  and  bears  the  stamp  of  a  feeble  neoplastic  process. 

2.  Primary  Splenomegaly  (Type,  Gaucher). — This  remarkable  condition 
consists  of  an  extensive  chronic  overgrowth  of  endothelial  cells  of  the  spleen, 
lymph-nodes,  and  bone-marrow,  with  secondary  foci  in  the  portal  canals 
of  the  liver,  and  is  associated  with  anemia,  hemorrhages,  and  pigmentation 


314 


NEOPLASTIC  DISEASES 


of  skin  and  other  organs.  It  begins  in  early  life,  chiefly  in  females,  commonly 
affects  more  than  one  member  of  a  single  generation  in  the  family,  and  pro- 
gresses over  many  years  (39  in  Schlagenhaufer's  case),  proving  fatal  or  termi- 
nated by  complications.  The  spleen  reaches  enormous  size  (6250  gms.  Bovaird) 
and  the  liver  is  greatly  enlarged,  while  the  lymph-nodes  are  much  less  promi- 
nent. The  pigmentation  affects  skin,  spleen,  lymph-nodes,  and  smooth  muscle- 
tissues. 

Microscopically  the  splenic  structure  varies  in  different  stages.  It  be- 
gins with  the  appearance  of  many  large  clear  polyhedral  cells  lying  loosely 
in  the  pulp  tissue  occluding  and  replacing  sinuses,  cords,  and  finally  the 
Malphigian  bodies.  Scattered  lymphocytes  long  persist,  but  eventually 
disappear.  At  the  acme  of  the  process,  as  in  Bovaird's  case,  the  tissue  is 


FIG.  HO. — Structure  of  splenic  lesion  in  Gaucher's  splenomegaly.     Note  that  the  large 
cells  lie  within  the  cords  and  do  not  line  the  splenic  sinuses. 

composed  almost  exclusively  of  closely  packed,  very  large,  clear  polyhedral 
cells  forming  diffuse  masses  or  large  alveoli.  Occasional  mitoses  may  be 
observed  and  it  is  evident  that  the  cells  are  not  only  well  nourished,  but 
possess  considerable  powers  of  growth.  Yet  the  cells  lack  the  hyperchro- 
matic  nuclei  of  tumor-cells  and  they  carefully  respect  anatomical  barriers. 
Necrosis  is  rare,  but  occurred  in  Schlagenhaufer's  case.  In  the  late  stages  a 
slow  fibrosis  overtakes  the  process  and  the  hyperplastic  cells  fade  into  a  form 
of  hyaline  or  fibrillated  tissue.  In  the  lymph-nodes  and  marrow  much  the 
same  process  is  observed,  beginning  in  the  sinuses.  In  the  liver  small  foci 
of  the  large  cells  appear  in  the  lymphatics  of  the  portal  canals. 

From  the  study  of  6  cases  (Bovaird,  Brill,  4  from  New  York  Hospital) 
I  am  satisfied  that  the  hyperplastic  cells  appear  first  within  the  pulp  cords, 
that  they  are  derived  from  the  lining  cells  of  the  splenic  sinuses  is  uncertain, 


ENDOTHELIOMA  3 1 5 

that  the  process  originates  secondarily  in  the  lymph-nodes  and  marrow, 
and  that  the  hyperplasia  falls  below  that  of  a  true  neoplasm.  Whether  the 
process  ^in  the  liver  arises  in  that  organ  or  results  from  cell  emboli  appears 
uncertain. 

In  the  etiology  a  chronic  irritant  affecting  especially  the  lymphoid  organs 
must  be  assumed  to  exist.  Many  features  suggest  an  atypical  tuberculosis. 
In  2  cases  (Gaucher,  Schlagenhaufer)  tuberculous  lesions  coexisted.  In 
Collier's  case  there  was  a  caseous  mass  in  the  mediastinum,  while  in  other 
cases  tuberculosis  was  not  eliminated.  Lutz  found  an  early  stage  of  the 
process  in  diabetic  lipemia. 

It  has  recently  been  shown  by  Anitschkow  that  a  very  similar  condition 
of  spleen  and  bone-marrow  may  be  produced  experimentally  in  animals  by 
feeding  large  amounts  of  cholesterin.  The  material  in  the  cells  does  not 
give  the  staining  reactions  of  myelin  bodies,  lipoids  or  fats,  nor  does  it  react 
to  Weigert's  myelin  stain.  Yet  it  is  probably  a  peculiar  lipoid  (Schlagen- 
haufer, Lutz). 

B.  Endothelioma. — i.  Endothelioma  of  Meninges. — This  common  tumor 
appears  in  two  main  forms:  (i)  As  a  pjriyas^uiar^endgthelJQma,  and  (2) 
as  pjsanimoma  in  which  small  perivascular  units  undergo  hyalinosis  and 
calcification.  The  tumors  are  single  and  as  large  as  a  hen's  egg,  or  multiple 
and  of  miliary  dimensions.  They  first  appear  as  flat  elevations  on  the  inner 
side  of  the  dura  which  slowly  enlarge  with  corresponding  displacement  or 
atrophy  of  brain  substance.  They  show  little  tendency  to  form  adhesions, 
but  may  be  surrounded  by  a  vascular  capsule.  An  infiltration  between  the 
thickened  layers  of  the  dura  may  occur.  They  are  usually  very  firm  in  con- 
sistence, gray  in  color,  with  nodular  surface  or  lobulated  structure.  Strands 
of  connective  tissue  from  the  dura  may  be  drawn  into  the  growth  separating 
lobules  of  endothelial  tissue.  The  psammomas  are  extremely  hard,  usually 
of  moderate  dimensions,  and  the  sand  grains  are  visible  in  the,gross.  Occa- 
sionally the  tumor  becomes  pedunculated.  On  gross  inspection  the  concentric 
units  may  usually  be  discerned,  but  old  hyaline  forms  exhibit  a  smooth, 
glassy  luster. 

The  chief  seats  are  the  dura  over  the  convexity,  in  the  falx  and  tentorium, 
and  along  the  basal  vessels,  and  they  may  develop  over  the  medulla,  and 
down  to  the  cauda.  The  cerebral  tumors  have  been  discussed  by  many 
authors,  while  the  less  known  spinal  tumors  were  described  in  detail  by 
Eppinger.  Schlesinger  collected  18  spinal  psammomas  located  chiefly  in 
the  central  and  lower  segment.  Hippel  found  a  large  cellular  psammoma 
in  the  cerebellum  and  multiple  calcified  nodules  throughout  the  spinal 
meninges.  Small  tumors  are  said  to  arise  from  the  pia  (Borst),  and  atypical 
forms  have  been  observed  in  the  ventricles  arising  from  ependyma.  The 
predisposition  of  the  dura  may  be  associated  with  the  frequent  occurrence 
of  "sand  grains"  on  its  inner  surface  producing  the  condition  called  by  Vir- 
chow  meningitis  arenosa.  Virchow  observed  several  cases  in  connection  with 
exostoses.  Henschen  describes  multiple  endothelioma  of  the  spinal  dura 
associated  with  tuberculous  pachymeningitis. 

The  structure  is  quite  characteristic  and  the  endothelial  features  are 
so  obvious  that  this  tumor  was  the  first  to  receive  the  designation  of  endothe- 
lioma (Golgi,  1869).  The  tissue  is  composed  of  systems  of  cells  congejitric- 
ally  arranged^  jibojil  ^-.central  lumen,  closed  or  patent,  which  represents  a 
rudimentary  vessel.  These  units  may  be  very  small,  numerous  and  sharply 
defined,  or  large  and  ill  defined.  Considerable  areas  may  be  composed  of 
diffuse  cells  without  concentric  arrangement,  or  the  masses  may  be  plexi- 
form  and  convoluted.  Borst  in  one  case  saw  a  uniform  thickening  of  the 


316  NEOPLASTIC  DISEASES 

meshes  of  subarachnoidal  tissue  by  cells  lying  loosely  within  these  strands. 
The  cells  are  polyhedral  or  of  elongated  spindle  form  with  the  usual  endothe- 
lial characters.  In  some  very  cellular  forms  the  cell  borders  are  less  distinct 
and  the  nuclei  hyperchromatic. 

The  origin  of  the  cells  has  been  referred  chiefly  to  the  endotheliuriL-of 
perivascular  lymph  spaces  and  to  perithelium  of  proliferating  vessels,  while 
Engert  regards  them  as  derivatives  of  the  lining,  cells,  of  .the_.dura.  On  the 
other  hand,  M.  B.  Schmidt  has  made  it  appear  very  probable  that  most  or  all 
of  the  endothelial  tumors  of  the  dura  are  derived  from  groups  of  endothelial 
cells  which  he  finds  in  a  large  proportion  of  adults  lying  in  the  meshes  of  the 
pia,~near  small  blood-vessels,  and  especially  in  connection  with  Pacchionian 
granulations. 

In  a  notable  case  described  by  Lindner  with  multiple  tumors  of  dura  and 
similar  growths  in  bladder  and  urethra,  the  cell  masses  inclosed  spaces  com- 
municating with  blood-vessels  and  containing  groups  of  nucleated  red  blood- 


** 


*  *£•/,.  "^  V  r  ^rV*«         * 

*?••  V-  <'»*  '•'•-.  •  i 


\ 

FIG.  in. — Endothelioma  of  dura  mater. 

cells.  According  to  Albrecht's  bizarre  interpretation  of  this  case  the  tumor 
was  derived  from  vasoformative  cells  which  retained  their  capacity  for  red-cell 
formation. 

The  blood-vessels  are  usually  scanty  and  are  carried  by  the  stroma  de- 
rived from  the  dura. 

Secondary  changes  are  frequent.  A  form  of  fibrosis  overtakes  old  tumors 
and  may  transform  them  into  dense  hyaline  masses  on  the  edges  of  which 
islands  of  growing  cells  may  be  preserved.  Here  the  cell  bodies  become  fused 
and  hyaline  without  the  intervention  of  any  special  intercellular  substance. 
Chronic  edema  may  occur  in  small  or  large  areas  in  which  the  cells  swell  to 
large  dimensions  and  polyhedral  form. 

Hyaline  degeneration  and  calcification  produce  the  characteristic  struc- 
ture of  psammoma.  These  processes  affect  chiefly  the  central  cells  of  the 
concentric  units,  hyalinosis  preceding  calcification.  Entire  cell  groups  may 
be  calcified  and  almost  the  entire  tumor  may  be  composed  of  sand  grains 


ENDOTHELIOMA 


317 


with  traces  of  concentric  or  irregular  striation.  The  walls  of  vessels  may  be 
extensively  affected,  hyaline  changes  altering  the  walls  and  the  contents, 
and  calcification  appearing  in  or  about  the  walls  and  in  the  contained  material. 
According  to  Ernst  hyaline  material  may  first  appear  as  an  intercellular 
secretion. 

Numerous  variations  from  the  typical  perivascular  structure  occur  in 
endothelioma  of  the  meninges.  Tumors  that  have  undergone  Considerable 
fibrosis  are  often  called  fibro-endothelioma.  The  appearance  of  alveolar 
endothelioma  is  sometimes  produced  by  cells  growing  in  a  fine  network  of 
connective  tissue  derived  from  dura  or  pia.  Very  vascular  tumors  occur  in 
which  the  vessels  seem  to  belong  to  the  tumor  process  and  these  may  be 
designated  as  angio-endothelioma. 


FlG.  112. — Slowly  growing  angio-endothelioma  of  meninges  of  base  of  brain.     Hyaline 
and  calcific  material  forms  the  walls  of  many  vessels. 

In  some  of  the  vascular  tumors  a  peculiar  structure  is  produced  by  the 
growth  of  large  cells  in  several  layers  covering  or  radiating  from  the  \  easels. 
They  may  involve  the  pia  mater  and  extend  down  the  sulci.  Borst  and  others 
derive  these  cells  from  the  perithelium  of  the  blood-vessels  and  designate 
the  tumors  as  perithelioma.  Similar  growths  arise  from  the  ependyma  and 
choroid  plexuses  where  they  produce  papillary  structures.  An  endothelioma 
of  the  meninges  of  the  dorsal  cord,  exhibiting  the  structure  of  perithelioma, 
has  been  reported  from  this  laboratory  by  Schlapp.  It  was  rather  clearly 
referable  to  a  severe  trauma  and  while  it  grew  rapidly,  was  completely  eradi- 
cated by  curetage.  It  is  difficult  to  determine  the  exact  position  of  these 
tumors,  but  in  Schlapp's  case  the  cylindrical  and  pavement  character  of  the 
cells  indicated  true  endothelial  properties  in  the  cells  of  origin. 


318  NEOPLASTIC  DISEASES 

Very  cellular  growths  are  frequently  described  as  sarcoma  or  endothelial 
sarcoma,  but  it  was  long  ago  pointed  out  by  Newmann  and  by  Bizzozero  and 
Bozzolo,  and  lately  by  Zenoni,  that  these  dural  sarcomas  are  probably  derived 
from  the  endothelial  cells.  Yet  the  carefuTanalysis  of  Lens  shows  that  true 
sarcoma  of  the  meninges  arises  from  the  adventiltial  cells  of  the  blood-vessels 
while  an  extensive  proliferation  of  arachnoidal  endothelium  occurs  as  a 
secondary  process  which  is  not  neoplastic.  The  true  meningeal  sarcomas 
usually  take  the  form  of  angiosarcoma  or  large  round-cell  sarcoma.  The 
clinical  features  of  sarcoma  are  usually  missing  in  the  endotheliomas,  wrhich 
pursue  a  slow  course  without  metastases  or  wide  local  extensions. 

The  course  of  dural  endothelioma  is  slowly  progressive.  Pressure  symp- 
toms are  usually  late  in  appearance  and  many  cases  are  first  discovered  at 
postmortem.  Even  the  vascular  growths  may  fail  to  alter  this  course,  and 
I  have  observed  an  extremely  vascular  and  very  cellular  diffuse  endothe- 
lioma compressing  the  pons  which  progressed  slowly  over  a  period  of  four 
years. 

On  the  other  hand,  pressure  symptoms  and  recurrence  after  operation 
marked  a  case  of  Taylor's,  and  a  small  tumor  between  falx  and  convexity 
was  found  by  Lunz  in  a  case  of  cortical  epilepsy.  Henschen  described  a  re- 
markable case  of  multiple  endothelioma  of  the  spinal  dura  associated  with 
old  tuberculous  meningitis,  while  Dufour  observed  a  somewhat  similar  case 
in  the  horse.  Metastases  are  extremely  rare,  but  Klebs  found  nodules  in  the 
lung  in  one  case,  and  Lindner  is  said  to  have  observed  a  metastasis  in  the 
bladder. 

Psammoma  of  nerve-trunks  has  been  described  in  a  considerable  group 
of  cases;  in  the  optic  nerve  (Knapp,  Ernst,  Tailer,  Braunschweig,  Lit.);  or 
acoustic  and  facial  (Fester);  but  the  exact  nature  of  some  of  these  tumors 
is  doubtful. 

Acoustic  neurofibromas  form  a  characteristic  group  of  intracranial  tumors 
and  are  described  under  brain  tumors. 

Endothelioma  of  Nerve-trunks  and  Ganglia. — In  many  nerve-trunks  and 
certain  ganglia  endotheliomas,  usually  of  the  perivascular  type,  have  repeat- 
edly been  observed.  In  some  of  the  common  neurofibromas  the  tumor-cells 
present  endothelial  characters  and  are  arranged  in  whorls  as  in  plexiform 
endothelioma.  It  is  difficult  to  distinguish  such  tumors  from  true  endothe- 
lioma on  the  one  hand  and  simple  neurofibroma  on  the  other. 

In  other  tumors  of  nerve-trunks  the  structure  is  that  of  typical  perivascu- 
lar endothelioma  as  occurring  in  the  dura  mater,  and  psammomatous  changes 
may  appear  in  them. 

In  the  orbit  perivascular  endothelioma  arising  from  the  sheath  of  the 
optic  nerve  is  a  well-defined  condition.  Of  12  extradural  tumors  of  the  optic 
nerve  collected  by  Parsons  9  were  this  form  of  endothelioma.  They  are 
usually  of  slow  growth,  6  to  8  years,  but  reach  considerable  size  (Billroth), 
producing  exophthalmos.  They  surround  the  nerve-trunk  in  conical  form 
or  are  attached  by  a  pedicle  or  appear  disconnected  from  the  optic  nerve, 
in  which  case  another  origin  may  be  assumed.  The  structure  shows  con- 
centric masses  of  endothelial  cells  in  which  hyalinosis  and  calcification  may 
be  prominent. 

Of  2  orbital  tumors  belonging  to  this  group  and  not  distinctly  connected 
with  the  nerves,  in  i  I  found  very  extensive  calcine  deposits  among  con- 
centric groups  of  cells  showing  very  hyperchromatic  nuclei  and  evidently 
malignant;  in  another,  1X2  cm.,  the  cells  in  broad  concentric  groups  were 
highly  pavement  in  type.  Both  failed  to  recur. 

In  the  extensive  literature  on  tumors  of  the  orbit  it  is  clear  that  many 


ENDOTHELIOMA  319 

other  tumors,  especially  carcinoma  of  the  lacrimal  gland,  have  been  inter- 
preted as  endothelioma.  Thus  in  a  full  discussion  of  orbital  tumors  not  con- 
nected with  the  optic  nerve  Parsons  includes  many  growths  of  cylindromatous, 
peritheliomatous,  and  sarcomatous  character,  but  none  of  clearly  endothe- 
liomatous  type.  Verhoef  has  shown  that  the  common  so-called  endothelioma 
of  the  orbit  is  a  carcinoma  of  the  lacrimal  gland.  Yet  it  would  be  unwise 
to  assume  that  all  the  suspected  endotheliomas  of  this  region  are  spurious. 
Thus  Frank  describes  a  congenital  tumor  attached  to  the  periosteum  of  the 
inner  wall,  containing  alveoli  of  cylindrical  cells,  diffuse  cell  masses,  and  vessels 
containing  blood  and  lined  by  tumor-cells.  Even  here  an  embryonal  carci- 
noma is  difficult  to  eliminate.  In  the  Gasserian  ganglion  Spill er  describes  a 
typical  perivascular  endothelioma  with  multiple  miliary  tumors  of  the  adjacent 
dura. 

Endothelioma  of  Serous  Membranes. — Highly  characteristic  conditions 
are  produced  in  the  pleura  and  peritoneum  by  endothelioma  of  these  struc- 
tures and  the  gross  and  microscopical  features  were  early  recognized  as  the 
results  of  a  specific  process  differing  from  ordinary  carcinoma.  There  are 
such  notable  differences  in  the  conditions  produced  in  the  pleura  and  in  the 
peritoneum  as  to  require  their  separate  consideration. 

(a)  Pleural  Endothelioma. — The  process  first  appears  in  the  form  of  multiple 
nodules  or  flat  elevations  widely  distributed  over  one  or  both  membranes. 
These  nodules  fuse,  the  layers  of  the  pleura  become  thickened  and  adherent 
and  converted  into  a  diffuse  firm  opaque  mass  covering  and  compressing  the 
entire  lung.  In  Gutmann's  case  the  tumor  consisted  of  a  limited  number  of 
nodules  and  distinctly  papillary  masses,  and  the  pleura  was  only  slightly 
thickened.  The  costal  pleura  only  may  be  affected  (Scagliosi).  A  sero- 
fibrinous  or  bloody  exudate  commonly  accompanies  the  growth  and  the 
fluid  gathers  in  small  cysts  or  in  larger  collections.  Invasion  of  the  lung 
may  be  entirely  missing,  as  in  Wagner's  and  Benda's  cases,  or  more  often 
the  tumor  invades  the  septa  and  parenchyma  producing  irregular  nodules  and 
masses,  and  metastases  appear  in  bronchial,  axillary,  cervical,  and  medias- 
tinal  nodes,  and  in  the  liver  and  spleen.  Perls  observed  metastases  in  the 
dura  and  choroid,  and  Eberth  found  a  second  endothelioma  primary  in  the 
pia.  The  process  may  extend  to  the  peritoneum  or  to  the  pericardium  (Bas- 
soe),  or  from  the  peritoneum  to  the  pleura  (Rossier,  Pollmann). 

The  structure  in  most  cases  is  rather  uniformly  that  of  alveolar  and  tubu- 
lar endothelioma.  The  cells  are  of  moderate  size,  of  polyhedral  or  flat  form, 
with  hyperchromatic  vesicular  nuclei  and  faint  nucleoli.  They  lie  in  small 
alveoli  or  long  single  or  multiple  rows  between  cellular  or  hyaline  connective 
tissue  to  which  they  are  usually  intimately  adherent.  Evidences  of  secretion 
are  usually  missing.  Borst  describes  as  an  endothelioma  of  pleura  a  tumor 
containing  very  large  cells  closely  resembling  squamous  epithelium  and  form- 
ing numerous  pearls,  but  the  massing  of  this  tumor  about  the  root  of  the 
lung  and  its  perforation  of  the  chest  wall  as  well  as  its  structure  render  the 
diagnosis  uncertain. 

The  origin  of  the  tumor  has  usually  been  referred  to  the  cells  of  the  sub- 
pleural  lymph  spaces  (Wagner,  Bostrom,  Neelsen,  Volkmann,  Adler),  which 
have  been  found  affected  in  very  early  stages.  Malassez,  Rossier,  Pollmann, 
and  others  were  unable  to  trace  the  origin  exactly,  but  were  sure  that  the 
tumor  did  not  arise  from  any  epithelial  structures.  Benda  and  Guttmann 
were  able  to  trace  the  tumor  to  the  lining  cells  of  the  pleura,  which  several 
observers  have  found  to  show  nodular  thickenings  due  to  proliferating  endo- 
thelial  plates.  All  agree  that  the  process  begins  over  a  wide  area.  It  is  pos- 
sible that  two  groups  of  serous  endotheliomas  should  be  recognized,  one  inva- 


320  NEOPLASTIC  DISEASES 

sive,  with  metastases,  and  derived  from  the  endothelium  of  lymph  spaces,  and 
another,  superficial,  nodular,  or  papillary,  and  originating  from  the  lining  cells. 

The  clinical  course  is  that  of  chronic  pleurisy  with  thickening  and  adhe- 
sions. Rossier  especially  emphasizes  the  inflammatory  character  of  the 
process,  claiming  that  it  begins  as  a  chronic  pleurisy,  and  the  wide  extent  of 
the  growth  suggests  that  it  may  signify  a  neoplastic  process  becoming  estab- 
lished in  predisposed  subjects  on  the  basis  of  inflammatory  hyperplasia. 
Perls,  Neelson,  Glockner,  and  others  even  consider  that  an  infectious  agent 
is  concerned  in  the  disease  and  that  it  is  not  a  true  tumor,  but  a  form  of  tumor- 
like  lymphangitis.  The  multiple  or  diffuse  origin  and  gradual  extension 
over  normal  areas  have  often  been  observed  and  Neelson  claims  that  the 
metastases  are  not  caused  by  embolic  cells,  but  arise  de  now  in  the  affected 
tissue.  It  may  be  noted  that  Brosch  in  a  very  early  case  of  pleural  endothe- 
lioma  observed  multiple  nodules  with  caseous  centers  surrounded  by  pro- 
liferating vessels  and  many  giant-cells  of  Langhans  type.  The  resemblance 
to  a  hemorrhagic  tuberculous  pleurisy  is  mentioned  by  Kaufmann,  and  the 
difficulty  of  distinguishing  the  early  nodules  from  miliary  tubercles  is  noted 
by  Wichern.  Yet  endothelioma  of  the  pleura  differs  widely  from  the  forms 
of  hyperplastic  lymphangitis  and  whatever  its  etiology  the  process  is  neoplas- 
tic. In  the  diagnosis  Fraenkel  and  Kaufmann  mention  the  importance  of 
blood  and  tumor  fragments  in  the  fluid  and  retraction  of  the  chest  wall.  The 
disease  occurs  chiefly  in  adults,  but  Hibler  has  observed  it  in  a  child  of  5  years. 

(b)  Peritoneal  Endothelioma. — Rokitansky  (1854)  described  primary  cancers 
of  the  peritoneum  composed  of  multiple  translucent  nodules  lying  under 
the  serosa  and  covering  many  organs.  Waldeyer  found  in  primary  peritoneal 
growths  the  structure  of  plexiform  angiosarcoma  and  cylindroma.  Birch- 
Hirschfeld  (1895)  distinguished  clearly  between  primary  jelly-like  "angio- 
sarcomas,"  which  he  derived  from  the  lymphatic  endothelium,  and  true 
colloid  cancer,  a  bulky  tumor  which  he  referred  to  an  aberrant  portion  of 
intestinal  mucosa.  A  characteristic  case  of  primary  endothelioma  with 
hundreds  of  small  nodules  universally  distributed  he  pictures  and  describes 
as  composed  of  small  groups  of  endothelial  cells  which  he  traced  to  the  endo- 
thelium of  dilated  lymph- vessels. 

In  1897  Glockner  collected  75  cases  of  endothelioma  of  serous  membranes, 
pleura,  peritoneum,  or  both,  and  since  that  time  the  condition  has  been  gener- 
ally recognized  as  the  result  of  a  specific  process. 

The  structure  of  these  tumors  generally  follows  the  description  given  by 
Birch-Hirschfeld  and  is  fully  presented  in  a  recent  case  by  Miller  and  Wynn. 
They  found  the  nodules  composed  of  a  framework  of  connective  tissue  earn- 
ing numerous  vessels  and  inclosing  groups  of  large  polyhedral  cells  with  clear 
cytoplasm.  The  cell  groups  often  contained  mucinous  material,  and  a  large 
amount  of  mucilaginous  ascitic  fluid  was  present.  Many  small  clear  cells 
and  many  multinucleated  giant-cells  were  present.  The  authors  trace  the 
tumor  to  the  lining  cells  of  the  peritoneum,  observing  all  stages  of  their  pro- 
liferation up  to  the  large  nodules.  They  found  intimate  connections  between 
the  cells  and  the  accompanying  fine  connective-tissue  fibrils,  and  describe 
the  fibrillation  of  cell  processes  leading  to  the  formation  of  connective  tissue. 
Hence  they  conclude  that  the  tumor  has  sarcoma tous  qualities.  The  intes- 
tinal walls  were  invaded  as  far  as  the  submucosa,  the  general  peritoneum 
only  in  subserous  tissue,  and  the  lymph-nodes  only  in  the  capsular  tissue. 

The  ascitic  fluid  was  alkaline,  specific  gravity  1017,  when  boiled  solid  still 
exuded  a  mucinous  fluid,  reduced  Fehling's  solution  only  after  boiling  with 
HC1,  and  gave  the  reactions  of  albumins  which  precipitated  on  half-saturation 
with  ammonium  sulphate. 


ENDOTHELIOMA 


321 


A  somewhat  atypical  case  is  described  by  Borst.  The  peritoneum  was 
everywhere  covered  with  nodules,  plates,  and  papillary  elevations,  and  numer- 
ous small  and  large  cysts  had  resulted  from  inclosure  of  mucinous  material 
not  in  the  tumor-masses,  but  by  adhesion  of  the  inflamed  peritoneum.  The 
diaphragm  was  perforated  and  the  pleura  involved.  The  cells  were  flat, 
cubical,  cylindrical,  or  syncytial.  The  structure  was  adenoid,  interfascicular' 
papillary,  and  often  peritheliomatous.  The  organs  were  not  invaded,  but  the 
abdominal  nodes  were  extensively  infiltrated.  The  origin  seemed  to  be  from 
the  subserous  lymphatics,  and  Borst  suspected  that  the  ovarian  region  had 
first  been  involved. 


FIG.  113. — Structure  of  a  primary  endothelioma  of  the  peritoneum. 

A  still  further  variation  from  the  usual  type  is  described  by  Kaufmann 
(loc.  tit.,  542)  who  found  multiple  nodules,  confluent  plates,  and  flat  masses  of 
partly  caseous  material  surrounded  by  strata  of  hyperplastic  cells  derived 
from  the  surface  endothelium.  In  many  alveoli  there  were  cylindrical  cells 
in  palisade  order.  The  diaphragm  and  omentum  were  chiefly  affected,  and 
a  hemorrhagic  exudate  accompanied  the  process. 

In  cases  reported  by  Nager  and  by  Henke  the  tumor  took  the  form  of  a 
multitude  of  miliary  or  larger  cysts  covering  all  the  organs,  causing  universal 
adhesions,  and  marked  thickening  of  the  mesentery  and  omentum.  Some 
of  the  reports  of  endothelioma  of  the  peritoneum  raise  the  suspicion  that 
the  authors  are  dealing  with  secondary  carcinoma  of  intestinal  origin  in  which 
the  primary  tumor  has  been  overlooked.  Especially  when  there  is  marked 
21 


322  NEOPLASTIC  DISEASES 

secretion  of  mucus  the  cases  closely  resemble  the  so-called  pseudomyxoma 
peritonei  which  has  been  definitely  traced  to  the  rupture  of  comparatively 
benign  ovarian  cysts.  This  suspicion  attaches  to  the  cases  of  Nager  and 
Hueter,  in  which  the  secretion  of  mucus  was  abundant,  the  cells  cylindrical, 
and  the  structure  adenocarcinomatous.  Very  similar  conditions  undoubtedly 
follow  peritoneal  dissemination  of  colloid  carcinoma  of  the  colon.  Further 
studies  in  this  field  are  desirable. 

The  proper  classification  of  endothelioma  of  pleura  and  peritoneum  still 
remains  a  somewhat  fruitless  matter  of  discussion.  Ribbert  insists  that 
the  lining  cells  of  the  large  serous  cavities  are  of  celomic  origin  and  epithelial 
nature  and  he  describes  these  tumors  as  carcinoma.  Kaufmann  adheres 
strictly  to  principle  in  separating  endothelial  tumors  derived  from  lymph 
spaces  and  carcinoma  derived  from  lining  cells,  of  both  pleura  and  peritoneum. 
The  majority  of  authors,  the  writer  among  them,  are  less  impressed  by  em- 
bryological  considerations  than  by  the  morphology  and  physiology  of  the 
cells  and  the  general  characters  of  the  tumors  derived  from  them,  and  they 
approve  of  the  classification  as  endothelioma.  The  impression  gained  by 
Birch-Hirschfeld,  Waldeyer,  and  Ziegler  that  all  these  tumors  have  sarcoma- 
tous  qualities  is  supported  by  the  recent  observations  of  Miller  and  Wynn 
of  connective- tissue  formation  by  the  tumor-cells.  I  cannot  trace  this  process 
in  the  few  cases  at  my  disposal,  but  consider  that  other  grounds  fully  support 
the  grouping  of  these  tumors  among  endotheliomas  (cf.  Monckberg). 

Endothelioma  of  Bone. — The  knowledge  of  endothelioma  of  bone  has 
progressed  under  many  difficulties,  so  that  the  importance  of  the  disease  is 
very  inadequately  recognized.  The  chief  difficulty  has  arisen  from  the  fact 
that  metastatic  tumors  of  very  variable  structure  frequently  occur  in  bones, 
and  since  endothelioma  is  not  always  of  highly  specific  appearance,  it  has 
been  difficult  to  eliminate  the  possible  origin  from  metastatic  carcinoma. 
Carcinoma  of  stomach,  thyroid,  prostate,  kidney,  and  adrenal  may  early 
produce  bone  metastasis,  often  as  the  first  symptom  of  disease,  and  the  struc- 
ture of  some  of  these  tumors  may  closely  resemble  endothelioma. 

It  is  further  necessary  to  consider  the  possibility  that  embolic  cells,  from 
normal  organs  may  yield  primary  tumors  of  the  bone-marrow.  Gierke  has 
collected  much  evidence  to  show  that  cell  emboli  from  benign  tumors  of  the 
thyroid  and  even  from  simple  goiter  may  lodge  in  the  bone-marrow  and  give 
rise  to  tumors.  A  certain  number  of  tumors  of  bone  described  as  endothelioma 
were  probably  of  this  nature  (Gierke,  Lit.).  A  similar  mode  of  origin  for 
certain  bone  endotheliomas  which  resemble  papillary  carcinoma  of  the  kidney 
with  clear  cells  has  often  been  suggested.  Pick  argues  that  the  close  con- 
tact of  normal  adrenal  cells  with  the  capillary  blood-stream,  and  the  discovery 
by  Stilling  of  buds  of  adrenal  cells  projecting  into  the  veins  in  the  regenera- 
tion which  follows  removal  of  the  adrenal  in  animals,  reveal  abundant  sources 
of  emboli  of  normal  adrenal  cells.  Yet  it  must  be  considered  that  such  vagrant 
cell  emboli  probably  soon  perish. 

Finally,  it  is  possible  that  definite  misplaced  islands  of  thyroid  or  adrenal 
tissue  may  occur  in  the  bone-marrow  and  give  rise  to  tumors,  since  the  rather 
wide  distribution  of  accessory  thyroid  and  adrenal  tissue,  mainly  in  their 
respective  regions,  is  fully  established. 

All  these  considerations,  however,  seem  contentious  and  have  proved 
unavailing  against  the  increasing  evidence  that  endothelioma  of  bone  is  a 
rather  well-defined  turaor  of  bone  occurring  in  several  subvarieties,  but  usu- 
ally submerged  under  the  diagnosis  of  round-cell  or  alveolar  sarcoma. 

It  is  now  sufficiently  attested  that  endothelioma  of  bone  is  a  specific  neo- 
plastic  disease,  marked  by  the  appearance  of  single  or  multiple  tumors  arising 


ENDOTHELIOMA 


323 


from  the  endothelium  of  bone-marrow  or  bone,  which  are  cellular  and  vascular, 
tending  to  absorb  and  perforate  the  bone,  never  producing  bone,  often  grow- 
ing to  considerable  dimensions,  invading  the  soft  parts,  but  usually  slow  in 
forming  metastases,  often  accompanied  by  a  peculiar  anemia  and  cachexia, 
and  tending  to  a  fatal  termination.  One  of  their  notable  characteristics  is 
marked  susceptibility  to  x-ray  and 
radium,  which  distinguishes  them 
from  osteogenic  sarcoma. 

A  possible  relation  to  some  forms 
of  multiple  myeloma  is  suggested  by 
the  occasional  occurrence  of  plasma- 
cells,  but  this  question  remains  to 
be  determined.  Hansemann,  Herx- 
heimer,  and  Schlagenhaufer  expressed 
the  feeling  that  some  of  these  tumors 
may  be  derived  from  osteoblasts. 
They  did  not  offer  definite  grounds 
for  this  impression,  which  I  believe  is 
incorrect. 

Having  found  in  a  considerable 
series  of  cases  all  gradations  in  struct- 
ure between  solid  diffuse  cell  masses 
at  one  extreme,  up  to  tumors  pre- 
senting very  many  capillary  blood- 
or  lymph- vessels  lined  by  cells  of  the 
identical  type  at  the  other  extreme, 
I  am  convinced  that  all  these  tumors 
belong  in  one  general  group,  derived 
from  the  endothelium  of  blood-  or 
lymph- vessels. 

Three  forms  of  endothelioma  of 
bone  seem  to  deserve  recognition: 

i.  Solitary  Bulky  Cystic  or  Telan- 
giectatic  Angio-endothelioma.  —  This 
tumor  develops  in  the  ends  or  shafts 
of  long  bones.  I  have  seen  3  cases  at 
the  lower  end  of  the  humerus.  It 
grows  steadily,  perforates  the  shaft, 
invades  the  soft  parts,  and  often 
produces  pulmonary  metastases,  but 
less  rapidly  than  does  osteogenic  sar- 
coma. The  tumor  may  pulsate  and 
yield  a  bruit  and  thus  be  classed  with 
malignant  bone  aneurysm,  which  is 
usually  a  variety  of  telangiectatic 

osteogenic  sarcoma.  For  this  reason  also  notable  fluctuations  in  size  may 
be  observed.  The  disease  affects  chiefly  adults  and  elderly  subjects  (Figs. 
114,  115). 

Volkman  described  a  large  multicystic  tumor  containing  gelatinous  fluid 
affecting  the  occiput  in  an  aged  woman.  Most  of  these  tumors  appear  to 
arise  within  the  bone  tissue  or  in  the  bone-marrow,  but  Hildebrand's  tumor 
appears  to  have  sprung  from  the  periosteum.  Periosteal  endothelioma  with 
calcification  and  bone  formation  has  been  described  by  Perthes,  who  finds 
30  such  cases  in  the  literature.  The  growth  is  rather  slow,  occupying  several 


FIG. 


1 14. — Angio-endothelioma 
merus. 


hu- 


324 


NEOPLASTIC  DISEASES 


months;  it  is  accompanied  by  pain  and  disability  and  often  results  in  sponta- 
neous fracture,  which  may  be  the  first  prominent  symptom. 

The  structure  presents  large  cuboidal  or  cylindrical  cells  arranged  in  cords 
or  columns  or  pseudo-alveoli,  and  inclosing  freely  circulating  blood.  The 
cells  are  large,  with  clear  cytoplasm,  sharp  cell  membrane,  and  small  nucleus. 
Solid  sheets  of  such  cells  may  form,  or  alveoli  lined  by  cylindrical  cells,  or 
wide  cystic  spaces  filled  with  blood.  Fragments  of  dissolving  bone  may  appear 
on  the  periphery,  but  bone  production  is  absent.  A  somewhat  similar  struc- 
ture may  be  produced  by  metastatic  carcinoma  of  the  kidney  or  adrenal, 
which  it  is  necessary  to  exclude  before  the  diagnosis  of  endothelioma  can  be 
established. 


FIG.  115. — Structure  of  angio-endothelioma  of  bone. 

Structures  of  this  type  were  recognized  in  solitary  primary  tumors  of 
bone  by  Billroth  (1869),  by  Kolaczek  (1878),  who  included  them  under  angio- 
sarcoma,  and  by  Hildebrand,  who  urged  the  designation  endothelioma,  and 
discussed  their  resemblance  to  benign  bone  aneurysm. 

In  a  series  of  cases  the  tumor  cells  have  not  inclosed  circulating  blood, 
but  formed  small  alveoli  or  small  cysts  containing  mucinous  material,  the 
cells  were  more  cylindrical,  and  the  structure  resembled  carcinoma  (Howard 
and  Crile,  Lit.).  These  authors  generally  assumed  that  such  tumors  had 
arisen  from  lymph- vessels.  It  is  of  these  cases  especially  that  the  possibility 
of  metastatic  origin  must  be  considered  and  eliminated. 

2.  Multiple  EmdffiheUoma  of  Bone. — Multiple  small  tumors  of  the  bone 
marrow  affecting  nearly  every  bone  in  the  body  occurred  in  a  remarkable 


ENDOTHELIOMA 


325 


case  described  by  Marckwald,  and  stands  as  a  type  of  genuine  endothelioma 
of  bone.  The  tumors  were  most  numerous  in  the  vertebrae  and  sternum, 
but  many  were  found  in  skull  and  pelvis.  Some  had  perforated  the  bone. 
All  other  organs  were  free.  The  patient  was  a  male,  aged  53  years,  duration 
14  months,  with  intermittent  fever,  pain,  and  advancing  anemia  and  cachexia. 
The  general  condition  resembled  that  of  multiple  myeloma,  but  the  structure 
of  the  tumors  was  entirely  different.  The  tumors  were  composed  of  a  con- 
geries of  clear  polyhedral  cells  in  diffuse  sheets,  and  often  surrounding  capillary 
channels  containing  intact  blood.  Neighboring  tissue  cells  were  pigmented. 
The  diagnosis  of  intravascular  endothelioma  seems  fully  justified. 


FIG.  116. — Structure  of  diffuse  endothelioma  of  bone. 

Marckwald  analyzed  several  cases  from  the  literature,  with  the  conclusion 
that  similar  tumors  had  been  described  by  Rustizky,  Zahn,  Kahler,  Wieland, 
and  Klebs.  Some  of  these,  however,  were  probably  multiple  myeloma.  Howard 
and  Crile  described  multiple  tumors  of  the  bones  which  closely  resemble 
Marckwald's  case,  and  they  offer  an  interpretation  of  the  much  discussed 
cases  in  the  literature.  They  conclude  that  endothelioma  arises  from  the 
endothelium  of  either  blood-  or  lymph-vessels.  In  one  of  their  cases  there 
were  primary  tumors  of  the  lumbar  vertebra,  others  in  the  clavicle  and  ribs, 
and  numerous  metastases  in  liver,  lungs,  heart  muscle,  skin,  and  many  lymph- 
nodes.  The  cells  were  large,  clear,  and  polyhedral.  Giant-cells  were  numer- 
ous. The  cells  did  not  inclose  blood,  but  formed  small  alveoli  or  solid  cords. 
Their  origin  could  apparently  be  traced  to  the  endothelium  of  lymph-spaces 
in  the  marrow. 


326 


NEOPLASTIC  DISEASES 


The  existence  of  this  group  of  cases  of  multiple  endothelioma  of  bone- 
marrow  and  their  separation  from  metastatic  carcinoma  seems  to  be  suffi- 
ciently attested.  Their  possible  relation  to  multiple  myeloma  of  plasma- 
cell  type  remains  for  future  studies  to  determine.  It  also  appears  uncertain 

whether  the  multiple  tumors  in  the 
bones  are  metastases  or  multiple  primary 
growths. 

3.  Solitary  Diffuse  Endothelioma.— 
This  relatively  frequent  and  quite 
specific  disease  is  usually  unrecognized 
and  passes  under  the  clinical  diagnosis 
of  round-cell  sarcoma  of  bone.  It  may 
be  distinguished  from  osteogenic  sarcoma 
by  its  somewhat  peculiar  clinical  history, 
the  location  in  a  considerable  portion  of 
the  shaft  rather  than  at  the  end  of  the 
bone,  by  a  characteristic  radiographic 
picture,  and  by  the  marked  susceptibility 
of  the  tumor  tissue  to  radium  and  :v-ray. 
Most  of  the  cases  that  I  have  seen 
have  been  in  young  subjects,  3  of  them 
14  years  of  age,  the  oldest  19  years. 
The  disease  begins  without  assignable 
cause  with  attacks  of  pain  aggravated 
by  exercise,  but  not  very  severe,  so  that 
the  patient,  is  able  to  go  about  for  weeks 
or  months.  A  spontaneous  fracture  may 
occur  early.  A  diffuse  swelling  slowrly 
forms  over  the  affected  bone,  and  the 
tumor  tissue  involves  the  soft  parts. 
Fluctuations  in  the  size  of  the  tumor 
may  then  be  noted.  The  growth  is  com- 
paratively slow,  several  months  elapsing 
before  the  external  swelling  demands  at- 
tention. At  this  time  the  radiograph 
shows  a  smooth  diffuse  rarefaction  of  a 
large  portion  of  the  shaft  of  the  long 
bone,  the  outlines  of  which  are  widened. 
The  location  in  the  shaft  rather  than  at 
the  end  of  the  bone,  and  absence  of  bone 
production,  distinguish  the  condition 
from  solid  osteogenic  sarcoma,  while 
the  failure  of  early  and  sharply  limited 
bone  destruction  is  contrasted  with  the 

radiograph  of  telangiectatic  bone  sarcoma.    Benign  giant-cell  tumors  greatly 
expand  the  shaft  over  a  sharply  limited  area  and  exhibit  a  bony  capsule. 

With  this  history  and  radiographic  evidence  it  would  seem  to  be  unneces- 
sary to  incise  these  tumors  for  diagnosis,  especially  if  they  also  respond 
promptly  to  radium  or  #-ray.  The  diagnosis  of  some  form  of  periostitis  has 
been  strongly  maintained  in  some  of  my  cases,  and  has  compelled  the  resort 
to  a  biopsy. 

The  later  history  of  these  cases  it  is  difficult  to  determine.  Although 
regressing  rapidly  under  radium  and  #-ray,  they  are  prone  to  recur  unless  the 
treatment  is  maintained,  and  the  ultimate  outcome  of  this  method  of  treat- 


FIG.  117. — Diffuse  endothelioma 
of  ulna.  Diffuse  widening  and  absorp- 
tion of  whole  shaft. 


ENDOTHELIOMA 


327 


ment  cannot  at  present  be  stated.  Many  tumors  have  been  amputated,  but 
this  procedure  is  commonly  followed  by  local  recurrence  and  metastases  in 
other  bones,  and  in  the  lungs,  lymph-nodes,  and  other  organs.  The  tendency 
to  involve  the  regional  lymph-nodes  is  a  further  differential  feature  from 
osteogenic  sarcoma. 

Whether  the  tumors  appearing  in  other  bones  are  metastases  or  later 
primary  manifestations  of  the  disease  it  is  impossible  to  determine,  but  this 
feature  of  the  disease  renders  the  prognosis  always  serious.  Pulmonary 


iHHHK 


FIG.  1 1 8. — Diffuse  endothelioma  of  radius.     Diffuse  absorption  without  destruction  of 
shaft.    Spontaneous  fracture.    Wide  invasion  of  muscle.    Duration  i  year. 

metastases  appear  to  form  much  later  than  with  osteogenic  sarcoma.    The 
total  duration  in  fatal  cases  has  been  about  2  years. 

The  structure  presents  solid  broad  sheets  of  small  polyhedral  cells,  with 
clear  cytoplasm,  pronounced  cell  borders,  small  hyperchromatic  nuclei,  and 
absence  of  intercellular  substance.  If  the  tissue  has  been  roughly  handled 
or  imperfectly  fixed  the  resemblance  to  some  form  of  lymphosarcoma  may  be 
considerable.  Isolated  foci  of  cells  may  show  marked  hydropic  degeneration. 
Blood-vessels  may  be  missing  over  large  areas.  Or  the  cells  inclose  very 
numerous  blood  channels  of  capillary  size  in  which  there  is  circulating  blood. 


328 


NEOPLASTIC  DISEASES 


In  the  same  tumor  I  have  found  both  types  of  structure,  but  the  solid  growths 
without  many  capillaries  are  the  more  frequent.  These  distensible  capillaries 
account  for  the  fluctuations  in  the  size  of  the  tumors. 

Rarely  the  cells  approach  the  type  of  plasma  cells,  suggesting  that  there 
may  be  some  relation  between  this  disease  and  multiple  myeloma. 


FIG.  119. — Diffuse  endothelioma.  after  radium     Same  case  as  Fig.  118. 

Endothelioma  of  Skin. — In  no  department  has  the  doctrine  of  endothe- 
lioma suffered  such  violent  transformation  as  in  the  field  of  tumors  of  the 
skin.  Here  several  quite  distinct  neoplasms  have  gradually  acquired  a  wide 
or  general  acceptance  as  endothelioma  only  to  lose  their  claims  for  recognition 
in  this  category  through  the  more  careful  studies  of  critical  observers.  These 
tumors  are  the  lymphangioma  tuberosum  multiplex  of  Kaposi,  the  endothe- 


ENDOTHELIOMA 


329 


liomas  of  the  skin  of  Braun  and  others,  and  the  soft  nevus  with  its  derivatives. 
With  the  elimination  of  these  groups  neither  Darier  nor  Unna  admit  the 
existence  of  any  genuine  endothelioma  of  the  skin. 

Lymphangioma  tuber osum  multiplex  was  first  described  in  1868  by  Kaposi 
as  a  tumor  composed  of  lymph-vessels  filled  with  proliferating  endothelial 
cells.  Although  Jacquet  and  Darier  in  1887  showed  that  these  cell  groups 
are  derived  from  the  epithelium  of  dilated  sweat-glands,  numerous  writers 
continued  to  describe  cases  as  endothelioma.  Many  authors  have  pointed 
out  their  true  nature  (Frick,  Lit.).  Stockman  has  reviewed  the  history  of 
this  tumor,  fully  supported  its  epithelial  origin,  and  accepted  its  designa- 
tion as  hydrocystoma  tuberosum  multiplex. 


FIG.  120. — Diffuse  endothelioma  of  bone.     Blood  lacunae  lined  by  tumor-cells. 

A  second  group  of  tumors  of  the  skin  presenting  the  structure  of  cylin- 
droma  was  long  regarded  as  endothelioma.  A  typical  case  of  this  class  and 
one  much  referred  to  is  that  of  Braun.  This  tumor  was  clearly  shown  by 
Krompecher  to  be  of  epithelial  origin  and  is  now  quite  generally  assigned 
to  the  class  of  epithelioma  adenoides  cysticum. 

With  another  group  of  somewhat  similar  tumors  it  has  been  more  difficult 
to  reach  a  conclusion.  In  1889  Spiegler  described  3  cases  of  multiple  tumors 
of  the  scalp  which  grew  over  a  long  period  and  eventually  covered  the  head 
with  numerous  discrete  tumors  resembling  small  "billiard  balls"  or  "tomatoes." 
The  clinical  condition  was  extremely  characteristic.  Similar  tumors  are 
also  observed  in  other  parts  of  the  body,  especially  of  face,  chest,  and  abdomen. 
The  clinical  course,  gross  section,  and  microscopical  structure  show  many 
resemblances  to  reticulated  epithelioma,  with  which  they  are  classed  by  Borr- 
mann,  Ribbert,  and  others.  Mulert's  case  was  disposed  of  by  Lubarsch. 


330 


NEOPLASTIC  DISEASES 


Many  others  closely  resemble  some  of  the  varieties  of  epithelioma  extensively 
illustrated  by  Coenen.  Juliusberger,  who  reviews  this  group  at  length,  regards 
most  of  the  cases  as  epithelioma,  but  considers  Haslund's  case  and  his  own 
as  true  endothelioma.  I  do  not  find  satisfactory  evidence  that  the  tumor 
described  by  Juliusberger  was  derived  from  endothelium,  but  in  Haslund's 
case  the  clinical  history  and  structure  are  rather  distinct  and  it  is  difficult 
to  eliminate  an  endothelial  origin. 

This  patient  suffered  from  multiple  tumors  of  the  scalp  which  grew  rapidly, 
involved  the  regional  lymph-nodes,  and  proved  fatal  in  18  months.  Micro- 
scopically the  polyhedral  or  spindle-cells,  the  formation  of  long  intercellular 
fibrils,  the  absence  of  definite  epithelial  characters,  the  striking  relation  to 


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FIG.  121.  —  Fibro-angio-endothelioma.    A 


mor  beneath  skin  of  thumb. 


vascular  spaces  and  channels,  and  the  various  stages  of  tumor  growth  which 
were  traced  in  great  detail  from  the  lymphatic  endothelium,  all  accord  with 
an  endothelial  character.  On  the  other  hand,  their  appearance  as  multiple 
tumors  ot  the  scalp  of  the  same  general  features  as  the  characteristic  epi- 
thelioma of  this  region  raises  the  suspicion  that  Haslund  had  to  deal  with 
unusual  histological  features  of  an  epithelioma.  Nevertheless  the  minute 
histological  study  of  this  case  brings  to  light  so  many  endothelial  characters 
as  to  leave  in  doubt  the  true  nature  of  the  growth,  and  with  it  the  existence 
of  a  true  endothelioma  of  the  skin.  It  has  already  been  pointed  out  that  the 
presence  of  circulating  blood  in  immediate  contact  with  tumor-cells,  which 
is  the  chief  endothelial  feature  of  Haslund's  case,  is  not  a  reliable  sign  of 
endothelioma,  but  occurs  also  in  epithelioma  of  the  skin. 


ENDOTHELIOMA  331 

The  cellular  nevus  has  been  the  subject  of  much  discussion  and  difference 
of  opinion.  First  regarded  as  an  endothelioma  derived  from  lymph-vessels 
(Recklinghausen,  Demieville,  Lowenbach),  the  opinion  of  Unna  who  inter- 
preted the  cells  as  misplaced  embryonal  epithelium  has  found  very  general 
acceptance  by  the  majority  of  observers.  Yet  Kaufmann,  Johnston,  Schutz, 
and  others  believe  that  there  are  nevi  of  endothelial  as  well  as  those  of  epithe- 
lial nature.  I  do  not  find  the  distinctions  between  these  groups  sufficient  to 
warrant  any  separation  of  the  cases,  which  seem  to  me  to  fall  in  the  class  of 
melanoma  (q.  v.). 

There  is  a  group  of  multiple  small  red  or  brown  tumors  of  skin,  in  children 
or  adults,  which  probably  represent  phases  of  regression,  or  rarely  of  slight  or 
even  active  neoplastic  growth  of  endothelial  cells  of  capillary  nevi.  Wise 
describes  them  in  2  cases  at  length,  but  does  not  clearly  connect  them  with 
capillary  nevi,  nor  distinguish  them  from  pigmented  moles. 

Endothelial  psammoma  of  the  skin  is  described  by  Winkler.  This  rare 
tumor  occurs  in  the  form  of  multiple  hard  nodules  in  the  cutis  or  subcutis 
which  follow  the  course  of  nerves  and  may  be  traced  down  to  the  periosteum. 
They  are  probably  derived  from  the  endothelium  of  nerve  sheaths  and  traces 
of  nerve-fibers  may  persist.  They  belong  in  the  group  of  psammoma  of 
nerve-trunks.  They  consist  of  concentric  masses  of  endothelial  cells  which 
are  often  calcified.  According  to  Winkler  certain  cases  of  calcified  endothe- 
lioma of  the  skin  (Perthes,  Linser,  Volkmann)  have  a  similar  origin.  Psam- 
moma of  deeper  nerve-trunks  is  more  frequent. 

Angio-endothelioma  of  the  skin  and  subcutaneous  tissue  occurred  in  several 
cases  which  I  have  examined.  They  were  slowly  growing  circumscribed 
tumors  of  the  sole  of  the  foot,  finger,  or  face.  They  were  composed  of  a  moder- 
ate number  of  small  blood  channels  traversing  wide  groups  of  endothelial 
geltsT"  The  preponderance  of  cells  over  vessels  calls  for  the  designation  of 
endothelioma  (cf.  Hemangio-endothelioma) . 

Endothelioma  of  Corpus  Cavernosum  Penis. — This  tumor  appears  in  the 
form  of  multiple  nodules  or  flat  infiltrations  of  the  corpora  cavernosa  behind 
the  glands  and  along  the  dorsum  of  the  penis.  Four  cases  are  recorded,  in 
2  of  which  the  course  was  moderately  slow,  the  growth  circumscribed,  and 
operation  was  followed  by  recovery  (Alexander,  Hildebrandt),  while  in  the 
others  the  disease  early  involved  the  lymph-nodes  and  the  patients  died  with 
general  metastases  (Maurer,  Colmers).  The  structure  consists  of  the  cavernous 
spaces  filled  with  large  polyhedral  or  rounded,  rather  clear  or  granular  cells 
with  large  nuclei  and  prominent  nucleoli.  The  central  portions  of  large  cell 
groups  are  necrotic  or  occupied  by  circulating  blood  (Colmers).  Invasion 
of  the  urethra,  septa,  skin,  and  especially  of  the  nerve-sheaths  is  observed. 
Occasionally  concentric  groups  of  cells  appear.  The  origin  of  this  tumor 
from  endothelium  has  not  been  fully  determined,  but  primary  tumors  of 
the  urethra  were  excluded.  Yet  Hildebrandt  considers  the  possibility,  and 
Borrmann  assumes,  an  origin  from  urethral  epithelium.  In  Alexander's  case 
I  must  agree  with  Dunham  that  the  structure  was  different  from  that  of 
epithelioma  and  strongly  suggestive  of  endothelioma. 

Creite  has  described  a  peculiar  urethral  carcinoma  of  undetermined  origin 
in  a  child  of  2  years  which  may  have  some  bearing  on  the  present  topic. 

Endothelioma  of  Ovary. — Among  the  tumors  of  the  ovary  Leopold  (1874) 
described  a  very  large  growth  which  he  derived  from  the  endothelium  of 
lymph-vessels,  while  numerous  small  cysts  composing  the  bulk  of  the  tumor 
he  referred  to  dilated  lymphatics.  In  1879  Marchand  described  papillary, 
cystic,  and  tubular  forms  of  ovarian  tumor  which  he  distinguished  from  sar- 
coma and  considered  as  very  probably  derived  from  endothelium  of  lymph- 


332  NEOPLASTIC  DISEASES 

or  blood-vessels.  Somewhat  similar  structures  were  next  observed  by 
Flaischlen  in  a  cystic  tumor  combined  with  a  dermoid  cyst. 

A  definite  relation  of  the  tumor-cells  to  the  endothelium  of  blood-vessels 
was  claimed  by  Olshausen  and  Ackermann  and  by  Eckardt,  who  described 
their  tumors  as  endothelioma  intravasculare.  On  the  other  hand,  Pomorski 
and  v.  Velits  traced  cystic  and  myxomatous  tumors  to  lymphatic  endothelium, 
and  Rosthorn  referred  a  somewhat  different  structure,  composed  of  large 
cell  groups  inclosing  blood-masses,  to  proliferation  of  perithelial  cells.  All 
three  structures  seemed  to  Amann  to  deserve  recognition  as  types  of  endothe- 
lioma. In  the  disposition  of  the  cells  L.  Pick  recognized  three  types  composed 
of  (i)  long  rows  and  whorls  of  cells,  (2)  cell  groups  resembling  adenoma  or 
carcinoma,  and  (3)  diffuse  masses  of  cells  resembling  sarcoma.  In  1896  a 
specific  structure,  designated  as  fibrosarcoma  ovarii  mucocellulare  carcino- 
matodes,  was  described  by  Krunkenberg  and  referred  in  all  probability  to  the 
endothelial  cells  of  this  organ  (Krunkenberg's  tumor). 

Thus  such  a  wide  variety  of  structures  of  such  uncertain  origin  were  now 
included  under  endothelioma  that  suspicion  arose  regarding  the  validity 
of  the  rapidly  growing  scope  of  this  ovarian  tumor.  Such  obvious  combina- 
tions as  pyloric  cancer  and  endothelioma  of  ovary  were  misinterpreted  by 
Rosinski  as  multiple  separate  tumors,  while  Linck  even  saw  in  the  pyloric 
cancer  a  metastasis  from  the  ovarian  growth.  *  Likewise  Krunkenberg  found 
the  typical  structure  of  perivascular  endothelioma  in  an  ovarian  tumor  in  a 
patient  who  2  years  later  required  hysterectomy  for  a  similar  tumor  of. the 
cervix.  In  Eymer's  case  also  the  cervix  was  involved. 

The  first  inroad  upon  endothelioma  of  the  ovary  was  accomplished  by 
Schlagenhaufer,  1902,  who  showed  that  the  majority  of  bilateral  tumors  of 
the  ovary  are  secondary  to  epithelial  neoplasms  of  stomach,  intestine, 
gall-bladder,  or  uterus,  and  the  typical  Krunkenberg  tumor  he  and  Glockner 
observed  as  a  metastatic  growth  from  pyloric  cancer  with  mucous  cells. 
Polano  (1904)  showed  that  ova-like  structures  and  perithelioma  could  appear 
in  adenocarcinoma,  that  metastatic  gastric  cancer  in  the  ovary  produced 
many  of  the  structures  of  the  so-called  endothelioma,  and  that  certain  mucoid 
endotheliomas  were  really  thyroid  struma  in  this  organ.  Papaioannou 
also  pointed  out  the  close  resemblance  of  metastatic  ovarian  carcinoma  to 
endothelioma  and  fibrosarcoma.  Stone  has  recently  reviewed  at  length  the 
subject  of  secondary  ovarian  carcinoma.  Glockner  denied  the  validity  of 
Pick's  histological  criteria  of  endothelioma,  especially  the  absence  of  an  in- 
tact layer  of  endothelial  cells  in  the  invaded  tissue  spaces,  and  claimed  that 
the  diagnosis  of  ovarian  endothelioma  could  not  be  based  on  histological 
structure  alone,  but  required  the  elimination  of  other  tumors,  especially  of 
the  uterus,  by  autopsy.  Thus  grave  doubts  arose  as  to  the  existence  of  any 
genuine  endothelioma  of  the  ovary.  R.  Meyer  was  disposed  to  discard  the 
entire  group,  and  Ribbert  states  (1912)  the  extreme  view  that  the  endothelial 
origin  of  any  ovarian  tumor  while  possible  is  unproved. 

During  this  long  discussion  lasting  over  30  years  it  became  apparent 
that  unusual  difficulties  surround  the  diagnosis  of  endothelioma  in  the 
ovary.  This  organ  does  not  meet  one  of  the  conditions  laid  down  by  Ribbert 
for  the  probable  endothelial  nature  of  any  primary  tumor,  viz.,  that  the  organ 
should  not  contain  epithelial  structures.  On  the  contrary,  the  remarkable 
physiology  and  changeable  morphology  of  the  germ  epithelium,  PfKiger's 
tubes,  Graafian  follicles,  and  corpus  luteum,  offer  unusual  sources  of  atypical 
epithelial  tumors.  The  average  quota  of  endothelial  cells  seems  to  be  defi- 
cient in  the  ovary  if  one  can  accept  Polano's  observation  that  no  lymph 
spaces  lined  by  endothelial  cells  exist  in  this  organ.  Again  it  has  transpired 


ENDOTHELIOMA  333 

that  the  ovary  is  peculiarly  liable  to  implantation  metastases  by  its  exposed 
position  in  the  peritoneal  cavity,  and  to  deposits  by  embolism  or  permeation. 
Finally,  the  doctrine  of  overgrowth  of  one  element  in  teratomas  has  offered 
a  peculiar  source  of  certain  supposed  endotheliomas  of  embryonal  type  or 
associated  with  dermoids  (Flaischlen,  Vogel)  or  teratomatous  structures 
(Ribbert,  Yamagiva). 

One  of  the  most  conclusive  features  of  certain  endotheliomas  is  the  rela- 
tion of  cell  groups  inclosing  blood-masses  as  in  angioblastic  sarcoma.  Yet 
this  structure  has  been  clearly  traced  in  the  testis  to  a  teratomatous  origin 
and  an  epithelial  derivation  (Wlassow),  and  while  Sternberg  and  Monckberg 
have  endeavored  to  establish  the  existence  of  a  special  variety  of  angioblastic 
sarcoma  or  endothelioma  apart  from  teratoma  and  Pfannenstiel  recognizes 
such  tumors  in  the  ovary,  their  teratomatous  nature  cannot  be  so  readily 
discarded. 

Thus  critical  research  fully  justifies  the  current  skepticism  regarding 
the  endothelial  nature  of  the  present  group  of  ovarian  tumors  and  especially 
their  origin  from  adult  endothelial  cells  of  any  type. 

There  is  nevertheless  a  restricted  group  of  ovarian  tumors  for  which  very 
strong  evidence  points  to  an  endothelial  origin  and  their  somewhat  peculiar 
clinical  course,  gross  appearance,  and  histological  structure  warrant  their 
separate  classification  as  probable  endotheliomas. 

These  tumors  are  usually  large,  sometimes  bilateral  (22  per  cent.,  Apelt), 
chiefly  solid,  yet  often  cystic.  The  solid  growths  show  marked  lobulation 
and  the  exterior  is  nodular,  while  the  general  form  of  the  ovary  is  maintained. 
The  cysts  are  small  and  numerous  as  from  dilated  lymph-vessels,  or  larger 
and  exhibiting  on  minute  inspection  papillary  outgrowths.  A  honeycomb 
appearance  is  noted  by  Pick.  The  consistence  is  firm,  and  the  color  varies 
greatly  with  the  blood  content.  Hydropic  areas  and  hyaline  or  colloid  de- 
generation alter  the  appearance  of  the  section,  which  in  general  resembles 
sarcoma. 

The  clinical  course  is  of  an  actively  growing  tumor  appearing  at  any 
period  of  life,  but  chiefly  in  adults,  v.  Velits  observed  a  case  continuing  for 
9  years,  and  Kubo  12  years,  while  Glockner  saw  a  fatal  result  in  6  months. 
Local  adhesions  with  ascites  and  permeation  through  lymphatics  are  variable, 
but  recurrence  is  frequent.  Kubo  found  no  case  of  recovery  from  bilateral 
tumors  reported  as  endothelioma,  but  single  tumors  have  been  successfully 
eradicated  by  several  operators  (Pfannenstiel).  It  is  generally  agreed  that 
the  malignancy  is  less  than  that  of  carcinoma. 

The  structure  falls  into  several  classes  (Pick,  Pfannenstiel) : 

1.  The  cells  are  arranged  in  orderly  rows  or  whorls  between  abundant 
fibrils,  an  appearance  which  has  been  likened  to  strings  of  pearls.    An  indefi- 
nite lumen  between  such  single  or  multiple  rows  of  small  cuboidal  cells  has 
often  been  interpreted  as  a  dilated  lymph-channel,  yet  the  origin  of  the  cells 
from  lymphatic  endothelium  has  never  been  traced,  and  it  is  obvious  that 
in  a  large  tumor  mass  original  lymph  paths  are  wholly  obliterated.    On  the 
other  hand,  the  remarkable  long  and  regular  cell  columns  as  pictured  by  Kubo 
may  well  signify  the  reassertion  of  the  physiological  tendencies  of  lymphatic 
endothelium  in  a  desmoplastic  tumor. 

2.  A  definite  lumen  of  small  or  large  dimensions  walled  by  one  or  more 
rows  of  tumor-cells  and  containing  lymph  or  blood  characterizes  a  second 
group   of   tumors   designated   as   alveolar   or   intravascular   endothelioma. 
The  structural  evidence  of  endothelial  origin  of  this  group  is  unusually  strik- 
ing, and  there  is  little  doubt  that  such  cases  as  those  of  Marchand,  Pfan- 
nenstiel, and  Kubo  are  properly  regarded  as  endothelioma.     They  show, 


334  NEOPLASTIC  DISEASES 

moreover,  numerous  transitions  up  to  structures  which  really  deserve  the 
name  of  angioma.  Tumors  consisting  of  one  or  more  large  cysts  lined  by 
layers  of  endothelial-like  cells,  described  by  Schurman  and  by  Lange,  are 
accepted  by  Monckberg  as  genuine  endothelioma.  If  so  they  represent  ex- 
treme examples  of  dilated  lymph-vessels.  Larger  plexiform  masses  of  cells 
often  form  in  which  small  groups  of  cells  surround  marrow  lumina  (Kubo) 
or  wide  lumina  filled  with  mucinous  material  appear.  Ova-like  structures 
formed  by  mucinous  degeneration  of  cells  occur  in  certain  tumors  of  this 
type  whose  endothelial  nature  is  doubtful.  Similar  bodies  are  found  in  un- 
doubted adenocarcinomas.  Hyaline  globules  in  and  between  the  cells  may 
also  become  a  prominent  feature  (Kworostansky).  The  lymph-channels 
may  become  dilated  and  papillary  projections  of  tumor-cells  may  partially 
fill  the  small  cysts  (Eymer),  or  the  channels  may  be  filled  with  blood  (Rosthorn). 

3.  Diffuse  growth  of  small  cuboidal  cells  forms  the  bulk  of  some  endothe- 
liomas  and  appears  in  portions  of  many  others.    Here  indications  of  alveolar 
tendencies  may  be  detected  at  many  points  and  the  tumors  bear  a  resem- 
blance to  alveolar  sarcoma.    The  true  nature  and  origin  of  such  tumors  is,  I 
think,  open  to  question. 

4.  In  a  group  of  cases  (Kubo,  Lit.)  the  tumor-cells  surround  vascular 
channels  which  possess  a  well-defined  wall  of  normal  endothelial  cells,  giving 
the  structure  of  perithelioma.    There  seems  to  be  little  reason  to  doubt  that 
such  tumors,  e.  g.,  Amann's  case,  are  of  endothelial  nature,  but  the  attempt 
to  derive  the  cells  from  specialized  perivascular  endothelium  has  not  been 
successful.      Pfannenstiel    interprets    as    angioplastic    endothelioma    ovarian 
tumors  described  by  Michel  and  by  himself  in  which  numerous  capillary 
blood  channels  without  walls  coursed  throughout  diffuse  cell  masses.    This 
tumor  is  probably  of  teratomatous  origin  and  choriomatous  type,  and  while 
the  cells  may  assume  angioplastic  qualities  the  tumor  has  a  different  significance 
from  the  present  conception  of  endothelioma. 

In  all  of  these  structural  forms  the  features  of  the  tumor-cells  strongly 
indicate  their  endothelial  nature.  They  are  of  very  uniform  small  size,  cuboidal 
or  rounded  form,  pale  staining  cytoplasm,  and  regular  oval  nuclei  with  minute 
nucleoli. 

In  the  stroma  mucinous  changes  may  be  prominent  or  hyaline  degenera- 
tion may  yield  the  appearance  of  cylindroma. 

In  the  effort  to  trace  the  origin  of  the  tumors  many  have  assumed  that  they 
could  be  subdivided  into  lymphangio-endothelioma  and  hemangio-endothe- 
lioma,  intravascular  and  perivascular,  and  Kubo  has  arranged  the  reported 
cases  according  to  this  plan.  Its  validity,  as  well  as  the  exact  nature  of  many 
of  the  tumors  included,  remain  to  be  established.  Especially  for  the  peri- 
vascular type  the  attempt  to  derive  the  growth  from  the  hypothetical  peri- 
thelial  cells  deserves  little  encouragement.  Polano  could  not  discover  any 
traces  of  such  cells  in  the  ovarian  vessels,  and  it  is  well  know  that  this  struc- 
ture may  be  produced  by  many  tumors. 

Endothelioma  of  Uterus. — In  the  uterine  mucosa  and  muscularis  and 
in  the  cervix  several  tumors  have  been  described  as  types  of  endothelioma, 
and  derived  by  the  authors  from  lining  cells  of  blood-  or  lymph-vessels.  From 
the  descriptions  of  these  cases  I  have  not  been  convinced  that  a  well-defined 
endothelioma  of  the  uterus  has  been  demonstrated  and  would  agree  with 
R.  Meyer  that,  while  such  tumors  may  occur,  it  is  more  probable  that  the 
alleged  cases  should  be  distributed  among  epitheliomas  and  sarcomas.  Meyer 
points  out  that  a  considerable  grade  of  endothelial  proliferation  may  occur 
in  the  cervix  and  uterus  as  a  result  of  inflammation,  that  the  remnants  of 
Gartner's  duct  in  the  cervix  have  been  overlooked  as  a  possible  source  of 


ENDOTHELIOMA  335 

atypical  epithelial  tumors,  and  that  many  of  the  structures  of  endothelioma 
uteri  may  be  explained  as  atypical  features  of  other  tumors. 

Neither  in  the  clinical  course  nor  in  the  gross  or  microscopical  structure 
have  the  reported  cases  shown  uniformity.  Thus  Pick  finds  endothelioma 
in  a  small  portion  of  the  mucosa  connected  with  a  myosarcoma.  Hansen 
describes  a  large  vascular  tumor  of  the  myometrium  which  showed  many 
features  of  an  angiosarcoma,  and  the  structure  in  Silberberg's  case  falls  in 
the  same  general  class.  Amann  who  recorded  the  first  case  was  content 
to  find  no  connections  between  the  tumor-cells  and  the  surface  epithelium, 
but  his  case  and  that  of  Braetz  strongly  suggest  embryonal  epithelioma. 
Pohorecky,  Kroemer,  and  Krischgessner  describe  structures  often  duplicated 
by  epithelioma.  Hurdon's  case  was  clinically  indistinguishable  from  cervical 
epithelioma  with  wide  extensions,  and  while  portions  of  the  structure  suggest 
endothelioma,  other  areas  correspond  to  epithelioma.  Rabb  considered 
his  case  clinically  epithelioma,  and  such  is  the  impression  clearly  conveyed 
by  Graefe's  report. 

Thus  the  recorded  cases  seem  to  fall  into  three  groups,  vascular  tumors 
of  the  angiosarcomatous  type,  embryonal  epithelioma,  and  atypical  forms 
of  ordinary  epithelioma  of  the  cervix.  Further  critical  study  would  seem 
to  be  demanded  before  the  existence  of  endothelioma  uteri  can  be  accepted. 

Endothelioma  of  Stomach. — For  many  years  a  peculiar  condition  of  cirrho- 
sis of  the  stomach  with  pyloric  stenosis  has  been  recognized  under  various 
terms  and  interpretations.  From  the  surgical  side  the  history  of  the  subject 
has  been  fully  reviewed  by  Lyle,  who  employs  Brinton's  term  linitis  plastica 
for  the  general  condition.  It  has  long  been  known  that  some  of  these  cases 
were  atypical  diffuse  carcinoma.  In  a  second  group  the  process  has  been 
recognized  as  neoplastic  and  interpreted  as  endothelioma  by  Fick,  Tilger, 
Jungmann,  Cignozzi,  Aldegarmann,  and  others,  and  Hansemann  and  Borst 
have  lent  some  support  to  this  view.  Szobelew  and  others  haye  found  the 
condition  both  at  the  pylorus  and  in  the  colon.  Yet  in  none  of  these  cases 
has  there  been  satisfactory  evidence  that  the  process  is  an  endothelioma. 
The  structure  shows  a  diffuse  and  scanty  infiltration  of  large  cells  with  hyper- 
chromatic  nuclei,  but  of  wholly  indefinite  origin.  Many  of  the  cells  may 
show  the  mucous  degeneration  with  signet-ring  nuclei  of  gastric  cancer,  and 
some  small  foci  of  such  cells  are  usually  found  on  careful  search.  I  have 
examined  5  cases  of  this  type  in  all  of  which  the  characteristic  mucous  cells 
have  been  found,  and  in  3  prolonged  search  revealed  alveoli  of  typical  gastric 
cancer.  Since  the  typical  appearance  of  endothelioma  may  appear  in  un- 
doubted gastric  cancer  there  appears  to  be  no  ground  for  the  assumption 
that  endothelioma  of  this  organ  exists. 

That  the  remaining  cases  of  cirrhosis  of  the  stomach  and  intestine  with 
pyloric  stenosis  in  the  adult  are  the  results  of  a  chronic  inflammatory  process 
has  been  clearly  shown  by  Krompecher,  who  attributes  the  changes  to 
edema,  fibrosis,  muscular  hypertrophy,  and  irritation  by  foreign  bodies. 
Recently  there  has  arisen  a  tendency  on  the  part  of  clinicians  to  call  many  of 
these  cases  syphilis. 

Endothelioma  of  Lymph-nodes. — Primary  endothelioma  of  lymph-nodes 
was  described  by  Chambard  in  1880  under  the  term  "primary  carcinoma." 
He  recognized  a  local  form  of  the  disease  affecting  one  node  or  one  chain, 
and  a  generalized  form  which  was  always  fatal.  The  structure  was  alveolar. 
Zahn  had  previously  interpreted  an  alveolar  tumor  of  the  cervical  nodes  as 
sarcoma  alveolar e  epithelioides.  In  1881  Hoffmann  and  Schottelius  used  the 
term  "endothelioma"  in  their  report  of  a  case.  The  endothelial  nature  of  these 
tumors  became  gradually  accepted,  so  that  Ziegler,  Birch-Hirschfeld,  and 


336 


NEOPLASTIC  DISEASES 


Kaufmann  admitted  their  occurrence  and  referred  to  single  cases  of  their 
own,  and  Recklinghausen  pointed  out  certain  distinctions  between  primary 
endothelioma  and  secondary  carcinoma  of  lymph-nodes.  More  recently 
quite  detailed  reports  of  the  gross  anatomy,  microscopic  structure,  and  clinical 
course  of  these  tumors  have  been  furnished  by  Ravenna,  Gallina,  Parlavec- 
chio,  and  the  writer. 

In  the  study  of  a  series  of  cases  collected  during  a  period  of  several  years 
I  have  drawn  the  conclusions  that  endothelioma  of  lymph-nodes  is  compara- 
tively frequent  in  occurrence,  that  the  tumors  often  arise  on  a  basis  of  chronic 
granulomatous  inflammation,  that  they  develop  from  the  endothelium  of 
the  lymph  and  cavernous  sinuses  and  are  then  usually  classed  as  secondary 
carcinoma,  that  somewhat  similar  tumors  arise  from  the  reticulum  cells  of 
the  lymph-nodes,  but  usually  take  the  form  of  large-cell  lymphosarcoma, 
occasionally  of  carcinoma,  and  that  the  characteristic  clinical  course  and 
microscopical  structure  of  the  tumors  constitute  them  specific  diseases. 


FIG.  122.- 


«*• 


-Perivascular  endothelioma  of  lymph-nodes.     Nearly  all  lymph-nodes  were 
involved  in  this  case.      (Flournoy.) 


Clinically  the  disease  appears  in  the  form  of  (i)  a  systemic  involvement 
of  many  lymph-nodes  with  a  progressive  and  fatal  course  lasting  from  one 
to  several  years,  and  (2)  as  single  or  multiple  tumors  of  cervical,  axiliary, 
or  other  lymphatic  chains,  often  preceded  by  granulomatous  infection,  but 
eventually  or  from  the  first  declaring  itself  as  a  locally  aggressive  recurring 
malignant  tumor. 

The  systemic  form  of  the  disease  usually  suggests  the  diagnosis  of  pseudo- 
leukemia,  as  emphasized  by  Parlevecchio.  Most  of  my  systemic  cases  were 
regarded  as  Hodgkin's  granuloma  and  in  some  certain  of  the  nodes  pre- 
sented the  typical  Sternberg-Reed  histology.  In  one  case  of  lymphatic 
leukemia  I  found  alveolar  endothelioma  of  the  bronchial  nodes.  Flournoy's 
case  ran  a  prolonged  course  of  4  years  and  developed  cervical,  thoracic,  and 
very  large  abdominal  tumors.  Gallina's  patient  lived  12  years. 

The  localized  tumors  develop  chiefly  in  neck,  axilla,  and  groin,  and  are 


ENDOTHELIOMA 


337 


commonly  regarded  as  tuberculosis.  In  one  case  I  followed  an  originally 
tuberculous  infection  of  cervical  nodes  recurring  repeatedly  over  a  period 
of  5  years,  and  gradually  assuming  the  structure  of  a  malignant  endothe- 
lioma  with  elimination  of  the  tuberculous  element.  Usually  the  tumors  are 
endotheliomatous  from  the  first.  In  some  cases  I  have  been  unable  to  sepa- 
rate the  local,  cervical,  or  axillary  tumors  from  a  systemic  disease  of  the 
type  of  Hodgkin's  granuloma.  The  local  disease  has  a  lethal  tendency,  but 
some  patients  enjoy  long  immunity  after  operation,  although  the  ultimate 
outcome  is  usually  unfavorable.  Zahn  and  Volkmann  describe  rapidly  fatal 
cases.  Extensive  tumors  of  the  neck  may  early  cause  asphyxia  and  in  others 
attempted  removal  proves  fatal. 

Gross  Anatomy. — The  systemic  disease  is  marked  by  uniform  enlargement 
of  several  chains  of  nodes,  some  of  which  reach  large  dimensions  and  give 


FIG.  123. — Diffuse  endothelioma  of  cervical  lymph-nodes. 

pressure  symptoms.  The  tumors  are  smooth,  at  first  firm,  later  very  hard, 
usually  solid,  opaque,  and  marked  by  areas  of  necrosis.  Recklinghausen 
saw  cystic  distention  of  the  abdominal  chains,  and  involvement  of  many 
retroperitoneal  nodes. 

The  local  tumors  are  at  first  circumscribed  and  the  capsules  free,  but 
later  they  become  large,  hard,  adherent,  and  multiple.  The  infiltration  of 
recurrent  tumors  involves  the  neighboring  structures  with  compression  or 
destruction,  as  in  carcinoma,  but  the  progress  is  usually  distinctly  slower 
than  in  epithelial  growths.  Very  extensive  fibrosis  and  large  areas  of  re- 
tained desiccated  lymph  or  necrotic  tissue  appear  in  late  stages.  Almost 
complete  sclerosis  may  overtake  some  of  the  tumor  masses. 

Metastases  are  difficult  to  distinguish  from  systemic  extensions,  but  the 
22 


338 


NEOPLASTIC  DISEASES 


lesions  tend  to  advance  over  wide  areas,  involving  thoracic  and  abdominal 
nodes  and  spleen.  There  appear  to  be  all  gradations  between  the  localized 
and  the  systemic  form.  Definite  metastases  were  found  by  Gallina  in  the 
adrenal,  and  in  the  portal  canals  of  the  liver  by  Ravenna.  Very  extensive 
lymphatic  lesions  from  which  skin  and  muscles  were  invaded,  with  edema  of 
chest  wall,  chylous  hydrothorax,  and  metastases  in  pleura,  stomach,  and 
adrenals  occurred  in  the  case  of  Da  Gradi  and  de  Amicis.  In  Flournoy's 
case  a  very  large  tumor,  1780  gm.,  surrounded  the  pancreas,  nearly  all  lymph- 
nodes  were  involved,  and  there  were  metastases  in  adrenal  and  thyroid. 

Structure. — The  structure  encountered  depends  on  the  stage  of  the  process 
and  on  the  rapidity  of  its  development.  On  the  one  hand,  it  may  be  difficult 
to  separate  the  early  stages  from  granulomatous  inflammation,  and  on  the 


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FIG.  124. — Diffuse  endothelioma  of  lymph-nodes.     Coherent  masses  of  large  cells  with 

clear  cytoplasm. 

other  the  late  stages  resemble  carcinoma.  The  earliest  stages  of  many  cases 
appear  as  a  granuloma  in  which  groups  or  coherent  syncytial  sheets  of  sinus 
endothelium  or  reticulum  cells  stand  out  prominently  by  virtue  of  their  size 
and  nuclear  hyperchromatism.  The  cells  are  large,  elongated  or  polyhedral, 
with  very  large  vesicular  nuclei  and  diminutive  nucleoli,  and  they  spring 
in  multiple  foci  from  the  lymphatic  tissue.  The  isolation  of  invading  tumor- 
cells  is  conspicuously  absent.  The  lymphocytes  are  passive  and  disappear. 
Ravenna  emphasizes  the  imperfect  outlines  of  the  cells  and  their  occurrence 
in  broad  sheets  of  cytoplasm  interspersed  with  large  vesicular  nuclei. 

In  some  cases  fibrosis  sets  in  early  and  then  the  tumor-cells  become  iso- 
lated and  very  prominent  and  the  structure  resembles  alveolar  carcinoma. 
Many  patent  lymph  paths  lined  by  tumor-cells  may  persist  or  cysts  may  form. 
Large  convoluted  masses  of  coherent  endothelium  may  make  up  the  bulk  of 


ENDOTHELIOMA 


339 


large  tumors  in  which  irregular  areas  of  necrotic  tissue  containing  fatty  crystals 
may  appear.  The  structure  may  be  designated  as  plexiform  endothelioma. 

In  several  cases  I  have  found  dilated  lymph-channels  lined  by  multiple 
layers  of  opaque,  elongated,  or  polyhedral  cells.  Or  the  cells  mingled  with 
lymphocytes  may  encircle  small  arterioles  as  in  perithelioma.  These  struc- 
tures suggest  the  term  peri-vascular  endothelioma. 

In  some  cases  the  whole  node  is  replaced  by  a  diffuse  growth  of  large 
polyhedral  or  rounded  cells  which  may  cohere  or  fall  apart.  Giant-cells  with 
multilobed  nuclei  may  appear  in  these  tumors,  which  may  be  called  diffuse 
endothelioma.  They  may  present  the  appearance  of  large-cell  lympho- 
sarcoma. 


FlG.  125. — Perivascular  endothelioma  of  cervical  lymph-nodes. 

Histogenesis. — Analysis  of  the  origin  of  endothelioma  of  lymph-nodes 
involves  at  once  the  somewhat  complicated  questions  of  the  structure  of 
lymph-nodes.  I  have  elsewhere  discussed  this  subject  in  some  detail  with 
the  following  conclusions: 

The  reticulum  cells  of  the  lymph-nodes  are  derived  from  connective-tissue 
cells,  and  form  a  meshwork  in  which  lymphocytes  gather  from  without.  The 
reticulum  of  the  follicles  and  pulp  does  not  produce  lymphocytes,  but  these 
two  cells  constitute  separate  series  (Saxer,  Gulland).  The  reticulum  of  the 
node's  is  not  covered  by  separate  endothelial  cells,  but  is  itself  a  cellular 
syncytial  structure  which  incloses  spaces  continuous  with  the  lymph  paths 
of  the  node.  In  the  cavernous  and  lymph  sinuses  the  lining  cells  have  pave- 
ment qualities  of  adult  endothelium,  while  in  the  cords  and  follicles  the 


340 


NEOPLASTIC  DISEASES 


reticulum  cells  retain  more  of  their  original  mesoblastic  tendencies.  Hence 
tumors  arising  from  sinus  endothelium  may  be  expected  to  show  pavement 
or  epithelial  characters,  while  tumors  of  reticulum  cells  should  exhibit 
some  of  the  mesoblastic  features  of  their  parent  cells. 

To  a  large  extent  these  expectations  are  realized  in  the  study  of  the  tumors. 
To  the  sinus  endothelium  has  been  traced  the  origin  of  several  tumors  pre- 
senting alveolar  or  perivascular  structures  composed  of  polyhedral  cells 
(Ravenna,  Ewing).  The  reticulum  cells  of  the  lymph  cords  are  found  multi- 
plying in  the  early  stages  of  many  tumors,  especially  in  the  outlying  nodes, 
and  it  is  probable  that  changes  in  the  form  of  these  cells  toward  adult  endo- 
thelium accounts  for  the  preponderance  of  large  polyhedral  cells  in  the  whole 
group  of  tumors.  From  the  reticulum  cells  of  the  follicles  I  have  repeatedly 
been  able  to  trace  the  development  of  large  round-cell  tumors  of  the  type  of 


FIG.   126. — Unit  structure  in  a  tumor  of  lymph-nodes.     Large  cells  growing  in  and 

about  small  blood-vessels. 

large  round-  and  giant-cell  lymphosarcoma,  which  tumors  must  be  separated 
from  lymphocytoma. 

That  the  tumors  are  not  secondary  carcinomas  is  sufficiently  attested 
by  the  failure  to  find  any  primary  tumor  and  by  the  very  wide  diffusion  and 
slow  course  of  the  systemic  disease.  That  they  do  not  arise  from  aberrant 
epithelial  rests  within  lymph-nodes  has  been  proved  by  the  detection  of  early 
stages  throughout  the  whole  node  or  several  nodes  of  a  chain  (Parlavecchio). 

With  this  complex  morphology  and  histogenesis  it  is  difficult  to  establish 
a  legitimate  nomenclature.  The  terms  employed,  endothelioma  of  various 
types,  emphasize  the  form  of  the  tumor-cells  and  their  probable  origin.  The 
tumors  of  loose  round-cells  derived  from  the  reticulum  of  the  follicles  differ 
markedly  from  the  others  and  it  seems  unwise  to  urge  any  change  in  their 
usual  designation  as  large-cell  lymphosarcoma  or  reticulum-cell  sarcoma. 


ENDOTHELIOMA 


341 


Etiology. — Many  observers  have  been  impressed  by  the  apparent  depend- 
ence of  endothelioma  of  lymph-nodes  upon  lymphatic  infection.  The  clin- 
ical features  of  the  systemic  cases  closely  resemble  those  of  pseudoleukemia 
or  of  Hodgkin's  granuloma.  Parlavecchio  stated  that  the  histological  struc- 
ture revealed  the  transformation  of  an  inflammatory  into  a  neoplastic  hyper- 
plasia  of  endothelium  and  he  clearly  pictured  these  transitions.  In  the  recur- 
rences of  one  case  I  was  able  to  trace  an  original  tuberculous  granuloma  into 
the  neoplasm  with  elimination  of  the  tuberculous  structure.  I  have  reported 
several  other  cases  in  which  various  phases  of  remarkable  endothelial  over- 
growth occurred  in  tuberculous  or  other  granuloma tous  lesions.  Many  of 
the  localized  tumors  present  in  outlying  nodes  the  changes  of  frank  or  atypical 
tuberculosis.  Most  of  the  localized  tumors  and  the  advanced  svstemic  lesions 


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FIG.  127. — Early  stage  of  diffuse  endothelioma  of  lymph-nodes.    These  cells  are  derived 
from  the  reticulum  and  sinus  endothelium. 

fail  to  show  any  traces  of  granuloma,  suggesting  that  the  tumor  soon  over- 
grows the  granuloma  or  arises  immediately  in  response  to  the  infection.  Other 
infectious  agencies  besides  tubercle  probably  figure  in  the  disease,  and  of 
these  Hodgkin's  granuloma  requires  first  consideration.  Syphilis  has  not 
thus  far  been  implicated. 

PERITHELIOMA 

That  a  definite  group'of  tumors  exists  which  deserves  recognition  under 
the  term  "perithelioma"  must  be  admitted,  but  the  exact  origin  of  these  tumors 
and  their  relation  to  other  neoplasms  are  questions  requiring  more  extensive 
data  than  we  now  possess. 

The  existence  of  a  special  type  of  cell  about  the  blood-vessels  of  the  pia 
mater  was  first  shown  by  Eberth.  In  salt  solution  he  was  able  to  isolate 


342  NEOPLASTIC  DISEASES 

a  thin  membrane  composed  of  polygonal  or  multipolar  cells  surrounding 
these  vessels.  These  cells  were  distinct  from  the  true  adventitial  cells  and 
formed  an  outer  boundary  between  the  vessel  wall  and  the  perivascular 
lymphatics.  Although  Eberth  did  not  clearly  separate  these  perithelial 
cells  from  the  endothelium  of  perivascular  lymphatics,  and  Kolliker  (1896) 
describes  only  perivascular  lymphatics  about  cerebral  vessels,  similar  cells 
have  been  described  about  the  blood-vessels  of  the  hypophysis  (Waldeyer), 
carotid  gland  (Paltauf),  adrenal,  breast,  salivary  glands  (Eberth,  Arnold, 
Sertoli,  Luschka),  and  testis  (Henle).  Nevertheless  the  existence  of  such 
cells  has  not  been  accepted  as  a  well-established  fact  in  normal  histology,  and 
the  derivation  of  an  important  group  of  tumors  from  them  rests  on  an  un- 
certain basis.  The  belief  that  certain  tumors  do  arise  from  Eberth's  peri- 
thelial cells  is  suggested  chiefly  by  the  peculiar  arrangement  of  the  tumor- 
cells,  radiating  out  from  the  supporting  vessels,  but  it  must  be  admitted  again 
that  all  the  tumors  in  this  class  do  not  exhibit  this  peculiar  arrangement 
of  cells.  Indeed,  one  must  agree  with  Ribbert  that  no  tumor  has  yet  been 
clearly  traced  to  perithelial  cells. 

Notwithstanding  these  obscurities  the  group  of  perithelioma  maintains 
its  existence  for  the  following  reasons:  (i)  These  tumors  present  as  a  structural 
unit  the  blood-vessel,  and  it  is  clear  that  they  originate  from  some  cells  in 
the  walls  of  the  vessels.  (2)  Although  originating  from  blood-vessels  they 
differ  in  structure  from  angioma  on  the  one  hand  and  from  endothelioma  on 
the  other.  (3)  Their  gross  and  clinical  characters  differ  from  those  of  an- 
gioma and  endothelioma. 

From  this  point  of  view  the  term  "perithelioma"  cannot  be  regarded  as 
fully  applicable,  and  many  other  terms  have  been  employed  by  different 
authors,  as  angiosarcoma  (Kolaczek),  plexiform  angiosarcoma  (Waldeyer), 
perivascular  endothelioma,  and  peri-endothelioma  (Borrmann).  Yet  many 
types  of  sarcoma  are  derived  from  blood-vessels  and  it  seems  better  to 
limit  the  term  "angiosarcoma"  to  the  cellular  and  malignant  forms  of  angioma. 
The  term  "endothelioma"  is  inadmissible  since  the  perithelial  tumors  differ 
notably  from  recognized  types  of  endothelioma  and  they  have  not  been  traced 
to  an  endothelial  origin. 

The  position  of  perithelioma  seems  to  be  intermediate  between  sarcoma, 
especially  angiosarcoma,  and  endothelioma,  and  atypical  and  diffuse  forms 
tend  to  vary  in  either  direction.  Thus  diffuse  perithelioma  may  be  difficult  to 
distinguish  from  large  spindle-cell  sarcoma,  while  certain  cases  which  it  is 
difficult  to  eliminate  from  the  peritheliomas  (Paltauf,  Hildebrand)  resemble 
alveolar  endothelioma. 

An  important  source  of  confusion  which  has  been  prominent  in  the  history 
of  angiosarcoma  and  perithelioma  arises  from  the  fact  that  many  other 
actively  growing  and  malignant  tumors  assume  the  structure  of  perithelioma, 
either  in  the  original  tumor  or  in  metastases  or  recurrences.  Hence  Roussy 
recognizes  perithelioma  only  as  a  peculiar  morphological  structure  without 
histogenetic  significance.  In  primary  carcinoma  of  liver  and  in  the  round- 
cell  teratoid  carcinoma  of  testis  a  peritheliomatous  structure  is  frequently 
observed.  In  the  third  recurrence  of  a  teratoma  testis  I  found  the  entire 
tumor  composed  of  blood-vessels  sheathed  with  large  radiating  cells.  For 
such  structures  the  term  secondary  perithelioma  may  be  suggested.  Again, 
the  tissue  giving  origin  to  a  malignant  epithelial  tumor  may  be  very  vascular 
so  that  the  tumor  from  the  first  assumes  the  form  of  spurious  perithelioma. 
These  conditions  exist  in  kidney  and  adrenal,  epithelial  tumors  of  which 
have  often  been  described  as  perithelioma.  Indeed,  it  is  open  to  question 
if  a  considerable  number  of  supposed  primary  peritheliomas  may  not  owe 


ENDOTHELIOMA  343 

their  structure  to  the  excessive  development  of  blood-vessels  supporting 
rapidly  growing  embryonal  epithelial  tumors.  Metastatic  melanoma  has  a 
persistent  tendency  in  this  direction,  so  that  one  may  well  look  for  active 
pigmented  moles  in  all  cases  of  perithelioma  of  groin  or  axilla. 

Gross  Appearance. — Perithelioma  usually  appears  as  a  well-circumscribed, 
very  vascular,  at  first  slowly,  later  rapidly  growing  tumor  which  may  reach 
considerable  dimensions.  It  is  very  subject  to  hemorrhage,  necrosis,  and 
ulceration.  In  early  stages  it  may  be  freely  movable  in  the  tissues,  exciting 
little  local  reaction,  and  may  be  firm,  soft,  or  almost  fluctuating  or  pulsating. 
On  cross-section  the  tissue  appears  to  be  composed  of  thick-walled  and 
variously  twisted  blood-vessels.  This  appearance  strongly  indicates  that 
the  predominant  unit  in  the  tumor  is  the  blood-vessel,  and  since  this  unit  is  less 
pronounced  in  secondary  and  spurious  perithelioma  its  presence  is  the  best 
indication  of  the  nature  of  the  growth.  Local  extensions  and  metastases 


FIG.  128. — Low  magnification  of  cross-section  of  perithelioma. 

occur  late,  but  after  imperfect  removal  recurrence,  rapid  extension,  metas- 
tases and  cachexia  supervene,  so  that  the  general  prognosis  is  unfavorable. 

Structure. — i.  The  typical  perithelioma  presents  a  very  characteristic 
structure.  It  is  composed  of  a  congeries  of  small  vessels  of  the  type  of 
arterioles  sheathed  with  large  polyhedral  fusiform  or  rounded  cells  which 
radiate  in  numerous  layers  from  the  vessel  wall.  At  a  certain  distance  from 
the  vessels  nutrition  often  fails  and  the  cells  undergo  anemic  necrosis  which 
serves  to  isolate  and  emphasize  the  vascular  units.  In  many  tumors  the 
vessels  disappear,  the  growth  is  of  diffuse  large  spindle-cells,  and  the  tumor 
resembles  simple  sarcoma.  Giant-cells  of  small  and  large  dimensions  with 
multilobed  nuclei  are  a  frequent  and  characteristic  feature,  especially  in  the 
diffuse  growths.  Intercellular  substance  appears  in  many  of  these  tumors 
and  completes  the  resemblance  to  sarcoma. 

2.  An  alveolar  arrangement  of  distinctly  polyhedral  or  cylindrical  cells 


344 


NEOPLASTIC  DISEASES 


appears  in  another  group  of  peritheliomas,  especially  in  tumors  of  the  carotid 
gland,  bone,  and  skin  (Paltauf,  Hildebrand,  Hanke).  Since  the  cells  remain 
polyhedral  or  rounded,  and  intercellular  substance  is  scanty  or  absent,  these 
tumors  resemble  endothelioma.  At  present  their  exact  position  must  remain 
uncertain. 

In  both  structural  varieties  of  perithelioma,  the  walls  of  vessels  and  the 
stroma  and  tumor-cells  may  undergo  hyaline  and  especially  mucoid  degenera- 
tion. Some  tumors  described  as  myxosarcoma  are  probably  myxomatous 
forms  of  perithelioma.  The  hyaline  degeneration  may  produce  the  structure 
of  cylindroma. 

Clinical  Types  of  Perithelioma. — i.  The  subcutaneous  tissue  is  one  of 
the  chief  seats  of  typical  perithelioma.  The  loose  tissues  of  the  anal  region, 
orbit,  axilla,  popliteal  space,  and  regions  of  embryonal  fissures,  but  not  the 


FIG.  129. — Topography  of  a  true  perithelioma. 

more  exposed  regions,  furnish  the  exact  points  of  origin,  and  this  distribution 
suggests  a  relation  to  embryonal  disturbances  of  superfluous  tissue. 

The  deep  fasciae  and  intermuscular  septa  are  sometimes  the  point  of  attach- 
ment of  peritheliomas  which  soon  appear  to  be  subcutaneous,  as  described 
by  Kolaczek,  Tillmanns,  and  others. 

The  buccal  mucosa  over  the  hard  and  soft  palate  is  the  seat  of  a  well- 
defined  clinical  group  of  typical  perithelioma  which  has  been  emphasized 
by  Eisenmenger  (Lit.). 

2.  The  pia  mater  is  the  seat  of  a  group  of  somewhat  atypical  perithe- 
liomas. A  well-circumscribed  growth  5  cm.  in  diameter,  displacing  the  brain 
tissue,  with  cells  concentrically  arranged  about  numerous  blood-vessels  as 
in  angioma,  was  early  described  by  Arnold.  A  flat  tumor  of  the  dura  mater 
of  the  base,  involving  roots  of  several  cranial  nerves  and  composed  of  many 
small  vessels  lying  among  loose  round  and  polyhedral  cells,  was  interpreted 


ENDOTHELIOMA 


345 


as  a  peri-endothelioma  by  Wells.  It  contained  calcine  areas  and  bone  spicules. 
In  the  brain  substance  perithelioma  has  been  described  by  Waldeyer  and 
Billroth  and  many  others,  and  Waldeyer  showed  that  these  tumors  had 
previously  been  mistaken  for  primary  carcinoma  of  the  brain  (Eberth,  Arndt). 
Probably  the  majority  of  bulky  sarcomas  of  the  brain  substance  present  this 
structure. 

3.  In  the  bones  perithelioma  appears  as  a  soft  vascular  tumor,  often 
pulsating,  which  early  perforates  the  shaft,  may  invade  the  surrounding 
tissues  and  tends  to  produce  distant  metastases  (Jaffe).  Hildebrand  has 
collected  a  series  of  cases  and  describes  one  in  which  the  congeries  of  vessels 
was  plainly  evident  in  the  gross.  The  origin  he  finds  to  be  in  the  bone  sub- 
stance and  the  growth  is  often  preceded  by  trauma  or  fracture  (Kocher, 


Lucke).  Howard  and  Crile  interpret  9  cases  in  the  literature  and  3  of  then- 
own  as  arising  from  perivascular  endothelium  which  they  identify  with  peri- 
thelioma. The  cells  are  epithelioid  in  form  and  their  arrangement  is  either 
alveolar  or  tubular.  It  is  not  certain  that  all  the  tumors  described  under 
this  term  have  been  clearly  separated  from  endothelioma  or  from  epithelial 
tumors  derived  from  aberrant  cell  groups.  Many  have  been  described  as 
angiosarcoma,  and  before  the  studies  of  Billroth  and  Waldeyer  they  were 
commonly  regarded  as  primary  carcinoma  of  bone.  They  are  probably 
identical  with  angio-endothelioma. 

4.  In  the  breast  perithelioma  is  one  of  the  common  forms  of  vascular 
sarcoma.  It  occurs  chiefly  in  adults  after  50  years  as  a  single  circumscribed 
small  or  large  tumor  movable  in  the  breast,  but  usually  adherent  to  the  skin. 


346 


N  EOF  LAST  1C  DISEASES 


The  density,  retraction  of  skin,  and  involvement  of  lymph-nodes  of  carcinoma 
are  absent.  Growth  is  slow,  but  recurrence  after  operation  is  frequent 
(Schmidt). 

In  the  ovary,  among  the  many  forms  of  so-called  endothelioma  there  is 
one  described  by  Amann  which  has  certain  features  of  perithelioma. 

5.  In  the  kidney,  Paoli  and  others  have  described  large  vascular  tumors 
which  they  interpreted  as  perithelioma,  but  it  seems  highly  probable  that 
these  growths  should  be  divided  among  adenocarcinoma  of  the  kidney  and 
hypernephroma.  The  cells  exhibit  epithelial  characters.  The  cases  of 
angiosarcoma  of  the  liver  described  by  Arnold  exhibited  the  structure  of 
this  type,  but  whether  they  are  primary  or  secondary  remains  to  be  shown. 
In  cases  of  primary  carcinomas  of  the  liver,  areas  of  typical  perithelioma  are 
very  frequent  (L'Esperance). 


FIG.  131. — Structure  of  a  carotid  gland  tumor. 

6.  Perithelioma  of  Carotid  Gland. — Since  the  appearance  of  the  simul- 
taneous studies  of  Marchand  and  Paltauf  describing  a  characteristic  tumor 
of  the  carotid  gland,  many  other  cases  have  been  reported,  minute  analysis 
of  the  structure  of  these  tumors  has  repeatedly  been  made,  and  the  normal 
histology  and  embryology  of  the  gland  itself  has  been  thoroughly  investigated. 

While  Marchand  suggested  the  origin  from  perithelial  cells,  and  Paltauf 
fully  accepted  this  view,  later  observers  have  been  less  confident  regarding 
the  exact  nature  of  the  growth.  Kauffmann  employed  the  term  "alveolar 
tumor,"  and  compared  it  to  a  hamartoma,  in  which  all  elements  of  the  gland 
participated.  The  complex  structure  of  the  organ,  as  shown  by  Kahn,  Stilling, 
and  Monckberg,  may  serve  to  explain  many  peculiarities  of  the  tumors  and 
the  difficulty  of  devising  a  satisfactory  designation.  While  the  tumor  belongs 
in  a  class  by  itself,  the  term  "perithelioma"  recalls  a  prominent  structural  fea- 
ture and  has  been  very  generally  employed. 


ENDOTHELIOMA  347 

These  tumors  arise  usually  about  puberty  and  slowly  reach  sufficient 
dimensions  to  protrude  from  the  side  of  the  neck,  producing  a  deformity  which 
has  been  pictured  in  detail  by  Keen  and  Funke.  Their  location  is  first  upon 
and  behind  the  bifurcation  of  the  carotid  artery  which  is  often  inclosed,  com- 
pressed, and  even  invaded  by  the  growth.  Owing  to  these  attachments  the 
tumors  are  movable  laterally,  but  not  vertically.  They  may  bulge  in  the 
pharyngeal  wall.  Prolongations  run  in  various  directions,  upward  toward 
the  skull,  inward  to  pharynx  (Reclus),  and  downward.  Most  of  the  tumors 
are  rounded,  lobulated,  and  encapsulated.  Rupture  of  the  capsule  may  occur 
(Monckberg,  Leithoff).  They  are  firm  or  soft,  may  yield  a  bruit,  frequently 
pulsate,  and  Reclus  was  able  to  largely  obliterate  a  tumor  by  compression. 
On  section  they  are  vascular,  grayish  red,  or  slightly  brownish  from  chromaffin 
substance  in  the  specific  cells.  The  markings  show  vessels,  plexiform  cell 
masses,  concentric  structures,  and  hyaline  areas. 

The  growth  is  slowr,  occupying  years.  Heinleth  observed  a  very  large 
tumor  existing  over  30  years.  While  numerous  adhesions  form  and  vessels 
may  be  infiltrated  and  penetrated,  a  skilful  enucleation  is  usually  successful 
in  preventing  recurrence,  but  Licini  estimates  the  mortality  from  the  opera- 
tion at  35  per  cent.  In  several  cases  recurrence  has  followed  operation,  and 
the  cervical  lymph-nodes  have  been  found  involved  (Kaufmann,  Kretsch- 
mar,  Kopf stein).  General  metastases  are  not  observed. 

The  structure  is  in  general  that  of  an  alveolar  perithelioma,  but  varies 
in  many  details.  Postmortem  changes  occur  rapidly  and  only  prompt  fixa- 
tion of  operative  material  in  Zenker's  or  Orth's  fluids  preserves  the  true 
structural  detail. 

The  chief  cells  are  distinctly  polyhedral,  granular,  and  may  contain  chro- 
maffin substance.  They  are  arranged  in  compact  groups  without  lumen, 
but  surrounded  by  hyperplastic  endothelium  lining  the  numerous  capillaries. 
Much  larger  cell  groups  are  often  observed,  the  central  portions  "of  which  are 
prone  to  degenerate  and  form  cavities  in  which  blood  may  be  found.  Definite 
capillaries  may  also  traverse  the  cell  groups  (Monckberg).  Hyaline  degen- 
eration of  the  cells  gives  rise  to  intracellular  globules,  and  affecting  the  stroma 
produces  peculiar  knobs  projecting  into  the  capillaries  (Kaufmann).  The 
numerous  vessels  may  produce  a  cavernous  tissue  or  they  may  be  much  re- 
duced in  hard  tumors.  They  are  lined  by  prominent  endothelial  cells  which 
sometimes  grow  out  into  the  vessels  in  syncytial  buds,  or  mingle  with  the 
chief  cells  of  the  tumor,  producing  complex  pictures.  The  stroma  may  be 
scanty  and  acellular  or  hyaline,  or  infiltrated  with  tumor-cells,  and  Leithoff 
describes  a  case  in  which  he  regarded  the  stroma  as  sarcomatous. 

These  and  many  other  structural  details  which  appear  in  many  combina- 
tions in  the  reports  of  numerous  authors  show  that  the  tumors  of  the  carotid 
gland  are  sui  generis.  Both  the  specific  cells  and  the  endothelium  partici- 
pate in  the  tumor  process,  yielding  organoid  growths  involving  the  entire 
gland.  Although  Monckberg  thought  he  could  identify  ganglion-cells  in  one 
case,  the  numerous  non-medullated  nerve-fibers  of  the  normal  gland  appear 
only  in  traces  and  do  not  participate  in  the  tumor  process.  Since  the  tumors 
arise  about  the  period  when  a  physiological  regression  usually  overtakes  the 
gland,  some  disturbance  in  the  course  of  this  regression  may  be  an  etiological 
factor  (Heinleth).  Advanced  osteomalacia  occurred  in  a  case  of  Oberndor- 
fer's,  and  various  authors  mention  other  possible  etiological  factors.  The 
occurrence  of  lemon-yellow  pigmentation  of  the  skin,  disappearing  after 
operation,  in  2  cases  reported  by  Reid  indicates  a  disturbance  of  endocrine 
function. 


CHAPTER  XXI 


LYMPHOMA  AND  LYMPHOSARCOMA 

Two  important  physiological  properties  influence  the  conception  of  tumors 
of  lymphoid  tissues. 

First,  lymphoid  tissue  responds  to  irritation  with  inflammatory  hyper- 
plasia  far  more  actively  than  any  other  tissue.  Second,  lymphoid  tissues 
are  relatively  mobile  rather  than  fixed,  and  lymphocytes  are  not  only  ame- 
boid, but  are  structurally  placed  in  easy  access  to  lymph  and  blood  paths. 
Hence  tumors  and  tumor-like  processes  in  lymphoid  tissues  are  frequent  and 
as  a  rule  tend  to  become  widely  diffused.  These  same  factors  render  unusually 
difficult  the  distinction  between  simple  and  neoplastic  hyperplasia  of  lym- 
phoid tissue  by  introducing  special  standards,  both  clinical  and  anatomical, 
in  the  interpretation  of  lymphatic  hyperplasia. 

For  these  reasons  the  discussion  of  lymphoma  in  general  necessarily  in- 
cludes the  consideration  of  various  processes,  some  of  which  are  chiefly  inflam- 
matory, some  neoplastic,  and  others  intermediate  in  position.  Lack  of 
knowledge  of  etiological  factors,  the  intricate  relation  of  many  forms  of 
lymphoid  hyperplasia,  and  the  occasional  transformation  of  one  process  to 
another,  render  this  method  of  treatment  practically  advantageous  and 
theoretically  sound. 

Extensive  tumor-like  hyperplasia  of  lymphoid  tissues  occurs  in  the  follow- 
ing scheme  of  clinical  conditions:  (i)  Simple  lymphoma;  (2)  leukemia, 
lymphatic  and  myelocytic,  in  its  various  phases;  (3)  pseudoleukemia;  (4) 
Hodgkin's  disease;  (5)  lymphosarcoma. 

The  complexities  of  the  subject  of  lymphoid  tumors  depend  chiefly  upon 
the  lack  of  knowledge  of  etiology  and  partly  upon  the  lack  of  accurate  ana- 
tomical classification.  It  seems  to  the  author  that  some  advantage  would 
result  from  the  rigid  application  of  simple  anatomical  principles  in  the  classi- 
fication of  these  processes,  even  at  the  risk  of  carrying  the  anatomical  dis- 
tinctions too  far. 

Anatomically  there  are  three  elements  in  lymphoid  tissues  capable  of  orig- 
inating lymphoid  tumors,  viz.:  (i)  lymphocytes;  (2)  reticulum  cells  of  follicles 
and  pulp,  and  (3)  endothelial  cells  of  pulp  and  cavernous  sinuses.  Connec- 
tive-tissue cells,  endothelium  of  vessels,  and  cells  of  vessel  walls  do  not  appear 
to  be  concerned  in  the  common  tumors  of  lymph-nodes. 

Classified  according  to  present  indications  of  histogenesis,  tumors  of 
lymphoid  tissue  appear  as  follows: 


Origin 
Lymphocytes 


Reticulum  cells 


Endothelial  cells 


Anatomical  Type 
Lymphocytoma 


Large  round-cell  hyperplasia 
or  neoplasia 


Endothelial  hyperplasia  or 
neoplasia 

348 


Clinical  Type 
Simple  lymphoma 
Tuberculous  lymphoma 
Lymphatic  leukemia 
Pseudoleukemia 
Malignant  lymphocytoma 
Granuloma  malignum 
Myeloid  leukemia 
Hodgkin's  sarcoma 
Large-cell  lymphosarcoma 
Endothelial  hyperplasia 
of  tuberculosis,  etc. 
Endothelioma 


LYMPHOMA  AND  LYMPHOSARCOMA 


349 


Several  difficulties  stand  against  the  finality  of  this  classification: 
i.  The  relation  between  lymphocytes  and  reticulum  cells  is  not  fully 
determined.  While  the  older  anatomists,  headed  by  Flemming,  held  that 
reticulum  cells  of  the  follicles  become  transformed  into  lymphocytes,  prac- 
tically all  the  recent  work  indicates  that  the  two  types  of  cells  are  entirely 
separate  (Gulland). 

It  would  greatly  simplify  the  questions  of  histogenesis  if  separation  of  the 
two  types  of  cells  were  established.  Most  pathologists,  however,  the  writer 
among  them,  are  unable  to  satisfy  themselves  that  reticulum  cells  during  the 
course  of  inflammatory  and  neoplastic  changes  may  not  assume  the  form  of 
lymphocytes.  Yet  the  separate  nature  of  the  two  cell  types  is  of  such  great 


FlG.  132. — Multiplication  of  follicles  in  simple  chronic  lymphadenitis,  in  postpyloric 
nodes  draining  a  chronic  ulcer  of  stomach. 

importance  in  the  study  of  lymphoid  tumors,  that  it  seems  wise  to  accept 
the  dictum  of  embryology  until  it  is  proved  incorrect.  In  most  pathological 
processes  the  two  cell  types  undoubtedly  maintain  their  ^individuality.^ 

2.  The  distinctions  between  reticulum  cells  and  sinus  endothelium  are 
much  less  definite.    In  fact,  in  the  development  of  lymph-nodes  both  arise 
from  modified  mesoblastic  cells.    Yet  in  a  study  of  endothelioma  of  lymph- 
nodes  the  writer  has  brought  evidence  to  show  that  the  reticulum  cells  give 
origin  to  the  large-cell  lymphosarcomas,  while  the  sinus  endothelium  yields 
tumors  of  a  different  structure. 

3.  While  the  lymph-nodes  in  lymphatic  leukemia  contain  an  excess  chiefly 
of  lymphocytes,  the  origin  of  the  larger  round-cells  in  the  nodes  of  myelocytic 


350 


NEOPLASTIC  DISEASES 


leukemia  is  not  satisfactorily  determined.  Their  classification  as  derivatives 
of  reticulum  cells  must  be  regarded  as  tentative. 

4.  If  a  complete  solution  of  the  etiology  of  lymphoid  tumors  were  provided 
it  might  destroy  much  of  the  value  of  an  anatomical  classification.  The 
best  known  excitant  of  lymphoid  enlargements,  tuberculosis,  produces  over- 
growth of  lymphocytes,  extensive  or  exclusive  hyperplasia  of  reticulum 
cells  and  endothelium,  and  also  introduces  many  blood-cells  by  exudation. 
Hodgkin's  granuloma  exhibits  similar  or  identical  tendencies. 

Yet  there  is  much  value  in  classifying  lymphatic  tuberculosis  from  the 
anatomical  standpoint,  and  similar  value  may  remain  for  the  anatomical 
subdivisions  of  other  diseases  when  their  etiology  is  known.  For  the  definite 
tumors  of  lymph-nodes  this  objection  loses  much  or  all  of  its  force,  but  it  is 
difficult  to  determine  when  one  is  dealing  with  a  granuloma  or  a  tumor  of 
this  tissue. 


SIMPLE  LYMPHOMA.    LYMPHADENOMA.    HYPERPLASTIC 
LYMPHADENITIS 

Local  or  regional,  circumscribed,  chronic  enlargements  of  lymph-nodes 
which  are  self-limiting  and  do  not  lead  to  systemic  invasion  are  rather  com- 


FIG.  133. — Inflammatory  reticulum  cell  hyperplasia  in  a  lymph-node. 

mon  pathological  conditions  (Le  Count,  Lit.).     They  appear  in  the  neck, 
axilla,   groin,    subcutaneous   tissue,    submucous   tissues,   parotid   and    other 


LYMPHOMA  AND  LYMPHOSARCOMA 


351 


glands,  and  occasionally  in  other  regions.  They  form  solid  masses  of  tumor- 
like  dimensions  and  firm  consistence,  and  on  section  exhibit  a  smooth  opaque 
uniform  surface  often  presenting  firm,  light,  more  prominent  areas,  and  re- 
vealing little  or  no  tendency  toward  degeneration  or  necrosis.  They  may 
be  composed  of  a  single  node  or  a  congeries  of  nodes  with  fused  capsules. 
After  reaching  a  certain  limit  of  growth  they  may  remain  stationary  for 
months  or  years  producing  only  local  symptoms.  The  tendency  toward 
regression  is  slight.  I  have  observed  a  simple  lymphoma  of  4  years'  dura- 
tion occurring  beneath  the  skin  of  the  scapular  region  which  failed  to  show 
signs  of  regression  or  fibrosis.  The  prolonged  course  is  a  feature  of  many 
cases,  that  of  Le  Count  continuing  for  1 5  years,  but  still  showing  hyperplastic 
germ  follicles.  The  tumor  described  by  Vagner  and  Hewitt  reached  dimen- 


FIG.  134. — Malignant  lymphadenoma. 

sions  of  7  X  5  cm.  in  6  years.    Internal  growths  of  uncertain  history  may  be 
found  at  autopsy. 

The  structure  varies  at  different  periods,  but  is  dominated  by  diffuse  over- 
growth of  typical  small  lymphocytes.  In  early  stages  lymph-follicles  are 
increased  in  size  and  number,  are  readily  visible  in  the  gross  and  exhibit 
enlarged  germ  centers,  the  pulp  tissue  is  composed  of  closely  packed  lympho- 
cytes, the  sinuses  are  indistinct  or  obliterated,  the  vessels  compressed  or 
packed  with  lymphocytes;  or  the  normal  landmarks  are  obliterated  by  a 
diffuse  growth  of  lymphocytes  and  the  distended  capsule  is  infiltrated.  Simple 
lymphoma  may  be  separated  from  leukemia  by  the  blood  test,  and  from 
pseudoleukemia  by  its  local  character,  but  from  neither  on  the  histological 
structure  alone.  From  lymphosarcoma  the  diagnosis  may  be  difficult,  and 


352 


NEOPLASTIC  DISEASES 


should  be  based  on  the  absence  of  the  usual  signs  of  malignancy,  as  rapid 
growth,  mitotic  figures,  active  destruction  of  trabeculse  and  capsule,  and 
atypical  quality  of  the  cells. 

However  obvious  may  be  the  inflammatory  origin  of  many  cases  of  simple 
lymphoma,  the  excessive  hyperplasia,  prolonged  course,  and  often  the  appar- 
ently idiopathic  origin  renders  the  condition  of  interest  in  the  field  of  tumors 
and  requires  the  recognition  especially  in  chronic  cases  of  certain  features 
of  true  neoplasms. 

I  have  observed  one  case,  structurally  requiring  classification  as  lymph- 
adenoma,  persisting  for  18  years  and  eventually  proving  fatal  with  rapid 
local  growth  and  asphyxia  (Figs.  134-136). 


FIG.  135. — Malignant  lymphadenoma.     Same  as  Fig.  134. 

In  the  etiology  of  simple  lymphoma  many  forma  of  chronic  bacterial 
infection  appear  to  be  concerned,  especially  tuberculosis.  According  to 
Paltauf  the  regeneration  of  lymphocytes  following  an  acute  infection  may 
be  excessive  and  prolonged,  giving  rise  to  a  tumor-like  overgrowth  which 
persists  long  after  the  removal  of  bacteria  and  their  products.  In  the  case 
of  tuberculosis,  it  has  been  shown  by  Bartels  and  others  that  the  structure 
of  simple  lymphoma  may  be  exhibited  by  lymph-nodes  harboring  viable 
but  attenuated  tubercle  bacilli,  and  the  frequency  of  simple  lymphoma  with- 
out tubercle  bacilli  in  tuberculous  subjects  suggests  that  this  lesion  may 
be  one  of  many  which  seem  to  be  referable  to  atypical  tuberculosis.  Such 


LYMPHOMA  AND  LYMPHOSARCOMA 


353 


cases_  may  be  designated  as  paratuberculous  lymphadenitis  (Adami).     In 
certain  cases  it  is  impossible  to  establish  any  relation  whatever  to  tuberculo- 


FIG.  136. — Malignant  lymphadenoma  of  cervical  nodes.     Detail  o£  Fig.  134. 

sis,  or  any  acute  infection,  or  any  chronic  disturbance  in  neighboring  mucous 
membranes  or  tissues. 

LEUKEMIC  LYMPHOMA 

The  leukemic  process  in  its  entire  scope  illustrates  many  phases  of  hyper- 
plasia  of  lymphoid  tissue.  The  disease  may  exhibit  as  its  anatomical  basis: 
(a)  A  transient  leukemic  blood-picture  with  slight  hyperplasia  of  the  cells 
of  lymph-nodes  or  marrow;  (£>)  acute  leukemia  associated  with  acute  hyper- 
plasia of  lymphoid  tissues;  (c)  chronic  leukemia,  with  leukemic  lymphomas 
and  hyperplasia  of  bone-marrow;  (d)  chronic  leukemia  with  partially  neo- 
plastic  hyperplasia  of  lymphoid  and  myeloid  tissues;  (e)  chloroma. 

While  it  is  impossible  to  prove  that  leukemia  is  always  caused  by  a  single 
infectious  agent  or  that  it  represents  anything  more  than  a  clinical  entity 
comparable  to  leukocytosis,  these  various  lesions  belonging  to  essentially 
the  same  condition  illustrate  every  gradation  from  an  acute  inflammatory 
process  up  to  a  chronic  and  spmewhat  malignant  neoplasm. 

The  lesions  of  leukemia,  both  lymphocytic  and  myelocytic,  involve  the 
bone-marrow,  lymph-nodes,  spleen,  and  the  other  preexisting  lymphoid 
tissues,  while  heterotopic  growths  of  lymphoid  tissue  appear  in  the  liver, 
kidney,  lung,  skin,  serous  membranes,  and  many  other  organs.  The  picture 
is  that  of  a  diffuse  systemic  involvement  of  blood-forming  organs  with 
secondary  invasion  of  other  tissues. 

In  the  bone-marrow  the  process  begins  in  multiple  hyperplastic  foci  which 
23 


354  NEOPLASTIC  DISEASES 

enlarge,  coalesce,  and  eventually  extend  the  limits  of  lymphoid  marrow 
throughout  all  portions  of  the  skeleton.  At  the  height  of  the  process  the 
new  tissue  is  firm,  light  colored,  opaque,  or  pyoid,  or  beset  with  foci  of  in- 
farction, necrosis,  hemorrhage,  or  mucoid  softening.  Fat  cells,  sinuses,  and 
all  other  normal  structures  of  the  marrow  are  commonly  obliterated  by  a 
diffuse  growth  of  hyperplastic  round-cells.  Banti  describes  an  initial  hypere- 
mia  with  widening  of  sinuses  and  atrophy  of  fat-cells.  Islands  of  hyper- 
plastic  marrow-cells  then  appear  in  and  about  the  sinuses  and  these  are  fol- 
lowed by  pure  lymphoid  growths  starting  from  the  walls  of  arterioles  and 
gradually  invading  the  entire  marrow.  The  spongy  trabeculse  are  often 
absorbed  and  even  the  shafts  may  be  thinned,  but  a  distinctly  aggressive 
destruction  of  bone  as  in  true  tumors  is  missing.  In  rare  cases  of  myelemia 
there  is  wide-spread  osteosclerosis  (Schmorl). 

In  the  lymph-nodes  the  disease  appears  hi  one  or  more  chains  spreading 
to  other  chains  and  involving  all  the  nodes  of  the  chain  simultaneously.  Bulky 
tumors  are  thus  produced  in  which  all  the  nodes  remain  discrete  or  the  cap- 
sules are  fused  by  inflammatory  reaction.  The  process  in  the  lymph-nodes 
differs  in  the  two  main  types  of  leukemia.  In  myelemia  the  pulp  cords  first 
show  increase  in  size  by  the  appearance  of  myelocytes  which  gradually  distend 
the  cords,  obliterate  the  sinuses,  cause  passive  atrophy  of  the  lymph-follicles, 
and  even  infiltrate  the  capsule  or  the  surrounding  fat  tissue.  Giant-cells 
and  nucleated  red  blood-cells  may  be  present,  but  in  the  more  pronounced 
lesions  only  large  myelocytes  are  present. 

In  lymphemia  the  condition  in  the  lymph-nodes  varies.  In  some  cases 
there  is  hypertrophy  of  lymph-follicles  which  become  greatly  enlarged  and 
fusing  with  the  pulp  cords  convert  the  entire  node  into  diffuse  lymphoid 
tissue.  In  such  nodes  the  lesion  is  primary  and  these  cases  may  be  desig- 
nated as  lymphoplastic  lymphemia  (Pappenheim,  Meyer,  Heinicke,  Hirsch- 
feld).  In  other  cases  the  lymph-follicles  fail  to  enlarge,  but  seem  passively 
compressed  by  new  growth  of  lymphocytes  beginning  in  the  pulp  cords. 
Opinions  differ  as  to  the  relative  frequency  of  the  two  types  of  lesions.  Ac- 
cording to  Walz,  Pappenheim,  Grawitz,  Kelly,  Gulland,  and  Goodall  lymphe- 
mia is  always  primarily  myelogenic,  while  Ehrlich  and  Pincus  maintain  that 
the  whole  lymphoid  system  may  be  primarily  involved.  My  own  cases  seem 
to  illustrate  both  conditions,  but  I  have  not  seen  active  growth  of  germ  centers 
in  lymph-nodes  of  leukemia.  The  extent  of  the  affection  of  lymph-nodes 
varies  greatly.  Thus  Walz  found  scanty  changes  in  nodes,  much  in  spleen 
and  marrow;  Pappenheim  describes  absence  of  changes  in  nodes,  few  in  spleen, 
much  in  marrow;  while  Meyer  and  Heinicke  record  early  and  extensive  lesions 
in  nodes,  later  in  spleen,  and  later  and  only  focal  hyperplasia  in  bone-marrow. 
Turk  ventures  to  conclude  from  clinical  signs  that  marrow  lesions  may  be 
absent  in  early  stages  of  lymphemia,  and  this  view  is  substantiated  by  Rosen- 
feld  and  others,  who  believe  that  the  marrow  lesions  may  appear  late  in  the 
disease. 

The  splenic  lesions  are  very  similar  to  those  of  the  lymph-nodes.  The 
organ  exhibits  a  diffuse  enlargement,  a  smooth  opaque  surface  and  section, 
areas  of  infarction  and  necrosis,  but  seldom  any  localized  tumor  growth.  In 
myelemia  there  may  be  a  simple  myeloid  transformation  of  pulp  with  atrophy 
of  follicles.  Here  myelocytes,  giant-cells,  nucleated  red  blood-cells,  and 
phagocytes  are  mingled,  much  as  in  the  marrow.  More  often  there  is  a  diffuse 
infiltration  with  cells  of  the  myelocyte  class.  In  late  stages  and  especially 
in  very  large  spleens  the  cells  are  greatly  reduced  and  fibrosis,  hyaline  degenera- 
tion, hemorrhage,  and  necrosis  are  prominent.  In  lymphemia  the  follicles 
may  be  intact  and  enlarged,  but  more  often  they  are  obliterated  by  a 


LYMPHOMA  AND  LYMPHOSARCOMA 


355 


diffuse  growth  of  lymphocytes  which  lie  loosely  in  the  disordered  cords  and 
sinuses. 

In  the  submucous  lymphoid  tissues  the  process  resembles  that  of  the 
lymph-nodes. 

The  heteroplastic  deposits  of  leukemia  occur  chiefly  in  the  liver.  Here 
there  is  a  diffuse  growth  of  round  cells  in  the  capillaries  which  has  little 
tendency  to  destroy  liver  cords,  but  miliary  or  larger  lymphomas  occur  in 
the  portal  canals.  A  certain  grade  of  these  lesions  is  practically  constant 
in  all  forms  of  leukemia.  In  lymphemia  the  portal  nodules  are  more  exten- 
sive than  in  myelemia. 

In  the  kidney  leukemic  infiltrations,  focal  or  diffuse,  frequently  occur. 
The  cutaneous  manifestations  of  leukemia  are  varied  and  complex  (Oertel, 
Lit.).  Lymphemia  has  been  observed  with  spindle-cell  sarcoma  of  the  skin,' 
with  multiple  lymphomas,  and  with  mycosis  fungoides  (Nekam,  Pincus, 
Lit.).  The  characteristic  lymphomas  appear  as  multiple  nodules  chiefly  on 
the  face  and  neck  or  widely  distributed  as  a  popular  eruption.  They  may 


• 

FIG.  137. — Advanced  chronic  myelocytic  leukemia. 

be  preceded  by  or  associated  with  other  eruptions.  The  older  lesions  may 
ulcerate  (Nicolau).  They  are  composed  of  lymphocytes  grouped  about  the 
vessels  of  the  corium. 

Cutaneous  lesions  occur  with  moderate  frequency,  but  in  great  variety, 
and  illustrate  in  their  course  many  phases  of  a  granulomatous  inflammation 
unfolding  into  a  tumor-like  process.  The  lesions  include  petechiae  and 
hematomas,  vesicles  and  bullse,  macules,  papules  and  pustules,  and  localized 
or  diffuse  tumors.  There  may  be  marked  pruritus  and  terminal  bronzing 
(Hazen,  Lit.).  Very  similar  conditions  occur  without  leukocytosis,  as  in 
Hodgkin's  disease,  pseudoleukemia,  and  mycosis  fungoides.  In  rare  cases 
the  lesion  is  diffuse  and  universal  (Arndt).  Other  organs  and  tissues  are 
occasionally  the  seat  of  leukemic  infiltrations. 

There  has  been  much  discussion  regarding  the  origin  and  nature  of  the 
heteroplastic  deposits.  Perhaps  the  majority  of  observers  have  concluded 
that  in  both  forms  of  leukemia  the  hepatic  deposits  arise  from  hyperplasia 
of  preexisting  lymphoid  structures  in  this  organ  which  undergo  simple  hyper- 
plasia in  lymphemia  and  myeloid  changes  in  myelemia  (Sternberg,  Lit.). 


356 


NEOPLASTIC  DISEASES 


Some  authors  assume  the  existence  of  latent  myeloid  foci  in  liver,  lung, 
etc.,  which  serve  as  a  source  of  the  new  tissue  in  myelemia  (Dominici,  Hirsch- 
feld,  Walz).  From  these  foci  may  arise  the  myeloid  changes  so  often  seen 
in  certain  infectious  diseases  attended  with  anemia  (Meyer,  Heineke).  Others 
accept  the  local  origin  of  the  heteroplastic  lymphomas  of  lymphemia,  but 
deny  the  existence  of  myeloid  foci.  Thus  Sternberg  distinguishes  sharply 
between  lymphemia  and  myelemia  in  the  origin  of  their  heteroplastic  deposits, 
and  Meyer  and  Heineke  deny  that  any  myeloid  foci  exist  in  normal  nodes, 
spleen,  or  liver,  although  they  find  the  source  of  lymphemic  growths  in  slumber- 
ing lymphoid  nodules.  At  the  other  extreme  Band  holds  that  all  heteroplastic 
leukemic  nodules  represent  metastatic  growths  of  embolic  cells. 


FIG.  138. — Bone-marrow  in  lymphatic  leukemia.     Focal  hyperplasia  of  small  lympho- 
cytes in  center  of  femur. 


At  present  it  seems  impossible  to  offer  proof  of  the  entire  validity  of  any 
of  these  theories.  I  believe,  however,  that  too  much  importance  may  be 
placed  upon  the  hypothetical  lymphoid  foci  of  such  organs  as  the  liver  and 
kidney.  In  the  normal  adult  human  organs  such  foci  are  conspicuously 
wanting,  but  in  lymphemia  such  organs  rapidly  develop  lymphomas.  For 
the  more  distant  lymphomas  of  skin,  brain,  and  serous  membranes,  espe- 
cially those  which  reach  a  bulky  growth,  it  is  more  difficult  to  accept  an  origin 
from  preexisting  lymphoid  foci,  while  the  origin  from  embolic  leukocytes  seems 
much  more  probable. 

Finally,  in  those  cases  in  which  the  lesions  exhibit  more  definite  neoplastic 
properties,  as  in  the  leukosarcomatosis  of  Sternberg  and  in  chloroma,  it  is 


LYMPHOMA  AND  LYMPHOSARCOMA 


357 


highly  probable  that  the  laws  of  neoplasms  control  the  development  of  the 
heteroplastic  nodules.    Hence  it  is  necessary  to  assume  that  in  mild  forms 


FIG.  139. — Lymph-node  in  chronic  lymphatic  leukemia.     Note. the  very  uniform  size 

and  distribution  of  the  cells. 


FIG.  140. — Chronic  myelocytic  leukemia.    Section  of  lymph-node  showing  diffuse  growth 

of  cells  of  uniform  size. 

of  lymphemia  the  heteroplastic  nodules  arise  in  loco,  while  in  the  more  intense 
grades  of  leukemic  hyperplasia  they  are  chiefly  embolic  in  origin  or  else  one 


358 


must  accept  their  embolic  origin  throughout.     The  latter  position  seems  to 
me  the  more  logical  and  more  in  accordance  with  observed  facts. 


FIG.  141. — Structure  of  spleen  in  a  case  of  lymphatic  leukemia.  Focal  and  diffuse 
overgrowth  of  lymphocytes,  which  are  found  in  cavernous  sinuses,  pulp  sinuses,  pulp 
cords,  and  in  enlarged  follicles. 

In  myelemia  the  evidence  in  favor  of  the  embolic  origin  of  heteroplastic 
foci  is  much  more  direct.  Myeloid  foci  do  not  exist  in  normal  adult  liver 
or  spleen,  and  while  they  develop  there  in  infectious  diseases  and  in  anemia 


FIG.  142. — Liver  in  lymphatic  leukemia.    Lymphocytic  infiltration  of  portal  canals  and 

hepatic  capillaries. 

their  constituent  cells  have  not  been  satisfactorily  traced  to  preexisting  cells 
in  these  organs.  In  leukemia  the  blood-vessels  in  and  about  myeloid  areas 
often  contain  thrombi  cf  myelocytes  and  giant-cells  which  offer  the  readiest 


LYMPHOMA  AND  LYMPHOSARCOMA 


359 


explanation  of  heteroplastic  nodules  (Meyer,  Heineke,  Schwartz,  Michaelis). 
Yet  an  embolic  origin  does  not  involve  a  neoplastic  nature  if,  as  Sternberg 
claims,  leukemic  cells  are  normal  marrow-cells  produced  in  large  numbers, 
for  sarcoma-cells  are  atypical  and  grow  without  normal  restraint.  Yet  Rib- 
bert  and  others  find  that  the  leukemic  cells  are  undifferentiated  and  abnormal 
and  exhibit  in  some  degree  the  characters  of  tumor-cells.  In  ordinary  myelemia 
the  myeloid  areas  show  little  of  these  neoplastic  properties,  but  in  the  atypical 
and  rare  forms  bulky  tumors  arise,  tissues  are  invaded,  cells  are  atypical,  and 
neoplastic  characters  are  rather  obvious. 

Changes  in  Blood. — Closely  dependent  upon  the  organic  lesions  are  the 
changes  in  the  blood,  the  full  discussion  of  which  falls  outside  the  scope  of 


FIG.  143.— Miliary  lymphocytomas  in  the  liver  of  lymphatic  leukemia 


this  work.  Briefly  they  consist  in  extensive  increase  of  leukocytes  and  pro- 
gressive anemia.  In  lymphemia  the  cells  are  small  and  medium-sized  lym- 
phocytes in  chronic  cases,  and  larger  undifferentiated  lymphocytes  or  mononu- 
clear  cells  in  acute  cases.  In  myelemia  the  new  cells  are  chiefly  neutrophile 
myelocytes,  many  of  which  are  of  abnormally  large  size,  atypical  eosinophile 
myelocytes,  excess  of  polynuclear  neutrophile  and  eosinophile  cells,  mast 
cells,  and  various  degenerative  forms.  While  in  typical  cases  the  leukocytosis 
is  the  first  demonstrable  symptom,  it  varies  greatly  in  degree,  in  its  relation 
to  the  extent  of  the  organic  lesions,  and  in  its  permanence.  While  the  leuko- 
cytes may  outnumber  the  red  cells,  leukemia  occurs  with  small  numbers 
of  atypical  cells  in  the  blood,  and  their  numbers  are  subject  to  extensive 
variations  from  numerous  factors. 


360  NEOPLASTIC  DISEASES 

The  cause  of  the  access  of  large  numbers  of  cells  to  the  blood-stream  still 
remains  obscure.  It  is  not  dependent  essentially  on  involvement  of  the  bone- 
marrow,  since  apparently  identical  marrow  lesions  in  pseudoleukemia  fail  to 
give  leukocytosis.  Multiplication  in  the  blood-stream  is  a  negligible  factor. 
The  theory  of  circulating  chemotactic  agents  is  unsatisfactory  (Gulland, 
Goodall).  In  many  cases  it  seems  to  be  dependent  upon  the  activity  of  the 
hyperplasia  in  the  organs,  but  the  more  aggressive  the  local  process  in  the 
neoplastic  sense,  the  less  is  the  leukocytosis.  It  may  appear  in  the  late  stages 
of  formerly  aleukemic  processes,  and  its  inception  has  once  been  clearly 
traced  to  rupture  of  the  tumor  mass  into  a  large  vein.  Essential  conditions 


FIG.  144. — Leukemic  deposits  in  the  heart  muscle.     Similar  tumors  in  spleen  and  kid- 
neys.    Enlargement  of  thymus  and  many  lymph-nodes.      (After  Seelig.] 

seem  to  include  the  association  of  a  certain  grade  of  hyperplasia  with  integrity 
and  patency  of  many  small  blood  and  lymph  paths. 

The  course  of  leukemic  lesions  depends  much  on  the  rapidity  of  the  proc- 
ess. Acute  cases  steadily  progress  until  the  fatal  issue.  In  chronic  cases 
there  is  a  definite  tendency  for  the  cellular  phases  of  the  lesions  to  be  followed 
by  fibrosis  and  there  is  a  distinct  limit  to  growth.  Likewise  the  leukemic 
lesions  as  well  as  the  leukocytosis  may  be  much  altered  by  intercurrent  in- 
fections, treatment  by  arsenic,  #-ray,  or  without  assignable  cause. 

Atypical  Leukemia. — Certain  atypical  forms  of  leukemia  vary  widely 
from  the  common  type  and  reveal  the  extensive  scope  of  the  anatomical 
processes  associated  with  the  condition. 

Leukanemia. — Under  this  term  Leube  first  described  a  condition  of  pro- 


LYMPHOMA  AND  LYMPHOSARCOMA  361 

gressive  pernicious  anemia  with  pronounced  leukocytosis  and  cellular  infil- 
trations in  the  organs  resembling  those  of  leukemia.  It  has  long  been  known 
that  in  certain  cases  of  pernicious  anemia  the  marrow  changes  may  be  very 
similar  to  those  of  leukemia  (myeloblastic  degeneration  of  Naegeli). 

In  such  cases  the  leukocytes  are  increased  and  myelocytes  are  present  in 
considerable  numbers.  Meyer  and  Heineke  report  cases  of  pernicious  anemia, 
leukanemia,  and  atypical  leukemia  in  which  the  organic  lesions  are  practically 
identical,  and  Preis  and  Nauwerck  and  Moritz  describe  cases  in  which  the 
blood-picture  at  certain  periods  resembles  that  of  pernicious  anemia.  These 
observations  seem  to  indicate  that  the  leukemic  process  in  a  mild  degree 
may  be  established  in  many  states  of  anemia  which  call  forth  excessive  pro- 
liferation and  degeneration  of  blood-forming  cells. 

Mixed-cell  Leukemia. — In  rare  cases  of  lymphemia  myelocytes  have  been 
found  in  the  blood  and  slight  myeloid  changes  in  the  organs  (Weber).  While 
these  cases  suggest  a  mixed  form  of  leukemia,  Pappenheim  and  others  inter- 
pret the  myeloid  changes  as  a  secondary  process  of  compensatory  myelocy- 
tosis  resulting  from  the  anemia  of  the  disease.  More  often  a  frank  myeloid 
leukemia  appears  to  change  into  a  large-cell  lymphemia  (Seelig,  v.  der  Wey, 
Wilkinson,  Mellard,  Turk).  In  these  cases  it  appears  probable  that  in  the 
advanced  stages  of  the  disease  degenerative  processes  affect  the  myelocytes 
so  that  they  lose  their  granules  without  any  genuine  change  in  the  type  of 
the  disease.  Thus  Wolff  and  Michaelis  describe  cases  of  leukemia  in  which 
they  interpret  the  proliferating  cell  as  the  mother  cell  of  both  lymphocyte 
and  myelocyte.  They  believe  that  the  acute  leukemias  are  chiefly  of  this 
nature.  While  Turk,  Hirschfeld,  and  others  argue  strongly  for  the  existence 
of  mixed  and  transitional  cases  of  leukemia  the  evidence  in  favor  of  their 
views  is  based  chiefly  on  blood  examinations,  lacks  the  support  of  anatomical 
studies  of  the  organs,  and  is  unsatisfactory. 

Aplastic  leukemia  is  a  term  applied  by  Wolff  to  a  conditipn  marked  by 
anemia,  slight  leukocytosis  with  96  per  cent,  of  large  atypical  lymphocytes, 
lymphomas  in  the  liver  and  a  deficiency  of  colorless  cells  in  the  marrow. 
The  significance  of  such  cases  is  not  clear,  but  the  condition  appears  more 
closely  related  to  pseudoleukemia.  Extensive  fibrosis  occurs  in  the  bone- 
marrow  in  late  myelemia  so  that  this  organ  becomes  virtually  aplastic  (Lehn- 
dorff,  Zak). 

Leukosarcomatosis  (Sternberg). — While  the  neoplastic  nature  of  the 
entire  leukemic  process  has  never  received  general  endorsement  it  has  long 
been  recognized  that  in  certain  cases  the  anatomical  condition  varies  from 
the  standard  type  in  the  direction  of  a  true  neoplasm.  The  more  conspicuous 
features  of  such  atypical  cases  have  been  emphasized  by  Banti,  who  in  view  of 
this  evidence  has  claimed  that  the  leukemic  process,  at  least  the  lymphatic, 
is  always  neoplastic.  They  consist  of  marked  invasion  of  bone  by  the  hyper- 
plastic  marrow,  the  penetration  of  the  shaft  and  invasion  of  periosteum  with 
miliary  leukemic  nodules,  the  fusion  of  leukemic  lymph-nodes,  the  appear- 
ance of  multiple  nodules  in  serous  membranes,  the  invasion  of  intestinal 
and  cardiac  muscle  by  lymphomas,  and  the  atypical  structure,  large  size,  and 
indefinite  character  of  the  cells  of  leukemic  infiltrations. 

In  a  considerable  series  of  cases  a  large  sarcomatous  tumor  of  the  thymus 
with  leukemic  blood-picture  has  been  the  chief  feature  (Fabian,  Lit.),  so 
that  leukemia  with  involvement  of  the  thymus  came  to  be  recognized  as  an 
atypical  and  malignant  variety.  Orth  speaks  of  these  growths  as  malignant 
leukemic  lymphoma.  With  thymic  tumors  the  other  lesions  of  leukemia 
have  not  always  been  fully  developed  (Heubner).  Lymphemia  is  not  infre- 
quently associated  with  an  infiltrating  process  in  the  tonsils  (Askanazy). 


362  NEOPLASTIC  DISEASES 

Other  regions  have  also  been  the  seat  of  lymphosarcomatous  tumors  with 
leukemic  blood-picture.  In  a  case  of  Warthin's  the  ileum  was  extensively 
involved  in  a  large  abdominal  tumor  which  extended  to  the  kidneys,  stomach, 
and  regional  lymphatic  system,  but  the  marrowT  was  normal.  Of  90,000 
leukocytes  86.6  per  cent,  were  atypical  mononuclears  resembling  those  of  the 
tumor.  Moritz  reports  a  somewhat  similar  case  of  tumor  of  the  cecum  in 
which  spleen,  nodes,  and  marrow  were  involved.  Pernicious  anemia  with 
terminal  leukocytosis  suggesting  leukemia  may  occur  with  extensive  sar- 
comatous  tumors  of  bones,  lymph-nodes,  and  spleen  (Grawitz,  Lazarus). 

At  this  point  is  encountered  the  possibility  that  tumors  essentially  dif- 
ferent from  leukemia  may  discharge  many  cells  into  the  blood  and  simulate 
leukemia.  The  well-known  case  of  Lucke's  illustrates  this  event.  Here  a 
round-  and  spindle-cell  sarcoma  of  the  axilla  ruptured  into  a  subclavian  vein 
and  the  patient  died  with  extensive  leukocytosis  as  in  leukemia.  That  this 
case  was  not  leukemia  is  shown  by  the  absence  of  lesions  in  spleen  and  lymph- 
nodes.  The  blood  contained  many  large  round  and  spindle  cells.  Martin 
and  Matthewson  report  several  cases  of  lymphosarcoma  with  leukocytosis 
in  which  they  found  it  difficult  to  establish  the  diagnosis  of  leukemia.  Where 
the  usual  systemic  lesions  are  present  there  seems  to  be  no  other  alternative 
than  to  class  the  condition  with  leukemia.  In  nearly  all  these  atypical  cases 
the  blood-picture  has  varied  from  the  usual  types,  and  the  abnormal  cells, 
not  always  very  numerous,  have  belonged  in  the  class  of  large  undifferentiated 
mononuclear  leukocytes. 

Out  of  this  group  Sternberg  attempts  to  establish  a  special  variety  of 
leukemia,  leukosarcomatosis,  which  he  would  sharply  separate  from  the 
ordinary  type,  on  the  ground  that  it  represents  a  true  tumor  process.  The 
atypical  characters  of  the  cells  he  regards  as  the  expression  of  a  neoplastic 
quality,  and  he  gathers  from  the  literature  a  series  of  cases  described  chiefly 
as  lymphatic,  acute,  and  chronic,  in  which  the  presence  of  these  cells  and  the 
infiltrating  characters  of  the  organic  process  indicate  the  existence  of  a  neo- 
plasm. Sternberg's  views  have  been  attacked  by  Turk  and  others,  who 
have  shown  that  many  of  the  anatomical  features  of  leukosarcomatosis  are 
observed  in  otherwise  typical  leukemia.  Nevertheless  Sternberg's  studies 
have  been  of  service  in  contrasting  different  types  of  leukemia  and  in  show- 
ing that  there  are  different  grades  of  hyperplasia  associated  with  leukemia 
and  that  in  some  cases  the  process  closely  approaches  a  malignant  tumor. 

Lymphoid-cell  leukemia  is  a  term  applied  by  Wolff  to  certain  cases  in 
which  the  blood  contains  many  large  indifferent  mononuclear  cells  which  he 
interprets  as  leukocytic  metrocytes.  The  structure  of  the  organic  lesions 
in  these  cases  shows  many  features  of  a  neoplasm  composed  of  proliferating 
atypical  leukocytes  (Babes).  This  condition  does  not  differ  essentially  from 
Sternberg's  leukosarcomatosis. 

Chloroma. — The  occurrence  of  greenish  tumors  of  skull,  vertebrae,  ribs, 
and  other  organs  had  been  recorded  by  many  others  before  1853  when  King 
employed  the  term  "chloroma"  for  these  growths.  In  1854  Aran  with  Lebert 
contributed  an  important  study  of  the  condition,  but  Recklinghausen  in  1885 
first  recognized  the  lymphomatous  nature  of  the  process  and  its  probable 
relation  to  leukemia,  as  a  systemic  disease  of  the  lymphatic  system.  The 
association  with  a  leukemic  blood-picture  seems  to  have  been  recognized 
first  by  Huber  in  1878,  but  observations  on  the  blood  remained  imperfect 
until  after  Recklinghausen's  study.  In  1893  Dock  fully  reviewed  the  history 
of  the  disease,  confirmed  the  relation  to  leukemia,  and  later  with  Warthin 
established  the  primary  myelogenous  origin  of  the  tumors  in  their  case.  De- 
tailed hematological  studies  by  Turk,  Klein  and  Steinhaus,  Sternberg  and 


LYMPHOMA  AND  LYMPHOSARCOMA  363 

Fabian  have  completed  the  parallel  with  leukemia  by  showing  the  existence 
of  both  lymphatic  and  myelocytic  types  of  chloroma. 

The  disease  occurs  chiefly  in  young  males,  average  age  18.8  years,  and  runs 
an  active  course,  terminating  fatally  within  an  average  observed  period  of 
5.5  months.  More  prolonged  cases  occur  in  older  subjects.  The  tumors 
appear  chiefly  in  the  skull,  affecting  the  orbit,  dura,  sinuses,  auditory  region, 
sphenoid  and  ethmoid  sinuses,  nares,  antrum,  pharynx,  palate,  and  alveolar 
processes.  The  early  symptoms  are,  therefore,  often  referable  to  the  eye, 
ear,  nose,  and  throat.  Very  often  the  tumors  affect  the  sternum,  vertebral 
column,  ribs,  pelvis,  and  occasionally  the  long  bones.  In  such  cases  the 
distinctions  from  multiple  myeloma  are  not  clear.  In  the  lymphatic  system 
the  cervical,  axillary,  mediastinal,  or  other  deep  chains  are  always  involved 
in  the  lymphatic  type,  and  have  escaped  in  only  one  myelocytic  case  (Klein, 
Steinhaus).  The  bone-marrow  is  regularly  involved,  sometimes  rather  slightly 
or  not  at  all,  often  very  extensively  (Sternberg).  The  spleen  is  much  enlarged, 
and  the  gastro-intestinal  lesions  may  be  extensive.  The  heterotopic  deposits 
while  irregular  are  a  very  prominent  feature,  occur  in  almost  every  organ 
and  tissue,  and  illustrate  the  widest  scope  of  the  leukemic  process.  The 
liver  and  kidney  frequently  show  deposits,  and  the  pancreas,  thyroid,  thymus, 
ovaries,  mamma,  and  prostate  have  been  found  involved  with  tumor-like 
growths.  A  special  tendency  to  invade  the  muscles  and  their  tendinous 
insertions  is  observed,  the  infiltration  passing  out  from  the  bone-marrow. 
The  walls  of  vessels  also  suffer  more  than  in  typical  leukemia.  In  several 
cases  there  have  been  infiltrations,  eruptions,  or  tumors  in  the  skin  (Stevens, 
Hitschmann.  Bramwell). 

The  most  conspicuous  gross  feature  is  the  color  of  the  growths,  which 
varies  from  a  grass  green  to  a  faint  greenish-yellow  tinge,  may  be  very  pro- 
nounced throughout  the  marrow  and  all  the  tumors,  or  may  be  limited  to  a 
few  areas.  The  heart  clots  and  the  sedimented  leukocytes  have  been  found 
greenish  (Trevithick).  A  similar  color  may  be  observed  in  the  marrow  of 
typical  acute  leukemia.  Its  source  is  undetermined,  but  it  has  been  referred 
to  transformed  blood  pigment  (Risel),  or  to  fatty  products  of  cell  metabolism 
(Sternberg).  Huber  and  Chiari  attributed  the  color  to  greenish  refractive 
lipoid  granules  which  they  found  in  the  cells.  Lang's  surmise  that  pigment- 
producing  bacteria  are  present  has  been  disproved  by  Lubarsch.  Since  the 
coloration  is  not  constant  and  may  be  observed  in  typical  leukemia,  its  presence 
is  inadequate  to  separate  the  disease  essentially  from  leukemia. 

In  form  the  tumors  appear  as  broad  flat  masses  i  to  2  cm.  thick,  firm  or 
fibrous,  surrounding  the  bones,  invading  muscles,  tendons,  and  vessels, 
stripping  up  the  periosteum,  or  yielding  more  circumscribed  nodular  growths. 
In  the  skull  and  spinal  canal  flat  masses  separate  the  dura  from  the  bone  or 
perforate  the  meninges  and  invade  neighboring  tissues.  The  lymph-nodes 
may  reach  large  dimensions  and  become  fused  with  each  other.  The  lesion 
in  the  marrow  is  diffuse  or  focal.  Diffuse  infiltrations  in  the  mucous  mem- 
branes of  eye,  mouth,  nose,  throat,  larynx,  or  gastro-intestinal  tract  produce 
deformities  and  ulceration. 

The  blood-picture  in  chloroma  varies  extremely.  The  cases  fall  into 
the  two  main  groups,  lymphemia  and  myelemia,  while  in  certain  instances 
the  leukocytosis  has  been  absent  or  transient.  Hence  one  may  assume  that 
there  are  leukemic  and  aleukemic  chloromas  of  both  lymphocytic  and  mye- 
locytic types.  The  lymphocytic  type  is  much  the  more  common.  Here 
the  circulating  leukocytes  have  usually  shown  a  large  proportion  of  large 
indifferent  mononuclear  cells.  Yet  the  cells  have  varied  greatly  in  size,  be- 
ing small  lymphocytes  (Rosenblath,  Stevens)  or  large  lymphocytes  (Dock 


364  NEOPLASTIC  DISEASES 

et  al.},  while  Trevi thick  commented  on  the  extreme  size  of  many  cells.  The 
numbers  of  leukocytes  also  vary  greatly,  Bramwell  finding  only  8000,  Stevens 
491,000,  while  the  increase  appears  early  or  late  or  in  transient.  Similar 
variations  occur  in  the  myelocytic  variety.  Dock  and  Warthin  describe 
many  peculiar  cells,  including  eosinophile  myelocytes,  which  were  abundant 
in  the  tumor-tissue.  Waldstein  described  a  case  of  extensive  chloroma  in 
which  the  blood-picture  of  pernicious  anemia  suddenly  became  leukemic 
in  the  terminal  weeks. 

The  structure  of  the  tumors  accords  with  that  of  lymphocytic  and  mye- 
locytic leukemia.  In  the  former  class  there  is  diffuse  infiltration  with  large 
mononuclear  non-granular  cells  displacing  normal  structures  and  exhibiting 
considerable  power  to  invade  capsules  of  nodes,  blood-vessels,  and  other 
surrounding  tissues.  In  the  latter  class  the  evidences  of  the  myeloid  charac- 
ter have  been  pronounced  and  neutrophile  myelocytes  have  been  abundant. 
In  a  case  interpreted  as  lymphatic  Warthin  found  a  very  large  proportion 
of  eosinophile  cells. 

The  chief  significance  of  chloroma  lies  in  the  fact  that  it  represents  a 
leukemic  process  of  a  pronounced  neoplastic  type.  The  bulky  tumors,  the 
destructive  local  infiltrations,  the  distant  heterotopic  metastases,  the  atypical 
character  of  the  cells,  and  their  very  active  proliferation  provide  all  the 
essential  features  of  a  malignant  neoplasm.  The  process  belongs  with  the 
systemic  sarcomas  of  blood-forming  organs,  affecting  primarily  either  the 
lymphatic  system  proper  or  the  bone-marrow.  It  appears  to  differ  only  in 
degree  from  the  other  more  aggressive  leukemic  processes,  so  that  Sternberg 
includes  it  in  his  class  of  leukosarcomatosis.  While  the  clinical  course  may 
resemble  acute  leukemia  the  process  is  quite  different  from  the  ordinary 
acute  febrile  leukemia,  in  that  the  cells  are  much  more  atypical,  the  local 
process  more  aggressive,  and  the  secondary  growths  are  more  clearly  of 
embolic  origin  and  of  much  wider  distribution.  The  evidence  furnished 
by  chloroma,  especially  the  myeloid  type,  tells  strongly  in  favor  of  the  metas- 
tatic  origin  of  all  heterotopic  deposits  in  leukemia.  Chloroma  illustrates 
also  the  access  to  the  blood-stream,  permanent  or  transient,  in  small  or  large 
numbers,  of  specific  tumor-cells. 

There  has  been  much  discussion  of  the  relation  between  chloroma  and 
the  lymphosarcomatosis  of  Kundrat,  but  the  two  conditions  are  anatomically 
distinct.  Being  clearly  a  tumor  of  lymphocytes  and  myelocytes  the  observa- 
tions on  chloroma  indicate  that  it  has  no  relation  to  myeloma,  although 
albuminosuria  has  been  detected  in  one  case  (Weinberger)  and  myeloma 
may  yield  many  tumor-cells  to  the  blood-stream.  Regarding  the  etiology  of 
chloroma  nothing  is  known,  but  a  combination  with  tuberculosis  has  been 
observed  in  several  cases  (Horing,  Schmidt,  Lubarsch,  Risel). 

Plasma-cell  Leukemia. — Turk  has  described  the  frequent  presence  in  the 
blood  of  a  peculiar  mononuclear  cell  with  eccentric  nucleus  and  amphophile 
cytoplasm,  the  "reizungsformen,"  and  Hoffmann  has  identified  them  with 
plasma-cells.  In  a  case  of  myeloma  Schridde  found  in  the  blood  typical 
plasma-cells  in  small  numbers,  but  Gluzinski  and  Reichenstein  report  a  case 
of  myeloma  in  which  a  large  proportion  of  39,640  leukocytes  were  of  the 
plasma-cell  type,  and  they  speak  of  plasma-cell  leukemia.  This  isolated 
observation  of  an  unusual  number  of  tumor-cells  reaching  the  blood  is,  how- 
ever, quite  inadequate  to  establish  any  relation  between  myeloma  and  any 
form  of  leukemia.  Myeloma  varies  in  other  directions  than  toward  leukemia, 
and  it  may  be  recalled  that  various  tumor-cells  even  of  cancer  have  appeared 
in  the  blood. 

Nature  of  Leukemia. — The  foregoing  data  relating  to  the  anatomical 


LYMPHOMA  AND  LYMPHOSARCOMA  365 

process  in  leukemia  seem  to  warrant  certain  conclusions  regarding  the  nature 
and  position  of  this  disease.  The  ordinary  picture  of  leukemia  is  so  character- 
istic as  to  lead  to  the  impression  that  it  is  a  definite  disease  of  uniform  etiology, 
but  when  the  wide  scope  of  the  clinical  features  and  anatomical  lesions  of 
atypical  leukemia  are  considered,  the  suspicion  arises  that  this  is  not  a 
definite  disease,  but  merely  a  variable  symptom  complex  of  diverse  etiology. 
From  this  point  of  view  leukemia  is  comparable  to  leukocytosis.  Both  condi- 
tions represent  a  response  of  the  blood-forming  organs  to  irritation,  but 
highly  essential  differences  exist  in  the  nature  of  this  response.  In  leuko- 
cytosis there  is  a  transitory  multiplication  of  leukocytes  of  normal  type  which 
in  its  various  phases  may  be  regarded  as  covering  the  entire  scope  of  simple 
hyperplasia.  The  organic  changes  may  be  considerable,  but  soon  subside 
when  the  irritant  is  removed.  In  leukemia,  on  the  other  hand,  the  response 
is  from  the  first  of  a  different  type.  Although  transient  leukemic  blood-pic- 
tures occur,  yet  with  rare  exceptions  the  appearance  of  signs  of  leukemia 
means  the  beginning  of  a  progressive  process  which  will  terminate  fatally. 
It  is  possible  that  some  peculiar  etiological  agent  will  be  found  to  explain 
this  progressive  quality,  but  it  seems  more  probable  that  it  depends  on  the 
nature  of  the  process  rather  than  on  its  cause.  Two  main  anatomical  features 
separate  leukemia  from  leukocytosis,  the  abnormal  types  of  cells  produced 
and  the  permanence  and  extent  of  the  organic  lesions. 

While  there  is  much  difference  of  opinion  regarding  the  variations  of 
leukemic  cells  from  normal  leukocytes  and  their  progenitors,  it  is  acknowl- 
edged that  even  in  ordinary  leukemia  the  new  cells  vary  from  the  normal, 
and  that  new,  possibly  ancestral  forms  appear,  while  in  atypical  cases  the 
cell  changes  may  be  quite  pronounced.  It  is  this  variation  in  cell  type  even 
more  than  increased  numbers  that  distinguishes  the  leukemic  process,  so 
that  in  recent  times  diagnoses  are  made  of  leukemia  without  leukocytosis. 
Nor  is  this  variation  in  cell  type  degenerative,  for  it  is  not  paralleled  by  any 
of  the  severe  acute  or  chronic  degenerative  processes  in  leukocytosis.  More- 
over, it  is  accompanied  by  evidence  of  great  proliferative  capacity,  such  as 
mitotic  figures  in  the  circulating  cells,  increase  in  number  beyond  any  limit 
of  leukocytosis,  and  by  permanent  enlargements  of  the  blood-forming  tissues. 
That  all  these  variations  are  steps  in  the  direction  of  a  neoplasm  seems  to 
the  writer  an  inevitable  conclusion.  Leukemia  represents  more  clearly  than 
any  other  condition  the  phases  of  neoplastic  transformation. 

Yet  it  is  not  necessary  to  dismiss  all  leukemias  as  frank  tumor  processes. 
In  the  numerous  discussions  of  the  neoplastic  theory  of  leukemia  controversy 
has  arisen  not  so  much  regarding  the  existence  of  neoplastic  tendencies  which 
have  always  been  recognized,  but  on  the  hasty  classification  of  leukemia  with 
tumors. 

Thus  Banti,  who  emphasizes  the  tumor  nature,  especially  of  lymphemia 
(of  myelemia  he  is  less  certain),  seems  to  overlook  important  distinctions 
between  acute  febrile  leukemia  and  prolonged  chloroma.  In  the  former, 
local  aggressive  properties  are  almost  entirely  wanting,  the  infiltrating  cells 
show  great  respect  for  the  invaded  tissues,  the  lymph-node  lesions  may  be 
very  moderate,  local  lymphomas  may  be  scanty,  and  any  neoplastic  quality 
present  is  confined  to  simple  multiplication  of  atypical  cells,  while  an  acute 
toxic  process  is  prominent.  In  chloroma,  on  the  other  hand,  a  very  different 
grade  of  neoplastic  properties  is  present,  and  the  effects  are  so  different  that 
it  seems  unwarranted  to  exactly  identify  the  two  processes.  Sternberg 
assumes  a  more  defensible  position  in  drawing  the  tumor  line  at  the  locally 
aggressive  lesions  of  leukosarcomatosis.  Below  that  line  leukemias  are  for 
him  peculiar  forms  of  leukocytic  overgrowth,  above  it  they  are  neoplasms. 


366  NEOPLASTIC  DISEASES 

Yet  for  the  reasons  mentioned  there  seems  to  be  no  ground  for  assuming  that 
the  specific  quality  in  the  leukemic  process  is  anything  other  than  neoplastic. 
Admitting  that  there  are  all  grades  of  neoplastic  hyperplasia,  this  theory 
accounts  for  the  essential  peculiarities  of  leukemia  and  admits  of  a  uniform 
conception  of  the  process  in  all  its  phases.  The  conception  of  leukemia  as 
essentially  neoplastic  does  not  exclude  the  most  complex  etiology  nor  a  close 
dependence  of  the  process  upon  irritants  or  parasites.  The  general  facts  of 
the  disease  rather  strongly  suggest  the  continued  presence  of  an  irritant,  of 
toxic  or  bacterial  nature,  as  the  exciting  cause  of  the  hyperplasia.  If  any  one 
known  bacterial  agent  is  chiefly  concerned  it  is  the  tubercle  bacillus.  The 
comparatively  frequent  association  of  some  form  of  tuberculosis  with  lym- 
phemia  and  the  known  tendency  of  tuberculosis  to  induce  extensive  lymphoid 
hyperplasia  even  without  the  demonstrable  presence  of  the  bacillus,  creates 
a  strong  suspicion  that  this  organism  is  a  frequent  excitant  of  leukemia. 
It  seems  possible  that  in  tuberculosis  may  eventually  be  found  a  connecting 
link  between  lymphemia,  pseudoleukemia,  some  cases  of  Hodgkin's  disease, 
and  some  forms  of  lymphosarcoma.  Among  the  other  possible  factors  has 
been  suggested  the  impulse  toward  lymphoid  hyperplasia  given  by  the  typhoid 
process,  a  field  in  which  specific  data  remain  to  be  gathered. 

For  the  etiology  of  myelemia  there  are  even  less  definite  indications,  but 
here  the  numerous  factors,  which  excite  anemia,  call  forth  the  regeneration 
of  granular  leukocytes,  and  injure  the  bone-marrow,  may  well  be  kept  in 
mind.  That  local  and  general  predisposing  factors  exist  can  only  be  assumed 
from  analogy.  Leukemia  is  chiefly  a  disease  of  early  years  when  the  blood- 
forming  organs  are  relatively  active. 

PSEUDOLEUKEMIA 

In  1865  Cohnheim  applied  the  term  "pseudoleukemia"  to  a  condition 
anatomically  resembling  leukemia,  but  with  reduction  of  leukocytes  in  the 
blood.  His  patient  in  the  course  of  9  months  developed  a  greatly  enlarged 
spleen  with  prominent  follicles,  diffuse  hyperplasia  of  cervical,  inguinal, 
mediastinal  and  retroperitoneal  lymph-nodes,  miliary  lymphomas  of  liver, 
and  extensive  diffuse  lymphoid  infiltration  of  the  kidneys. 

Since  that  time  many  authors  have  described  as  pseudoleukemia  miscel- 
laneous forms  of  systemic  disease  of  the  lymphatic  system  without  leukocy- 
tosis,  so  that  the  term  came  to  have  a  very  wide  scope.  In  recent  years  ex- 
tensive inroads  have  been  made  upon  the  domain  of  pseudoleukemia,  so 
that  today  it  is  somewhat  doubtful  in  the  minds  of  many  if  there  is  any  con- 
dition to  which  this  term  may  properly  be  applied. 

The  first  definite  condition  to  be  separated  from  pseudoleukemia  was 
lymphatic  tuberculosis. 

Lymphatic  Tuberculosis. — That  general  tuberculous  lymphadenitis  can- 
not always  be  distinguished  clinically  from  pseudoleukemia  was  early  recog- 
nized and  the  scope  of  the  disease  was  by  some  widened  to  include  such  cases. 
Many  of  the  cases  of  intermittent  fever  with  swelling  of  lymph-nodes  de- 
scribed by  Pel,  Ebstein,  Renvers,  and  others  probably  belong  in  this  class 
(Combemale).  In  1887  Delafield  showed  that  the  course  of  pseudoleukemia 
could  be  exactly  imitated  by  lesions  of  lymph-nodes  which  were  typically 
tuberculous,  with  miliary  tubercles,  foci  of  necrosis,  and  stainable  bacilli. 
Waetzoldt,  however,  found  nodes  which  showed  pure  lymphoid  hyperplasia, 
with  scanty  foci  of  hyaline  material  and  yet  many  tubercle  bacilli  in  sections. 
Finally  Brentano  and  Tangl  described  a  case  in  which  with  tuberculous  ulcer 
of  cecum  and  peritonitis  the  thoracic  and  retroperitoneal  lymph-nodes  showed 


LYMPHOMA  AND  LYMPHOSARCOMA  367 

only  lymphoid  hyperplasia,  no  bacilli  in  sections,  but  inoculation  proved 
positive.  In  Sab  razes'  case  of  "lymphadenoma"  the  firm  nodes  showed 
lymphoid  hyperplasia  without  caseation,  while  in  lungs,  liver,  spleen,  and 
peritoneum  were  miliary  lymphomas,  microscopic  criteria  of  tuberculosis 
were  absent,  but  rabbits  inoculated  died  with  tuberculosis. 

It  thus  appears  that  the  clinical  picture  of  pseudoleukemia  may  be  asso- 
ciated with:  (i)  Ordinary  miliary  and  caseous  tuberculosis  of  many  lymphnodes 
(Delafield) ;  (2)  Frank  tuberculous  lesions  in  one  locality  and  pure  lymphoid 
hyperplasia  of  many  nodes  which  yield  no  stainable  bacilli,  but  prove  in- 
fective (Brentano,  Tangl);  (3)  pure  lymphoid  hyperplasia  without  stainable 
bacilli,  but  giving  positive  results  by  inoculation  (Waetzoldt,  Sabrazes). 

In  all  these  cases  in  which  a  tuberculous  infection  has  been  demonstrated 
it  appears  that  the  extent  of  the  lesion  is  rather  less  general  and  locally  more 
destructive  than  in  many  examples  of  pseudoleukemia.  Yet  the  purest 
forms  of  the  disease  exhibit  these  same  characters  as  compared  with  leukemia. 
That  the  tuberculous  infection  in  all  these  cases  may  be  secondary  or  unre- 
lated to  the  pseudoleukemic  process  appears  to  the  writer  quite  unwrorthy 
of  consideration.  On  the  contrary,  there  can  be  no  doubt  that  the  clinical 
picture  and  anatomical  lesions  of  pseudoleukemia  are  often  produced  by 
tuberculosis. 

HooGKiN'S  GRANULOMA.    LYMPHOGRANULOMA 

A  considerable  group  of  the  cases  formerly  classed  as  pseudoleukemia 
present  a  specific  histological  structure  which  is  now  regarded  as  pathogno- 
monic  of  Hodgkin's  disease.  The  Vienna  school  of  pathologists  early  recog- 
nized this  characteristic  structure  and  Sternberg  clearly  described  it  in  a 
group  of  cases  in  most  of  which  he  claimed  to  find  tubercle  bacilli.  This 
specific  histology  has  been  emphasized  by  Reed.  The  structure  shows 
diffuse  cellular  hyperplasia  with  varying  proportions,  sometimes  excessive, 
of  proliferating  endothelial  cells,  endothelial  giant-cells,  plasma-cells,  and 
eosinophile  leukocytes.  While  there  are  numerous  variations  in  the  pro- 
portions of  these  cells,  especially  of  the  endothelium,  the  typical  picture  of 
Hodgkin's  granuloma  with  the  confusion  of  so  many  cell  forms  is  unmistak- 
able, is  very  probably  caused  by  a  single  agent,  and  forms  a  rational  basis 
for  classification  of  many  obscure  cases  of  clinical  lymphomas. 

Unfortunately,  the  clinical  picture  of  Hodgkin's  disease  is  not  always  asso- 
ciated with  this  particular  histological  structure.  It  is  the  common  experience 
of  pathologists,  as  stated  by  Christian  and  Warthin,  to  find  an  absence  of  the 
typical  picture  described  by  Sternberg,  in  nodes  removed  under  the  diagnosis 
of  Hodgkin's  disease,  and  in  its  place  indefinite  forms  of  lymphoid  hyperplasia. 
Without  the  knowledge  of  the  etiological  factor  it  remains  almost  as  difficult 
as  before  to  determine  the  true  scope  of  this  infectious  granuloma,  for  all 
the  phases  of  the  disease  cannot  be  recognized  with  the  same  certainty.  It 
is  not  known,  for  example,  whether  a  pure  lymphoid  hyperplasia,  or  a  pure 
plasmoma  (myeloma),  or  pure  endothelial  hyperplasia  belong  in  this  group, 
and  these  questions  cannot  be  settled  until  the  problem  of  etiology  is 
determined. 

In  this  dilemma  one  may  follow  the  plan  adopted  by  H.  Ziegler  and  in- 
clude under  Hodgkin's  disease  all  conditions  which  seem  to  have  any  probable 
relation  to  the  specific  process.  This  plan  means  hardly  less  than  to  replace 
the  term  "pseudoleukemia"  with  Hodgkin's  disease.  Thus  Ziegler  describes 
Hodgkin's  disease  as  (a)  Acute,  (6)  Localized,  (c)  General,  (d)  Mediastinal, 
(e)  Larval,  (/)  Splenic,  (g)  Osteitic,  (h}  Atypical  (intestinal  form,  Mikulicz's 
disease),  (i)  Mycosis  fungoides. 


368  NEOPLASTIC  DISEASES 

In  the  description  of  these  forms  he  includes  many  histological  processes 
which  differ  considerably  from  Hodgkin's  granuloma  and  whose  relation 
to  which  is  far  from  certain.  Nevertheless  there  is  a  strong  probability 
that  the  scope  of  this  disease  is  very  wide  and  that  the  above  classification 
deserves  adoption  as  a  working  hypothesis.  The  writer  would  prefer  to 
exclude  from  Ziegler's  scheme  such  diseases  as  multiple  myeloma,  mycosis 
fungoides,  and  any  form  of  systemic  pure  lymphocytic  hyperplasia. 

Clinical  Course. — The  disease  occasionally  exhibits  as  prodromal  symp- 
toms an  itching  or  eczematous  eruption  of  the  skin  which  may  precede  other 
symptoms  by  months  or  years,  bears  considerable  relation  to  the  subsequent 
course  of  lymph-node  lesions,  and  may  result  in  the  definite  and  progressive 
cutaneous  lesions  of  Hodgkin's  disease.  Gastro-intestinal  disturbances  may 
also  be  observed  (Rolleston,  B  ram  well). 

More  often  the  initial  symptom  is  enlargement  of  a  chain  of  lymph-nodes, 
cervical  (50  per  cent.)  axillary,  inguinal,  and  the  continuous  or  irregular 
extension  to  other  chains.  A  splenic  tumor  develops  in  60  to  70  per  cent,  of 
the  cases,  and  may  reach  very  large  proportions.  At  the  same  time  and  with 
equal  frequency  the  liver  enlarges.  With  this  generalization  of  the  disease, 
fever,  night-sweats,  anemia,  and  cachexia  appear.  The  fever  occurs  early 
or  late,  may  be  slight  or  absent,  but  is  often  of  sharply  intermittent  type, 
and  may  dominate  the  clinical  picture. 

The  anemia  is  of  the  secondary  chlorotic  type  and  may  become  severe  or 
pernicious.  The  leukocytes  are  usually  under  10,000,  often  there  is  leuko- 
penia,  occasionally  leukocytosis  of  30,000  or  more.  Relative  or  absolute 
lymphocytosis  usually  prevails,  but  the  neutrophile  cells  are  much  increased 
in  exacerbations.  Eosinophilia  is  so  frequent  and  marked  as  to  form  an 
important  diagnostic  sign  (Bunting).  Mast  cells  may  be  increased.  Evi- 
dences of  a  hemorrhagic  tendency  are  frequently  observed,  as  minute  hemor- 
rhages in  skin,  petechiae,  or  purpura  hsemorrhagica  (Sabrazes,  Hippel).  The 
terminal  cachexia  is  marked  by  numerous  extensions  or  inflammatory 
complications  in  many  organs,  and  in  about  25  per  cent,  of  the  cases  by  miliary 
tuberculosis  (Ziegler).  Amyloidosis  of  spleen  and  other  organs  is  recorded 
in  22  cases  (Fabian).  The  duration  varies  from  a  few  weeks  in  acute  cases 
to  many  years,  but  is  usually  about  18  months.  The  cutaneous  lesions  are 
more  chronic.  Clinical  types  are  numerous. 

Clinical  Types. — i .  Acute  cases  lasting  4  and  6  weeks,  marked  by  fever, 
anemia,  swelling  of  cervical  and  axillary  nodes  and  spleen,  or  by  general 
swelling  of  lymph-nodes,  lymphomas  in  liver,  and  cutaneous  ulcers  are  de- 
scribed by  Hirschfeld  and  Isaak,  and  Beitzke.  The  structure  of  the  lesions 
is  characteristic  of  Hodgkin's  granuloma.  Focal  necrosis  in  liver,  nodes, 
and  spleen  are  prominent  in  this  group. 

2.  Chronic  generalized  lesions  accompany  the  usual  clinical  course  de- 
scribed above.     In  this  group  several  chains  of  superficial  nodes,  usually 
the  cervical,  are  extensively  involved,  and  the  lesion  extends  to  thoracic 
and  abdominal  nodes,  spleen,  liver,  and  bone-marrow.     All  the  lymphoid 
tissue  of  the  body  may  be  slightly  hyperplastic.    Secondary  deposits  in  lungs 
and  serous  membranes  are  often  observed. 

3.  Splenic  Hodgkin's  disease  occurs  as  a  primary  lesion  of  this  organ  or  as 
a  part  of  the  generalized  infection.    The  peculiar  color  of  the  organ  led  Benda 
to  apply  the  term  "porphyry  spleen"  to  this  condition.    The  primary  splenic 
lesion  is  extremely  rare,  some  authors  denying  its  existence.    Yet  in  a  case 
described  by  Symmers  and  studied  in  this  laboratory  the  structure  was  prac- 
tically identical  with  Hodgkin's  granuloma.    Primary  splenic  lesions  extend- 
ing to  the  lymph-nodes  appear  to  have  been  observed  also  by  Kummel  who 


LYMPHOMA  AND  LYMPHOSARCOMA  369 

found  tubercle  bacilli  in  the  tissues,  while  Doncaster  has  reported  a  case  of 
primary  splenic  lesion  which  is  probably  genuine.  The  great  majority  of 
cases  of  primary  splenomegaly  which  resemble  Hodgkin's  disease  prove 
on  examination  to  belong  elsewhere,  chiefly  among  splenic  neoplasms.  For 
the  primary  splenomegaly  of  Gaucher  a  relation  to  tuberculosis  or  Hodgkin's 
disease  seems  improbable. 

The  secondary  invasion  of  the  spleen  in  Hodgkin's  disease  is  common, 
and  not  infrequently  the  splenomegaly  becomes  the  dominant  symptom. 
Here  the  primary  lesion  may  appear  in  the  peripheral  nodes  (Nowak)  or  in 


FIG.  145. — Retroperitoneal  region  in  a  case  of  Hodgkin's  disease.  Lymph-nodes, 
mesentery,  and  perirenal  tissues  are  fused  into  a  mass  of  granulomatous  tissue  which  oc- 
cludes vena  cava  and  constricts  aorta. 

deeper  chiefly  retroperitoneal  chains.  Remittent  fever,  anemia,  and  ca- 
chexia  are  leading  clinical  symptoms.  In  a  case  lasting  16  months  and  marked 
by  severe  febrile  attacks  with  intermittent  swelling  of  cervical  nodes,  the 
spleen  continued  to  enlarge  and  at  autopsy  was  found  to  contain  very  numer- 
ous necrotic  foci  surrounded  by  typical  Hodgkin's  granuloma.  The  lymph- 
nodes  showed  only  hyaline  areas.  Tubercle  bacilli  could  not  be  identified. 
Many  of  the  cases  of  Ebstein's  disease  must  be  classed  in  this  group.  ^ 

4.  Castro-intestinal  Hodgkin's  granuloma  is  an  ill-defined  condition  diffi- 
cult to  separate  from  tuberculosis,  on  the  one  hand,  and  lymphosarcoma  on 
the  other.    The  group  of  diffuse  lymphomas  affecting  a  large  portion  of  or 
the  entire  gastro-intestinal  mucosa  (Stoerk,  Wells,  Symmers)  must,  I  believe, 
24 


370  NEOPLASTIC  DISEASES 

be  given  a  separate  position,  since  they  differ  widely  in  structure  and  dis- 
tribution from  typical  Hodgkin's  granuloma.  There  remains  a  considerable 
group  of  locally  destructive  hyperplastic  lesions  located  in  any  portion  of 
the  gastro-intestinal  tract,  especially  in  stomach,  ileum,  and  cecum,  in  which 
the  structure  is  distinctly  granulomatous  and  in  which  tubercle  bacilli  are 
missing.  I  have  studied  several  cases  of  this  type,  with  local  ulceration  and 
extensive  swelling  of  regional  nodes,  in  which  the  lesions  resembled  Hodgkin's 
granuloma.  Coupland  and  La  Roy  have  described  typical  cases,  but  reports 
in  the  literature  are  scanty,  since  most  of  the  cases  are  interpreted  as  lympho- 
sarcoma. 

5.  Mediastinal  tumors  may  form  the  chief  lesion  in  Hodgkin's  disease,  and 
their  structure  is  usually  typical  of  the  granulomatous  or  of  the  sarcomatoid 
process  arising  in  the  thymus.     With  or  without  enlargement  of  palpable 
nodes  it  forms  a  bulky  tumor  of  the  mediastinum,   compressing  bronchi, 
vessels,  and  nerves  with  corresponding  pressure  symptoms.     Extensions  to 
pleura  and  pericardium,  heart  muscle,  lung,  liver,  supraclavicular,  and  axillary 
nodes  have  been  observed.     (Palma,  Lorrain,  Schottelius,  Jacquet,  Brigidi, 
Piccoli).    In  the  case  of  Weber  and  Ledingham  a  high  grade  of  pulmonary 
osteo-arthropathy  was  observed.    Although  in  this  last-mentioned  case  the 
structure  was  typical  and  extensions  were  chiefly  regional,  yet  in  most  cases 
the  tumor  is  bulky,  local  invasive  properties  are  pronounced,  distant  second- 
ary deposits  occur,  and  the  tissue  is  composed  chiefly  of  large  round  cells 
with  few  lymphocytes  and  no  necrosis,  so  that  many  have  regarded  this 
condition  as  true  lymphosarcoma.    In  a  case  studied  in  this  laboratory  by 
Symmers  a  bulky  but  encapsulated  tumor  occupied  the  mediastinum  and  had 
caused  ulceration  of  the  trachea.    The  nodes  on  both  sides  of  the  neck  were 
difficult  to  separate  from  the  tumor  and  the  bronchial  nodes  were  also  in- 
cluded in  the  mass.    There  were  no  distant  deposits.    The  structure  approached 
the  sarcomatous  type,  being  composed  of  regularly  placed  bands  of  dense 
connective  tissue  inclosing  areas  of  large  round  cells  derived  from  the  reticulum, 
a  few  lymphocytes,  giant-cells,  and  eosinophile  cells.     Here  some  relation 
to  Hodgkin's  granuloma  is  probable,  but  neoplastic  characters  seemed  to  be 
present  also.    Leukemia  occurs  with  somewhat  similar  processes  in  the  thy- 
mus, and  in  a  case  reported  by  Coenen  it  is  difficult  to  determine  whether 
leukemia  or  granuloma  should  be  recognized  (cf.  Tumors  of  Thymus). 

6.  Abdominal  Hodgkin's  granuloma  often  appears  clinically  as  a   larval 
form  of  the  disease,  since  enlargement  of  palpable  lymph-nodes  is  late  or  want- 
ing.    In  this  group  intermittent  or  continuous  fever  is  common,  the  course 
may  be  rapid,  and  a  typhoidal  condition  is  established.    Local  pain,  gastro- 
intestinal symptoms,  jaundice,  and  a  diazo-reaction  of  the  urine  strengthen  the 
resemblance  to  typhoid  fever. 

The  lesion  usually  begins  in  mesenteric  or  retroperitoneal  nodes  and 
extends  along  the  spine  into  the  thorax.  It  may  remain  in  the  abdominal 
nodes  producing  a  bulky  tumor  (Symmers,  longcope),  or  more  often  extends 
widely,  involving  spleen,  liver,  lungs,  bone-marrow,  and  eventually  superficial 
nodes.  Or  a  primary  affection  of  the  cervical  nodes  may  subside  after  exten- 
sive invasion  of  the  thorax  and  abdomen  (Gutig).  The  lesions  are  therefore 
the  most  extensive  occurring  in  the  disease. 

The  structure  illustrates  the  typical  granuloma  and  most  of  its  varia- 
tions. Focal  or  bulky  necroses  are  common  in  severe  febrile  cases.  Ziegler 
describes  excess  of  plasma-cells  in  lesions  in  some  of  his  cases.  The  gross 
appearance  may  strongly  suggest  a  neoplasm  and  many  cases  have  been 
described  as  lymphosarcoma.  In  Symmers'  case  the  tumor  was  composed 
almost  entirely  of  large,  flat,  endothelial  cells. 


LYMPHOMA  AND  LYMPHOSARCOMA  371 

7.  Mikidicz's  disease  is  an  infectious  granuloma  affecting  the  salivary  and 
lacrimal  glands,  occasionally  the  lips  and  eyelids.     It  has  sometimes  been 
associated  with  leukemia;  with  systemic  involvement  of  the  lymphatic  sys- 
tem interpreted  as  pseudoleukemia ;  and  with  tuberculosis  (Brun,  Fleischer). 
The  cervical  and  axillary  nodes,  spleen,  and  liver  are  often  involved  in  the  later 
stages,  and  many  of  the  symptoms  resemble  those  of  Hodgkin's  disease.    The 
structure  varies,  but  in  certain  cases  it  has  resembled  Hodgkin's  granuloma 
(Haeckel,  Jacobeus). 

8.  Bone-marrow  lesions  of  typical  structure  are  commonly  observed  in 
generalized  Hodgkin's  disease,  but  as  a  rule  the  bone  tissue  and  periosteum 
remain  intact.     Ziegler,   however,   believes  that  many  peculiar  osteal   and 
periosteal  lesions  attributed  to  primary  tumors  of  bone  and  marrow  or  to 
obscure  inflammatory  processes  belong  in  this  group,  and  he  has  collected  a 
series  of  such  cases,  including  myeloma  with  plasma-cells,  and  lymphosarcoma, 
which  he  would  class  with  Hodgkin's  granuloma. 

9.  Dermal  lesions  occur  in  the  course  of  many  cases  of  Hodgkin's  disease. 
The  itchy   eczematous  or   urticarial  exanthem  that  marks  the  prodromal 
stages  may  be  repeated  throughout  the  later  course  and  may  lead  to  excoria- 
tion, scarring,  and  pigmentation  so  marked  as  to  suggest  a  complicating 
affection  of  the  adrenal.     Or  a  bullous  eruption  may  appear  with  extensive 
erythema  and  scaling.    A  second  group  of  lesions,  clinically  and  anatomically 
specific,  have  been  designated  as  lymphogranulomatosis  cutis.    The  specific 
nature  of  certain  multiple,  nodular,  or  ulcerated  infiltrations  of  the  skin, 
formerly  classed  as  pseudoleukemia,  was  pointed  out  by  Grosz  in  1906,  who 
found  in  them  the  typical  structure  of  Hodgkin's  granuloma.     Several  cases 
of  this  character,  with  or  without  systemic  lesions,  have  since  been  described 
(Arndt,  Lit.).     Pick  emphasized  the  prominent  eosinophile  cells,  and  Arndt 
detected  scanty  acid-fast  bacilli  in  one  case.     Extensive  ulceration  of  the 
skin  occurred  in  Beitzke's  acute  case.     Ziegler  would  here  include  nearly 
all  the  cases  of  generalized  lymphosarcomatosis  of  the  skin,  and  it  seems  very 
probable  that  some  of  the  sarcoid  growths  in  dermatological  literature  may 
eventually  be  placed  in  this  group.    Ziegler  finds  many  resemblances  between 
mycosis  fungoides  and  lymphogranulomatosis,  but  the  structure  of  the  two 
processes,  as  well  as  the  clinical  aspects,  show  notable  differences,  and  Arndt 
from  a  careful  comparison  is  not  disposed  to  identify  the  diseases. 

10.  Besides  these  more  definite  clinical  varieties,  lymphogranuloma  has 
been  observed  in  many  other  organs  as  thyroid,  pancreas,  adrenal,  heart  and 
voluntary   muscles,    esophagus,   tonsils,   breast,   and   ovary    (Fabian,   Lit.). 
Jessup  has  described  a  typical  case  in  the  uterus.    In  the  lower  animals  the 
disease  appears  to  be  not  infrequent  (Ziegler,  Lit.). 

Structure. — Typical  Hodgkin's  granuloma  presents  a  characteristic 
structure  on  which  depends  its  recognition  as  a  specific  disease.  It  consists 
of  a  recticulum  in  which  lie  a  few  small  lymphocytes,  large  lymphocytes, 
plasma  cells,  eosinophile  cells,  proliferating  endothelium,  and  endothelial 
giant-cells.  There  are  many  variations  in  the  proportions  of  these  cells. 
In  the  early  stages  lymphocytes  are  abundant,  but  follicles  and  sinuses  are 
soon  obliterated.  The  nodes  on  the  outskirts  of  invaded  chains  may  show 
a  simple  hyperplastic  lymphadenitis,  but  the  specific  process  attacks  the 
supporting  tissue  and  endothelium  and  seems  to  cause  little  hyperplasia  of 
lymphocytes.  Later  the  lymphocytes  largely  disappear  with  the  multi- 
plication of  other  cells.  Endothelial  proliferation  is  prominent  from  the 
first,  so  that  large,  loose,  rounded  cells  with  clear  cytoplasm  and  single  or 
multilobed  hyperchromatic  nuclei  are  an  important  diagnostic  feature.  These 
cells  may  increase  in  size  and  number  so  that  they  may  compose  the  bulk 


372 


NEOPLASTIC  DISEASES 


of  the  tissue.  When  in  excess  they  may  appear  as  large,  flat,  almost  pavement- 
like  cells,  or  as  a  collection  of  giant-cells,  or  as  a  diffuse  growth  resembling 
sarcoma.  They  long  resist  the  advance  of  fibrosis. 

Eosinophile  cells  are  usually  numerous,  sometimes  extremely  abundant, 
occasionally  absent.  They  are  mononuclear  or  polynuclear,  and  they  prob- 
ably arise  as  a  result  of  small  extravasations  of  blood  which  mark  the  early 
lesions.  A  peculiar  brownish-yellow  color  of  the  Hodgkin  nodes  on  section 
may  perhaps  be  connected  with  this  tissue  eosinophilia.  Polynuclear  neutro- 
phile  cells  are  not  prominent.  A  few  plasma-cells  are  regularly  present  and 
they  may  become  so  numerous  as  to  lead  to  the  designation  of  plasmoma. 
Necrosis  is  missing  in  the  characteristic  stages  of  the  process,  but  in  acute 


FIG.  146. — Diffuse  growth  of  reticulum  cells  in  a  case  of  Hodgkin's  disease. 

febrile  cases  and  in  old  and  bulky  lesions  there  may  be  focal  or  extensive 
necrosis.  Fibrosis  becomes  established  in  many  advanced  lesions  and  acellular 
connective  tissue  in  bands  and  masses  composes  a  considerable  portion  of 
certain  bulky  tumors. 

Apart  from  the  specific  structure  presented  by  typical  stages  of  the  process 
and  the  variations  which  are  readily  derived  from  it,  the  scope  of  this  granu- 
loma  is  difficult  to  determine.  Very  early  lesions  are  often  typical  and  the 
terminal  stages  are  commonly  recognizable.  Besides  the  typical  picture 
described  by  Sternberg  and  Reed,  characteristic  cases  may  be  associated  with 
pure  lymphoid  hyperplasia,  various  forms  of  proliferation  of  reticulum 
cells,  as  well  as  with  subvarieties  of  tuberculosis  (cf .  Endothelioma  of  Lymph- 
nodes). 


LYMPHOMA  AND  LYMPHOSARCOMA 


373 


The  locally  invasive  and  destructive  properties  of  lymphogranuloma 
constitute  a  notable  feature.  While  the  capsules  of  nodes  long  remain  intact, 
yet  from  many  primary  foci  the  surrounding  tissues  may  be  invaded  by  a 
process  which  is  typically  granulomatous.  The  walls  of  blood-vessels  may 
be  extensively  invaded,  and  the  lumina  may  be  occluded  by  the  new  cells. 
These  appearances  have  often  suggested  that  the  process  is  sarcomatous. 
Yet  similar  lesions  are  observed  in  tuberculosis  and  so  long  as  the  new  tissue 
maintains  a  typical  structure  it  should  not  be  classed  with  malignant  tumors. 

Hodgkin's  Sarcoma. — The  transformation  of  Hodgkin's  granuloma  into 
a  sarcomatous  process  occurs  in  a  certain  proportion  of  cases,  and  since  the 
new  cells  are  of  endothelial  origin  this  tumor  might  be  classed  with  endothe- 


%_  *• 


~  >  *k  •     w«      • 


^  .:'^^v 


FIG.  147. — Diffuse  endothelial  overgrowth  in  atypical  Hodgkin's  disease. 

lioma.  Yet  the  proliferating  cells  lose  their  endothelial  characters  and  appear 
as  large  round  cells,  the  tumors  differ  markedly  in  behavior  from  other  endo- 
theliomas,  and  they  constitute  a  considerable  group  of  the  processes  com- 
monly called  lymphosarcoma  or  pseudoleukemia,  so  that  it  seems  admissible 
to  consider  them  in  this  connection  under  the  term  "Hodgkin's  sarcoma." 
This  process  runs  the  clinical  course  of  Hodgkin's  disease,  especially  that 
form  which  terminates  in  invasive  and  destructive  lesions  resembling  sarcoma. 
It  also  appears  in  single  chains  of  nodes,  chiefly  the  cervical,  but  recurring 
after  operation  it  goes  on  to  a  fatal  issue.  These  cases  correspond  to  Bill- 
roth's  malignant  lymphoma.  Mediastinal  Hodgkin's  disease  furnishes  a 
large  proportion  of  the  cases  terminating  in  sarcoma.  The  spleen  and  bone- 


374  NEOPLASTIC  DISEASES 

marrow  are  commonly  involved,  but  the  more  malignant  the  growth,  the  less 
extensive  is  its  distribution.  Metastatic  growths  of  considerable  extent  are 
found  in  the  liver  or  lung.  In  Welch's  case  there  was  a  metastatic  tumor  of 
the  spinal  dura  causing  paraplegia.  On  section  the  tumors  are  soft  and  of 
peculiar  brownish-yellow  tint,  or  more  often  firmer,  fibrous,  and  opaque. 

The  structure  varies  from  a  close  counterpart  of  Hodgkin's  granuloma 
to  a  tissue  composed  exclusively  of  large  round  cells  with  faintly  staining 
granular  cytoplasm  and  moderately  chromatic  vesicular  nuclei.  Large, 
round  giant  cells  with  multiple  or  multilobed  nuclei  may  predominate.  The 
proportion  of  lymphocytes  may  be  considerable,  as  in  Karsner's  case,  but 
in  more  definite  neoplastic  processes  these  cells  are  missing.  The  structure 
may  not  be  uniform  in  all  the  lesions  nor  at  all  periods.  The  cells  are  not 
lymphocytes,  but  derivatives  of  the  reticulum  cells.  That  a  true  lympho- 
sarcoma  composed  of  neoplastic  lymphocytes  may  develop  in  Hodgkin's 
disease  has  not  been  demonstrated.  The  original  process  does  not  tend  to 
stimulate  the  growth  of  lymphocytes. 

That  the  sarcomatous  structure  represents  a  terminal  stage  of  Hodgkin's 
disease  is  strongly  indicated  by  the  observations  of  Yamasaki,  Karsner,  and 
others,  and  has  been  clearly  shown  in  Welch's  case.  Here  a  cervical  node 
removed  6  months  before  death  showed  Hodgkin's  granuloma,  while  the 
tumors  removed  at  autopsy  from  neck,  dura  mater,  liver,  and  lung  showed 
replacement  of  lymphocytes,  chiefly  by  large  round  cells  resembling  sarcoma. 

Cases  of  this  type  are  by  no  means  uncommon.  Many  cases  described 
in  the  literature  as  lymphosarcoma  are  probably  of  this  nature.  Several 
have  been  observed  in  this  laboratory,  including  Welch's.  From  a  com- 
parison of  their  very  characteristic  structure  with  that  of  certain  malignant 
lymphomas  I  am  led  to  believe  that  localized  tumors  of  lymph-nodes  of  this 
same  origin  are  relatively  common. 

The  exact  position  of  this  form  of  sarcoma  it  is  difficult  to  determine. 
Its  clinical  malignancy  may  depend  on  the  dissemination  of  an  infectious 
agent  or  its  toxins,  and  the  local  recurrences  are  probably  recrudescences  in 
new  lymphoid  structures.  Yet  the  metastatic  growths  in  dura  and  lung 
and  the  changes  in  the  type  of  the  cells  demonstrate  that  it  is  a  malignant 
tumor. 

The  histological  signs  of  malignancy  are  not  very  pronounced.  The  per- 
foration of  capsules  of  nodes  is  slow,  and  liver  tissue  seems  to  be  passively 
displaced.  A  large  mediastinal  tumor  I  found  still  well  encapsulated  and  an 
ulce ration  of  a  bronchus  appeared  to  be  mechanical.  The  nuclei  of  the  chief 
round  cells  are  uniform  and  only  slightly  hyperchromatic.  The  tendency 
to  fibrosis  is  marked.  Hence  Hodgkin's  sarcoma  differs  distinctly  from  true 
lymphosarcoma,  in  the  type  of  cells,  in  its  slight  invasive  power,  and  in  its 
origin.  Since  Hodgkin's  sarcoma  is  established  by  increasing  proliferation 
of  cells  incited  by  an  inflammatory  agent  there  must  be  transitional  stages  of 
the  change,  and  it  becomes  a  difficult  matter  to  decide  when  certain  lesions 
should  be  classed  with  the  granuloma  and  when  with  sarcoma.  This  diffi- 
culty has  long  disturbed  the  surgeon,  and  it  appears  throughout  the  case 
reports  of  Hodgkin's  disease  collected  by  Ziegler.  I  believe  that  clinical  data 
are  inadequate  in  this  field  and  that  the  microscopical  evidence  of  complete 
predominance  of  one  atypical  cell,  and  usually  the  presence  of  metastases, 
should  be  secured  before  the  diagnosis  of  sarcoma  is  made.  Hodgkin's  sarcoma 
is  therefore  unique  among  tumor  processes  and  a  disease  sui  generis.  It 
illustrates  in  the  same  patient  and  in  its  various  gradations  as  a  primary 
tumor,  the  transformation  of  an  infectious  granuloma  into  a  true  neoplasm. 
It  demonstrates  the  relation  of  a  tumor  to  the  presence  of  a  microorganism 


LYMPHOMA  AND  LYMPHOSARCOMA  375 

or  its  toxins.  Its  malignancy  is  apparently  founded  upon  peculiar  features, 
rather  less  upon  cellular  anaplasia  than  upon  the  association  with  a  toxic 
agent  which  is  readily  disseminated  and  seems  to  prepare  the  soil  for  its  sub- 
sequent changes. 

Since  the  etiology  of  Hodgkin's  disease  is  not  determined,  one  is  reduced 
to  speculation  regarding  the  mode  of  dependence  of  the  tumor  process  upon 
the  irritant.  It  seems  reasonable  to  suggest  that  this  condition  is  analogous 
to  the  epithelioma  arising  upon  lupus  or  syphilis  and  to  assume  that  the 
microorganism  is  present  only  in  early  stages,  and  that  the  tumor  process, 
established  indirectly,  progresses  of  its  own  momentum  and  apart  from  the 
parasite. 

In  a  recent  study  of  thymus  tumors  I  have  collected  evidence  suggesting 
that  many  of  the  cases  of  Hodgkin's  disease  exhibiting  sarcomatous  qualities 
originate  in  the  thymus,  and  that  the  peculiar  characters  of  the  infiltrating 
cells  are  referable  to  their  origin  from  the  epithelial  reticulum  cells  of  the 
thymus. 

Etiology  of  Hodgkin's  Granuloma. — The  cause  of  Hodgkin's  disease  still 
remains  imperfectly  determined,  the  majority  of  writers  holding  that  it  is 
not  tuberculous.  The  evidence  supporting  this  position  consists  in  the  usual 
absence  of  tubercle  bacilli  in  sections,  the  negative  results  of  inoculation, 
and  the  specific  structure.  Karsner  holds  that  the  tuberculous  lesion  resem- 
bling Hodgkin's  may  be  distinguished  by  somewhat  minute  characters  of  the 
giant-cells.  Sternberg,  who  originally  described  the  condition  as  a  peculiar 
form  of  tuberculosis,  has  partly  modified  his  position  and  is  inclined  to  admit 
the  existence  of  a  non-tuberculous  Hodgkin's  granuloma. 

The  evidence  in  favor  of  the  tuberculous  origin  is  nevertheless  somewhat 
formidable. 

In  the  material  as  gathered  in  New  York  where  the  disease  is  very  common 
tuberculosis  follows  Hodgkin's  disease  like  a  shadow.  Tuberculous  stigmata 
or  tuberculous  family  history  or  tuberculous  lesions  in  the  body  are  the  rule. 
In  a  case  of  phthisis  I  was  much  impressed  by  finding  in  three  small  adjoining 
bronchial  nodes  miliary  tubercles  in  one,  diffuse  lymphocytes  in  another,  and 
typical  Hodgkin's  granuloma  in  the  third.  The  association  of  local  or  wide- 
spread tuberculous  lesions  with  Hodgkin's  granuloma  is  frequently  observed. 
According  to  Ziegler  about  20  per  cent,  of  the  cases  show  tuberculous  lesions 
in  the  organs,  and  in  10  to  12  per  cent,  tubercle  bacilli  have  been  demonstrated 
by  inoculation.  Acute  miliary  tuberculosis  often  terminates  the  disease. 

The  idea  of  a  mixed  infection  coextensive  with  such  wide-spread  lesions 
is  a  strained  hypothesis.  An  examination  of  the  protocols  of  many  inocu- 
lation tests  shows  that  they  were  carried  out  in  a  perfunctory  or  incompetent 
manner.  Some  observers  used  rabbits.  Others  employed  small  quantities  of 
single  nodes  in  single  guinea-pigs.  In  this  laboratory  4  cases  of  Hodgkin's 
disease  have  infected  guinea-pigs  with  tubercle  after  a  period  of  9  months 
to  i  year.  Yet  Longcope  failed  to  infect  monkeys,  and  I  have  had  negative 
results  in  this  animal  with  fresh  emulsions  and  concentrated  antiformin 
sediment.  While  the  stainable  bacilli  are  usually  missing,  yet  Sternberg 
found  them  in  many  cases.  I  have  never  found  them  numerous,  but  after 
prolonged  search  have  occasionally  detected  scanty  acid-fast  rods.  It  is 
clear  that  acid-fast  tubercle  bacilli  are  practically  absent  in  these  tissues. 
Yet  they  are  regularly  absent  in  many  known  tuberculous  lymphomas. 
Much's  claim  that  a  granular  form  of  the  tubercle  bacillus  exists  in  many 
lesions  demands  attention  in  this  field.  Fraenkel  and  Much  claim  to  find 
many  of  the  granules  in  the  antiformin  sediment  of  Hodgkin's  nodes  and  in 
sections  of  the  bone-marrow  stained  by  itensified  Gram.  O.  Meyer  found 


376  NEOPLASTIC  DISEASES 

them  in  8  of  9  cases,  the  remaining  case  giving  tubercle  bacilli.  I  have  found 
these  granules,  but  am  not  convinced  of  their  tuberculous  nature.  Long 
ago  Arrigo  found  slightly  acid-fast  tubercle  bacilli  and  granules  in  old  tubercu- 
lous nodes.  Such  granules  are  regularly  present  in  Hodgkin's  disease,  but 
again  their  nature  appears  uncertain.  Sticker  states  that  tubercle  bacilli, 
probably  bovine,  may  be  demonstrated  in  Hodgkin's  granuloma  by  repeated 
passage  of  material  through  guinea-pigs. 

All  of  these  data  seem  to  me  to  require  further  consideration  of  the  tuber- 
culous theory  of  Hodgkin's  disease.  Yet  before  this  view  can  be 'accepted 
several  deficiencies  in  the  evidence  must  be  supplied.  Especially  the  absence 
of  stainable  bacilli,  and  the  negative  results  of  inoculation  must  be  satis- 
factorily explained.  Besides  the  tubercle  bacillus,  some  other  microorganisms, 
including  the  sporothrix  of  Beurmann,  and  the  oidia  seem  to  deserve  con- 
sideration. Pick  claims  to  have  found  Hodgkin's  granuloma  in  the  nodes 
of  a  case  of  prolonged  staphylococcus  infection,  and  Mosler  found  a  very 
similar  structure  in  leprosy.  Several  cases  have  occurred  in  active  syphilitic 
subjects  (Fabian,  Lit.).  Syphilitic  lymphoma  may  clinically  simulate  Hodg- 
kin's disease,  but  it  regresses  promptly  under  iodids  and  it  has  not  been  shown 
that  syphilis  can  produce  the  characteristic  structure  of  Hodgkin's  granuloma. 

Recent  studies  by  Bunting  and  Yates  have  centered  attention  on  the 
diphtheroid  bacilli  of  Hodgkin's  disease.  These  microorganisms  are  very 
frequently  but  not  constantly  to  be  isolated  from  Hodgkin's  lymph-nodes, 
but  they  are  present  in  many  other  diseases  and  their  pathogenic  powers  in 
monkeys  are  unsatisfactory.  Torrey  reports  the  isolation  of  five  different 
varieties,  aerobic  and  anaerobic,  of  diphtheroids  from  Hodgkin's  as  well  as 
some  other  diseased  lymph-nodes.  He  describes  the  constant  presence  of  a 
very  minute  anaerobic  bacillus  in  the  nodes,  but  its  pathogenic  properties 
are  feeble.  Bloomfield  has  also  identified  this  same  minute  anaerobic  bacillus. 

SYSTEMIC  ALEUKEMIC  LYMPHOMATOSIS.    TRUE  PSEUDOLEUKEMIA 

The  observation  of  Cohnheim  that  the  anatomical  picture  of  leukemia 
may  occur  without  leukemic  blood  changes  is  constantly  being  verified, 
While  it  may  very  well  be  that  the  blood  changes  are  of  secondary  importance 
and  that  their  absence  does  not  call  for  the  separation  of  this  form  of  pseudo- 
leukemia  from  leukemia,  nevertheless  the  enormous  increase  of  leukocytes 
in  leukemia  forms  a  very  notable  morphological  feature  of  this  disease,  and 
one  which  may  prove  to  be  of  fundamental  importance.  Moreover,  the  pseudo- 
leukemic  counterparts  of  leukemia  present  some  other  peculiarities  not  ob- 
served with  leukemia,  so  that,  adhering  to  the  morphological  criteria  on 
which  we  are  chiefly  dependent,  there  seem  to  be  certain  grounds  for  recog- 
nizing a  somewhat  separate,  although  closely  related  position  of  this  group 
of  cases. 

The  general  features  of  aleukemic  lymphomatosis  have  been  clearly  stated 
by  Wunderlich:  "There  is  a  peculiar  disease,  pseudoleukemia,  which  is  chiefly 
characterized  by  a  gradual  development  of  very  numerous  and  sometimes 
very  large  swellings  of  superficial  and  internal  lymph-nodes,  and  by  peculiar 
deposits  in  the  internal  organs,  especially  in  the  spleen,  also  in  liver,  less 
often  in  kidneys,  gastro-intestinal  lymphatic  system,  lungs,  pharynx,  and 
elsewhere." 

Histologically  these  wide-spread  lesions  have  been  found  to  consist  in  hy- 
perplasia  of  lymphocytes,  so  that  this  form  of  pseudoleukemia  is  the  counter- 
part of  the  lymphatic  type  of  leukemia. 

Uniform  microscopical  distinctions  between  the  pseudoleukemic  and  the 


LYMPHOMA  AND  LYMPHOSARCOMA 


377 


V 


leukemic  process  have  not  been  demonstrated.  There  is  the  same  oblitera- 
tion of  sinuses  and  follicles,  the  respect  for  capsules,  the  wide  diffusion  of  the 
process,  the  tendency  to  fibrosis,  and  the  exclusive  participation  of  lympho- 
cytes, as  in  leukemia.  Baumgarten  found  that  the  leukemic  nodes  permit 
the  passage  of  injection  fluids,  while  the  pseudoleukemic  do  not. 

The  blood  shows  a  relative  lymphocytosis,  and  Ehrlich  and  Pincus  find 
that  a  slight  absolute  increase  of  lymphocytes  is  characteristic  of  pseudo- 
leukemia,  _  but  this  condition  is  inconstant.  The  anemia  is  less  severe  than 
in  lymphemia.  The  persistent  lymphocytosis  and  low  proportion  of  neutro- 
phile  and  eosinophile  cells  distinguish  pseudoleukemia  from  lymphogranuloma. 

There  are  also  certain  clinical  and 
anatomical  features  which  frequently 
separate  pseudoleukemia  from  leuke- 
mia. Acute  forms  of  pseudoleukemia 
are  very  rare,  most  of  the  rapidly 
fatal  lymphoid  hyperplasias  without 
leukocytosis  proving  sarcomatous. 
Moritz's  cases  of  acute  pseudoleu- 
kemia bear  a  suspicious  resemblance 
to  typhoid  fever  which  may  give 
very  extensive  lymphoid  hyperplasia. 
As  a  rule  the  pseudoleukemic  tumors 
of  lymph-nodes  are  larger  than  the 
leukemic,  and  the  invasions  of  organs 
while  not  destructive  are  more  cir- 
cumscribed and  tend  to  reach  a  large 
size.  The  confluence  of  hyperplastic 
lymph-follicles  in  nodes  and  spleen  I 
find  more  frequently  than  in  lymph- 
emia. The  exclusive  presence  of 
typical  normal  lymphocytes  is  per- 
haps more  uniform  in  pseudoleuke- 
mia. In  the  pseudoleukemic  pro- 
cesses in  the  dog  and  fowl  these 
distinctions  are  often  quite  pro- 
nounced. None  of  them  seems  to 
furnish  any  ground  for  assuming  that 
the  processes  are  essentially  different. 

The  necessity  of  recognizing  clinical  subvarieties  of  this  form  of  pseudo- 
leukemia  is  not  urgent.  A  pure  lymphoid  splenic  pseudoleukemia  with  dif- 
fuse hyperplasia  of  lymphocytes  I  do  not  find  in  the  literature.  Pappenheim, 
who  recognizes  splenic  pseudoleukemia,  states  that  the  group  is  heterogeneous 
and  imperfectly  studied.  Of  the  many  forms  of  splenomegaly  none  shows 
lymphoid  hyperplasia.  French  writers  recognize  a  cutaneous  pseudoleu- 
kemia (Jaccoud),  but  these  cases  seem  to  fall  rather  with  lymphosarcoma. 
Medullary  lesions  of  general  pseudoleukemia  are  often  pronounced  and  con- 
sist of  focal  or  diffuse  lymphoid  hyperplasia.  That  a  primary  or  predominant 
medullary  pseudoleukemia  exists  remains  doubtful.  The  custom  once  com- 
mon of  interpreting  the  marrow  lesions  of  certain  cases  of  pernicious  anemia 
as  medullary  pseudoleukemia  terminated  with  Litten's  argument  in  1877. 
The  excess  of  lymphocytes  in  the  marrow  of  pernicious  anemia,  which  may 
sometimes  approach  a  leukemic  picture,  is  probably  a  secondary  condition 
and  is  not  comparable  to  a  primary  pseudoleukemia  (cf.  Bloch  and  Hirsch- 
feld).  More  recently  a  few  cases  of  apparently  pure  and  primary  lymphoid 


FIG.  148. — Ileum  in  diffuse  gastro- 
intestinal lymphomatosis,  showing  en- 
larged solitary  follicles  and  Peyer's 
patches. 


378 


NEOPLASTIC  DISEASES 


hyperplasia  of  the  bone-marrow  have  been  described.  In  the  cases  of  Baum- 
garten  and  Rubinstein  this  process  was  associated  with  extensive  osteo- 
sclerosis  and  in  one  there  were  also  lymphomas  of  liver  and  dura  mater.  Noth- 
nagel's  "lymphadenia  ossium"  probably  belongs  in  this  group.  In  a  case 
of  severe  pernicious  anemia  of  acute  aplastic  type  Senator  found  diffuse 
lymphoid  hyperplasia  of  the  marrow.  He  interpreted  the  condition  as  medul- 
lary pseudoleukemia.  A  similar  observation  is  recorded  by  Domarus. 

The  exact  relation  of  these  cases  to  other  forms  of  pseudoleukemia  is 
uncertain.  Senator  has  collected  a  series  of  cases  in  which  the  marrow  showed 
active  lymphoid  hyperplasia  and  which,  he  thinks,  indicates  a  relation  be- 
tween pernicious  anemia,  leukanemia,  lymphemia,  and  pseudoleukemia. 


FIG.  149. — Pseudoleukemia.  Anatomically,  gastro-intestinal,  mediastinal,  and 
cervical  lymphomatosis.  Structurally,  lymphadenoma.  Section  of  spleen  showing 
lymph-follicles  in  pulp  and  sinus. 

The  identity  of  this  apparently  secondary  tissue  lymphocytosis  with  the  true 
pseudoleukemic  process  appears  doubtful  (cf.  Hirschfeld). 

Gastro-intestinal  Pseudoleukemia. — The  gastro-intestinal  tract  is  the 
seat  of  a  remarkable  form  of  primary  lymphoid  hyperplasia  which  lacks 
the  destructive  character  of  lymphosarcoma  and  fails  to  give  lymphocytosis 
in  the  blood.  The  process  may  be  chiefly  limited  to  a  portion  or  involve  the 
whole  of  the  gastro-intestinal  tract,  or  it  may  be  associated  with  wide-spread 
lesions  of  most  other  lymphoid  structures. 

The  disease  was  first  mentioned  by  Briquet  in  1835,  was  fully  described 
by  Stoerk,  and  Symmers  collected  10  cases  from  the  literature.  The  first 
symptoms  may  be  enlargement  of  cervical  nodes,  or  gastro-intestinal  irritation 
with  persistent  diarrhea. 


LYMPHOMA  AND  LYMPHOSARCOMA  379 

In  Symmer's  case,  studied  in  this  laboratory,  the  extent  of  the  lymphoid 
growth  was  enormous.  The  entire  gastro-intestinal  tract  from  cardia  to 
anus  was  the  seat  of  myriads  of  discrete  pea-sized  nodules  projecting  into  the 
lumen.  Peyer's  patches  were  represented  by  flat  polypoid  tumors.  In  the 
stomach  the  lesion  was  diffuse  and  this  organ  was  greatly  thickened  and 
enlarged.  Cervical,  mediastinal,  retroperitoneal,  and  other  chains  of  nodes 
were  much  enlarged  or  formed  compact  masses  of  nodes  of  which  the  outlines 
were  still  preserved.  The  spleen  was  much  enlarged,  and  the  bone-marrow 
diffusely  affected.  There  was  general  peritonitis  without  demonstrable  origin. 
The  structure  of  the  lesions  was  peculiar,  consisting  of  extensive  multipli- 
cation of  lymphoid  follicles  which  became  greatly  enlarged  and  eventually 
fused,  a  true  lymphadenoma.  Yet  the  cells  in  the  centers  of  these  aggre- 
gations of  follicles  were  medium-sized  lymphocytes.  Mitoses  were  missing. 
The  process  showed  no  capacity  to  invade  resisting  structures.  The  changes 
were  more  localized  in  the  gastro-intestinal  tract  and  the  pylorus  was  partly 
occluded  in  the  case  of  Wells  and  Mayer. 

Stoerk  observed  many  superficial  ulcers  and  peritonitis  from  perforation 
of  a  deep  ulcer.  He  found  considerable  variations  in  the  cell  types,  some 
foci  resembling  germ  centers  of  follicles.  In  one  of  his  cases  the  process  pene- 
trated the  wall  of  the  colon  and  invaded  pelvic  organs,  thus  exhibiting  a 
transition  to  sarcoma.  Ulceration  of  Peyer's  patches  may  partly  simulate 
the  lesions  of  typhoid  fever. 

The  etiology  of  this  remarkable  condition  is  quite  obscure.  The  chief 
location  of  the  process  suggests  the  action  of  a  diffusible  irritant  of  intestinal 
origin,  but  the  cervical  nodes  may  be  involved  very  early.  Tuberculosis 
was  present  in  one  of  Stoerk's  cases,  and  in  Glinski's  case,  limited  chiefly 
to  the  colon,  there  was  advanced  pulmonary  tuberculosis  and  foci  of  necrosis 
with  giant-cells  in  the  mesenteric  nodes.  The  process  illustrates  the  most 
extreme  degree  of  orderly  proliferation  of  lymphocytes,  which  seems  to  occupy 
the  position  of  a  relatively  benign  neoplasm.  The  occasional  appearance 
of  infiltrating  properties  illustrates  the  transition  to  and  the  sharp  distinction 
from  lymphosarcoma.  Flexner  describes  2  cases  which  seem  to  belong  in 
this  intermediate  field.  This  form  of  pseudoleukemia  is  never  followed  by 
leukemia. 

Myeloid  Pseudoleukemia. — That  the  spleen,  lymph-nodes,  and  marrow 
may  be  the  seat  of  an  extensive  myeloidization,  as  the  result  of  blood  destruc- 
tion and  regeneration  in  many  forms  of  infection,  has  recently  been  shown  by 
numerous  observers.  The  absence  of  leukocytosis  places  this  condition  in 
the  light  of  a  myeloid  pseudoleukemia.  Apart  from  these  infectious  diseases 
and  their  immediate  sequels  the  existence  of  chronic  myeloidization  of  the 
organs  is  imperfectly  established.  Sternberg,  however,  refers  to  cases  of 
general  myeloid  transformation  of  the  spleen  and  lymph-nodes  without 
leukemic  blood  changes.  In  certain  cases  of  splenomegaly  with  anemia  the 
splenic  changes  approach  the  type  of  chronic  myeloidization.  It  is  possible 
to  interpret  the  "anemia  infantum"  of  v.  Jaksch  as  a  chronic  myeloid  pseudo- 
leukemia. 

Certain  multiple  myelomas,  especially  those  composed  of  plasma-cells, 
have  been  compared  with  medullary  pseudoleukemia,  writh  the  chief  result 
of  emphasizing  their  sharp  morphological  distinctions.  The  transformation 
of  pseudoleukemia  into  lymphatic  leukemia  has  been  described  in  a  consider- 
able series  of  cases,  thereby  establishing  a  close  relation  between  these  processes. 

Not  all  of  these  cases  withstand  critical  analysis,  as  I  have  elsewhere 
noted,  but  some  of  them  appear  to  be  genuine.  As  a  rule  the  leukemic  blood 
changes  appear  a  short  period  before  the  termination  of  the  disease,  and 


380  NEOPLASTIC  DISEASES 

persist.  Or  the  leukocytosis  may  diminish  shortly  before  death.  Turk  ob- 
served intermittent  leukemic  changes  in  the  blood  of  pseudoleukemia.  On 
the  part  of  leukemia  approach  to  a  pseudoleukemic  condition  is  exhibited 
by  those  cases  in  which  there  is  a  temporary  decline  in  the  leukocytosis. 
That  the  histological  structure  of  the  lesions  in  the  two  conditions  cannot 
be  sharply  separated  has  already  been  pointed  out.  Klein  and  Turk  have 
especially  emphasized  the  close  parallel  between  leukemic  and  aleukemic 
lymphoma  and  lymphosarcoma.  All  of  these  features  point  to  the  conclusion 
that  leukemia  and  pseudoleukemia  are  essentially  the  same  disease  (Turk, 
Klein). 

On  the  other  hand,  it  is  clear  that  the  great  majority  of  cases  of  pseudo- 
leukemia  never  show  any  tendency  to  develop  leukemia.  The  transforma- 
tions which  are  exclusively  of  the  lymphatic  type  do  not  reproduce  the  typical 
picture  of  chronic  lymphemia,  but  the  leukocytosis  is  a  terminal,  or  ante- 
mortem,  or  transitory  condition.  It  does  not  reach  the  extreme  degree  of 
typical  lymphemia,  but  recalls  the  leukocytosis  of  certain  malignant  tumors. 
There  are  some  minor  anatomical  distinctions  between  leukemic  and  aleukemic 
lymphomas  and  some  of  the  latter  never  run  into  leukemia.  Hence  there 
are  many  considerations  which  favor  the  view,  emphasized  especially  by 
Pincus,  that  leukemia  and  pseudoleukemia  are  not  different  stages  of  the 
same  disease.  Until  they  are  connected  by  an  etiological  factor  there  seems 
to  the  writer  little  advantage  in  merging  the  two  conditions. 

LYMPHOSARCOMA 

A  true  malignant  neoplasm  arising  in  lymphatic  tissue  from  proliferation 
of  atypical  lymphocytes  occurs  as  a  (i)  localized  or  a  (2)  diffuse  process. 
The  former  is  more  malignant  than  the  latter,  but  its  rapid  course,  as  well 
as  the  occurrence  of  intermediate  types  of  cases,  indicate  that  there  is  no 
other  important  distinction  between  them. 

Lymphosarcoma,  formerly  included  with  pseudoleukemia,  secured  an 
independent  position  chiefly  through  the  studies  of  Kundrat  and  Paltauf, 
who  recognized  very  notable  gross  and  microscopical  distinctions  between 
this  process  and  other  aleukemic  lymphomas.  From  the  surgical  side  Bill- 
roth  especially  found  it  necessary  to  recognize  under  the  term  "malignant 
lymphoma"  locally  destructive  and  recurring  tumors  of  lymph-nodes,  but  he 
could  not  separate  the  different  types  of  such  processes. 

Kundrat  described  lymphosarcoma  as  a  tumor  arising  only  from  groups 
of  lymph-nodes,  not  from  single  nodes,  and  from  adenoid  tissue  of  mucous 
membranes,  from  which  points  it  extended  to  neighboring  nodes  and  the 
surrounding  tissue,  or  along  the  submucous  tissue.  The  systemic  character 
of  leukemia  and  pseudoleukemia  was  missing,  and  the  spleen,  marrow,  and 
liver  were  rarely  involved.  Secondary  tumors  occurred  almost  exclusively 
in  the  intestinal  mucosa,  serous  membranes,  and  lymph-nodes,  and  were 
joined  by  continuous  growth  through  lymph-channels,  two  features  dis- 
tinguishing this  process  from  true  metastatic  cancer.  Robust  males  between 
the  ages  of  25  to  55  were  chiefly  attacked,  and  a  tuberculous  history  was  rare. 
Structurally  the  tumor  was  composed  of  lymphoid  cells  of  variable  size  lying 
in  an  atypical  reticular  tissue.  Cellular  and  fibrous  stages  of  the  process 
could  be  distinguished,  but  necrosis  was  rare. 

Kundrat  separated  this  process  from  the  true  neoplasms  on  the  ground 
that  it  was  not  a  spontaneous  growth  of  multiple  origin  and  with  extensions 
by  metastasis,  but  a  regional  disease  of  lymphoid  tissues  which  propagated 
itself  through  the  lymph  paths.  Yet  it  was  one  of  the  most  malignant  of 


LYMPHOMA  AND  LYMPHOSARCOMA  381 

diseases,  resisting  attempts  to  extirpation,  and  proving  a  veritable  "noli- 
me-ta'ngere."  It  was  more  closely  related  to  pseudoleukemia  and  "granuloma 
malignum,"  from  both  of  which  he  had  observed  the  development  of  lympho- 
sarcoma. 

The  picture  drawn  by  Kundrat  is  now  generally  accepted  as  depicting 
a  specific  group  of  cases  which  require  separation  from  other  lymphoid  tumors. 
The  extension  of  the  process  solely  by  permeation  of  lymphatics  is  probably 
not  invariable,  but  in  other  details  his  criteria  may  be  followed  rigidly  in 
diagnosis. 

Anatomical  and  Clinical  Features. — Lymphosarcoma  is  distinguished 
from  other  forms  of  lymphoma  by  its  local  destructive  capacity  and  by  the 
formation  of  true  metastases  in  distant  organs. 

The  tumors  arise  in  a  chain  of  lymph-nodes  or  in  a  localized  lymphatic 
structure,  and  rapidly  produce  bulky  growths  which  obliterate  the  outlines 


FIG.  150. — Lymphosarcoma  of  cervical  lymph-nodes. 

of  the  separate  nodes,  infiltrate  surrounding  tissues,  and  tend  to  result  in 
necrosis  and  ulceration  of  skin  and  mucous  membrane.  The  more  rapid 
cases  are  fatal  while  the  growth  is  chiefly  local,  but  wide-spread  extensions 
and  metastases  are  commonly  observed.  Fever  is  often  a  prominent  symptom, 
but  anemia  and  cachexia  may  not  appear  until  toward  the  end  of  the  disease. 
In  comparing  cases  of  lymphosarcoma  with  those  suffering  from  Hodgkin's 
disease  it  may  often  be  noted  that  the  former  do  not  appear  to  be  very  ill 
until  shortly  before  death,  while  the  typical  Hodgkin's  case  is  feeble,  emaciated, 
and  cachectic  for  a  long  period.  Leukocytosis  is  usually  present,  and  may 
be  so  marked  as  to  suggest  leukemia  (Sadler).  The  excess  is  usually  of  poly- 
nuclear  cells  (Grawitz),  occasionally  of  lymphocytes  (Turk),  rarely  of  eosinp- 
phile  cells  (Reinbach).  Atypical  cells  found  in  the  tumor  may  also  appear  in 
the  blood  and  in  such  numbers  as  to  suggest  leukemia  (Martin-Matthewson, 
Warthin).  In  fact,  the  distinctions  between  lymphosarcoma  and  leukemia 
cannot  always  be  sharply  drawn  (cf.  Leukosarcomatosis) . 


382 


NEOPLASTIC  DISEASES 


Extension  of  the  process  in  the  earlier  stages  appears  to  be  exclusively 
by  way  of  the  lymphatics,  as  stated  by  Kundrat,  but  in  many  advanced  cases 
true  metastatic  growths  form  in  the  lungs,  brain,  kidneys,  skin,  and  other 
organs,  which  are  satisfactorily  explained  only  by  invasion  of  the  blood-vessels. 

The  duration  of  the  disease  varies  widely.  Birch-Hirschfeld  observed 
an  intestinal  case  following  typhoid  fever  which  was  fatal  in  6  weeks.  Kauf- 
mann  refers  to  a  mediastinal  tumor  which  caused  suffocation  after  3  months. 
Libmann's  cases  resembling  appendicitis  were  very  rapidly  fatal.  The  usual 
course  is  progressive  and  fatal  within  a  few  months.  Wide  extensions  are 
observed  chiefly  with  more  prolonged  course.  After  local  treatment,  extirpa- 
tion, internal  use  of  arsenic,  or  application  of  x-ray,  the  disease  has  often 
appeared  to  be  arrested  only  to  recur  after  a  brief  period.  Yet  not  a  few 
cases  have  been  reported  as  cured  (Chiari,  Lit.).  The  true  nature  of  some 
of  these  older  cases  is  uncertain,  but  Ruff  has  collected  a  series  of  more  recent 
reports  illustrating  the  regression  of  lymphosarcoma  after  infectious  diseases, 


FIG.  151. — Reticulum  in  a  lymphosarcoma.    Tannin-silver  stain.     (After  Hulisch.) 

and  irradiation.  Koscher  reports  regression  of  a  tonsillar  growth  after  removal 
of  a  portion  of  tissue  for  diagnosis,  followed  by  a  recurrence  in  abdomen. 
Longcope  reports  the  complete  spontaneous  disappearance  of  extensive 
lymphosarcomatous  tumors  followed  by  death  of  the  patient  from  asthenia. 

The  structure  of  lymphosarcoma  is  rather  specific.  It  presents  a  diffuse 
growth  of  lymphoid  cells  lying  in  reticular  tissue.  The  structure  of  the 
affected  node  or  follicle  is  obliterated.  The  cells  I  find  to  vary  in  size,  being 
small,  medium,  or  large.  The  nuclei  are  compact  or  vesicular,  always  hyper- 
chromatic,  and  nucleoli  are  not  prominent.  Giant-cells  do  not  belong  to 
this  process,  but  large  multinuclear  cells  are  occasionally  seen. 

In  the  origin  of  lymphosarcoma  two  specific  cells  participate,  giving  rise 
to  two  specific  forms  of  the  tumor.  These  cells  are:  (i)  the  reticulum  cell 
of  the  germ  centers  of  follicles  and  pulp  cords,  and  (2)  the  lymphocyte.  Thus 
arise  two  types  of  lymphosarcoma  which  may  be  designated  as 

1.  Reticulum  cell  sarcoma,  or  large  round-cell  lymphosarcoma. 

2.  Malignant  lymphocytoma. 


LYMPHOMA  AND  LYMPHOSARCOMA  383 

It  may  sometimes  be  possible  to  establish  these  two  histological  varieties 
as  separate  diseases.  In  the  great  majority  of  cases  they  retain  permanently 
their  separate  identity,  and  they  appear  to  arise  under  different  clinical  con- 
ditions and  from  different  causative  factors.  But  until  the  relation  of  the 
lymphocyte  to  the  reticulum  cell  is  fully  established  the  two  conditions  may 
be  discussed  together. 

The  reticulum  of  the  tumor  is  irregularly  distributed,  being  deficient  in 
places,  and  thickened  in  areas  tending  toward  fibrosis.  Kaufmann  and  Ribbert 
recommend  washing  out  the  cells  for  its  demonstration. 

The  pure  lymphoid  type  of  structure  is  not  always  present.  In  certain 
cases  there  is  an  admixture  of  plasma-cells,  eosinophile  cells,  and  normal 
lymphocytes,  which  may  signify  a  secondary  inflammatory  process  (cf.  Kanter). 
When  these  features  of  an  infectious  granuloma  are  pronounced  the  diagnosis 
of  lymphosarcoma  must  remain  uncertain. 


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FIG.  152. — Lymphosarcoma.     Reticulum-cell  sarcoma  of  lymph-nodes. 

Regressive  changes  in  lymphosarcoma  are  rare,  but  the  occlusion  of  vessels 
in  bulky  growths  may  lead  to  extensive  necrosis,  while  superficial  ulceration 
is  common. 

The  local  aggressive  quality  of  the  process  is  a  notable  feature.  The 
capsules  of  nodes,  muscle  tissue,  and  periosteum  are  readily  penetrated  and 
destroyed.  The  adventitia  of  large  blood-vessels  is  invaded,  but  the  media 
resists. 

The  primary  lesions  of  lymphosarcoma  in  mucous  membranes  usually 
begin  with  swelling  of  many  lymph-nodules,  followed  by  ulceration  and  widen- 
ing of  the  lumen,  while  secondary  invasions,  as  of  pharynx  and  intestine,  are 
diffuse  and  may  cause  constriction. 

The  histolog  ical  characters  of  the  process,  together  with  its  gross  anatomy 


384 


NEOPLASTIC  DISEASES 


usually  separate  typical  cases  of  lymphosarcoma  from  pseudoleukemia, 
leukemia,  and  Hodgkin's  granuloma,  and  from  other  tumors  of  lymph-nodes. 
Yet  since  some  of  the  above  conditions  may  occasionally  give  rise  to  lympho- 
sarcoma it  is  impossible  always  to  distinguish  between  them  without  very 
full  clinical  data.  Pseudoleukemia  and  lymphatic  leukemia  are  lympho- 
cytomas;  in  myelocytic  leukemia  the  cells  resemble  those  of  lymphosarcoma, 
but  are  more  evenly  distributed,  less  atypical,  and  the  process  is  less  aggres- 
sive. Any  group  of  lymph-nodes  or  any  lymphoid  structure  may  be  the 
primary  seat  of  lymphosarcoma,  but  the  tumors  of  spleen  and  bone-marrow 
differ  in  many  respects  from  those  of  lymph-nodes  and  are  separately  con- 
sidered. In  systemic  lymphosarcoma  the  spleen  is  usually  enlarged  by  a 
moderate  overgrowth  of  follicles  and  pulp  cells,  and  occasionally  by  metastases. 


FIG.  153. — Beginning  reticulum-cell  sarcoma  of  lymph-nodes.     Proliferation  of  reticu- 
lum  cells  in  centers  of  three  follicles. 

Harbitz  and  Wieland  describe  primary  myelogenous  lymphosarcoma,  but  the 
exact  nature  of  their  cases  is  uncertain  and  their  separation  from  myeloma 
appears  impossible.  In  the  discussion  of  myeloma  the  writer  has  pictured 
a  case  of  diffuse  lymphocytic  myeloma  of  humerus  which  eventually  proved 
fatal  with  systemic  lesions  (Figs.  103, 104). 

Of  lymphatic  lymphosarcoma  several  well-defined  groups  may  be  recog- 
nized. 

Clinical  Subvarieties. — The  most  frequent  form  of  lymphosarcoma 
is  a  primary  affection  of  a  definite  chain  of  lymph-nodes  from  which  the 
disease  extends  to  other  chains  of  nodes,  and  often  to  the  spleen  and  other 
organs.  The  cervical,  mediastinal,  retroperitoneal,  and  mesenteric  nodes 
are  commonly  involved  and  in  the  order  named,  less  often  the  inguinal  and 
axillary. 


LYMPHOMA  AND  LYMPHOSARCOMA 


385 


With  the  cervical  nodes  the  lesion  may  invade  the  wall  of  the  pharynx, 
tonsils,  base  of  skull,  or  it  may  lead  to  extension  into  thorax  and  abdomen 
(Freudweiler).  With  the  mediastinal  type  the  bronchial  nodes  may  be  in- 
volved with  extensions  to  pericardium,  or  pleura  or  lung,  with  marked  pul- 
monary symptoms.  Schlagenhaufer  and  Kundrat  each  report  2  cases  of 
lymphosarcoma  of  bronchial  nodes  with  extensive  infiltration  of  esophagus. 
From  the  cervical,  mediastinal,  or  peritoneal  nodes  very  extensive  invasion 
of  the  pleura  and  peritoneum  may  occur,  in  the  form  of  diffuse  infiltration, 
globular  masses,  or  myriads  of  miliary  nodules  (Kundrat,  Martin). 

Most  of  the  mediastinal  lymphosarcomas  arise  from  the  thymus  and 
are  to  be  considered  as  varieties  of  thymoma  (q.  v.}. 

Primary  pharyngeal  lymphosarcoma  is  a  very  common  type,  and  the  fact 
that  with  the  cervical  forms  they  constitute  the  majority  of  the  cases,  sug- 
gests that  an  infectious  agent  commonly  enters  through  this  area  (Chiari, 
Lit.).  The  initial  symptom  is  swelling  of  lymphoid  tissue  and  diffuse  infiltra- 
tion of  mucosa  of  tonsillar  ring  or  pharyngeal  wall,  and  the  early  appearances 


FIG.  154. — Malignant  lymphocytoma  of  cervical  lymph-nodes. 

are  characteristic  (Kundrat).  According  to  Eisenmenger  the  process  regularly 
begins  in  the  pharyngeal  mucosa  and  not  in  the  tonsils.  Yet  in  several  cases 
at  the  Memorial  Hospital  the  disease  was  recognized  shortly  after  removal 
of  enlarged  tonsils.  In  a  fatal  case  with  gastro-intestinal  metastases  I  found 
the  original  ulcerative  lesion  of  the  sinus  laryngis  completely  healed.  Ulcera- 
tion  is  soon  established  and  remains  a  persistent  or  recurring  complication. 
The  process  extends  to  the  nares,  cervical  nodes,  base  of  skull  or  cranial 
cavity,  orbit,  larynx,  and  thereafter  in  the  usual  manner  to  internal  nodes, 
intestinal  wall,  and  other  organs.  Local  treatment,  extirpation,  and  internal 
use  of  arsenic  may  cause  marked  or  complete  regression  of  the  original  lesion, 
but  with  rare  exceptions  the  process  recurs. 

In  the  advanced  stages  the  tissues  of  pharynx,  face,  and  neck  may  be- 
come fused  in  a  bulky  infiltrating  tumor  which  compresses  the  vessels  without 
rupturing  into  them,  and  causes  marked  symptoms  from  involvement  of 
vessels,  nerves,  trachea,  and  special  sense  organs.  Many  cases  terminate 
without  notable  extension  to  other  regions. 

Lymphosarcoma  of  the  gastro-intestinal  tract  is  a  common  type.    The  seats 
of  election  are  the  stomach,  lower  ileum,  and  rectum. 
25 


386 


NEOPLASTIC  DISEASES 


The  literature  on  this  subject  presents  a  chaotic  picture  in  which  morpho- 
logical details  are  obscure  and  the  data  regarding  histogenesis  and  etiology 
are  imperfectly  presented.  From  the  reported  cases  it  is  necessary  to  exclude, 
first,  an  infectious  granuloma  which  is  probably  a  form  of  Hodgkin's  disease, 
but  in  which  the  structure  is  atypical,  characteristic  giant-cells  being  usually 
absent  (cf.  Haberer).  Diffuse  pseudoleukemia  must  also  be  excluded.  Some 
of  the  so-called  round-cell  sarcomas  of  the  stomach  are  probably  of  myogenic 
origin.  Finally,  it  must  be  noted  that  diffuse  carcinoma  of  the  stomach 
may  produce  lesions  which  closely  resemble  lymphosarcoma  in  the  gross, 
and  a  structure  which  can  be  identified  as  carcinomatous  only  when  care 
and  industry  are  used  in  the  examination. 


FIG.  155. — Lymphosarcoma  of  stomach.     Invasion  of  arteriole. 

i.  True  lymphosarcoma  of  the  stomach,  which  is  always  separated  with 
difficulty  from  the  granulomatous  pseudosarcoma,  occurs  chiefly  in  young 
subjects  and  produces  a  bulky  circumscribed  or  diffuse  growth  in  the  pylorus 
or  in  the  curvatures.  It  is  often  difficult  to  determine  whether  the  primary 
growth  is  in  the  wall  of  the  organ  or  in  adjacent  lymph-nodes  which  are  com- 
monly involved.  The  majority  of  these  tumors  are  diffuse  (Kundrat,  Cayley, 
Hammerschlag,  Menge,  Thursfield);  others  produce  several  projecting,  sub- 
mucous  masses  (Kaufmann);  some  are  polypoid  or  pedunculated  (Pitt); 
and  a  few  become  quite  bulky  (Stahelin,  Howard).  Ulceration  and  pyloric 
stenosis  are  frequent  (Fleiner),  and  local  or  wide-spread  extensions  or  metastases 


LYMPHOMA  AND  LYMPHOSARCOMA  387 

are  common.  Maas  described  a  bulky  subserous  lymphosarcoma.  The 
gastric  tumor  is  often  only  a  part  of  a  very  general  lymphosarcomatosis,  as 
illustrated  by  the  case  of  Ziesche  and  Davidsohn.  Here  a  very  extensive 
tumor  of  the  stomach  was  associated  with  lymphosarcoma  of  tonsils,  medias- 
tinal  and  retroperitoneal  lymph-nodes,  and  the  entire  small  intestine,  while 
other  growths  occurred  in  the  heart,  kidney,  and  bone-marrow. 

2.  Lymphosarcoma  of  the  intestine  is  an  important  type  of  the  disease. 
While  usually  found  in  the  lower  ileum,  it  may  appear  at  any  point  from 
the  duodenum  to  the  anus.  The  rectal  tumors  are  less  frequent,  but  equally 
characteristic  (Glinski,  Key,  Lit.).  Rarely  the  appendix  is  the  primary  site. 
The  earliest  stages  appear  as  a  localized  thickening  of  the  submucosa  with 
or  without  ulceration.  The  process  extends  laterally  and  invades  and  de- 
stroys the  muscular  layers  and  appears  as  a  subserous  tumor  which  soon 
forms  adhesions.  Thereafter  central  ulceration  excavates  the  tissue  or  pro- 
duces aneurysmal  dilatation  which  with  peripheral  growth  yields  a  large 
tumor  with  roomy  cavity.  Large  polypoid  growths  protruding  into  the 
widened  lumen  without  ulceration  are  also  observed  (Baltzer).  Rarely 
marked  stenosis  results  and  perforation  may  occur.  Chronic  peritonitis 
with  chylous  ascites  is  often  observed. 

Metastases  appear  early  in  regional  nodes  and  they  may  extend  to  many 
of  the  organs  (Libman).  The  disease  often  occurs  in  childhood  as  well 
as  at  other  ages  and  usually  runs  a  rapid  course,  terminating  fatally  in  a 
few  weeks  or  months.  Acute  cases  resemble  appendicitis  (Libman,  Jopson, 
White). 

The  structure  of  the  growths  is  that  of  small  or  large  round-cell  lympho- 
sarcoma. The  reported  cases  are  variously  designated,  but  there  is  no  satis- 
factory evidence  that  more  than  one  type  of  tumor  is  represented  in  this 
group.  The  cells  are  large  or  medium  mononuclears  with  liberal  cytoplasm, 
lying  irregularly  in  a  meshwork  of  fine  fibrils.  Fragile  blood-vessels  and 
many  small  lymphocytes  may  accompany  the  tumor  cells.  It  is  especially 
in  this  group  of  cases  that  the  process  may  resemble  an  infectious  granuloma. 
Retroperitoneal  lymphosarcoma  is  a  characteristic  type  of  the  disease. 
It  produces  a  large  abdominal  tumor  composed  of  fused  lymph-nodes,  while 
the  extensions  may  be  either  very  wide  or  rather  limited.  Such  tumors  may 
be  associated  with  intestinal  lesions  so  that  it  is  difficult  to  determine  the 
primary  seat.  Various  complications  arise  in  the  course  of  these  tumors, 
including  peritonitis  with  chylous  ascites,  constriction  of  intestine,  occlu- 
sion of  bile-ducts  with  jaundice,  and  compression  of  vessels  with  edema. 

Cutaneous  lymphosarcoma  occurs  only  as  a  metastatic  process  from  other 
regions  (Sedziak);  mediastinum  (Romberg,  Packard);  mesentery  (Kutzner); 
antrum  (Kaposi).  The  cutaneous  tumors  appear  early  or  late  in  the  disease 
and  form  multiple  papules  or  subcutaneous  nodules  of  varying  size.  They 
may  regress  spontaneously  or  after  arsenic  (Arning),  and  Kaposi  saw  a  very 
large  lymphoid  tumor  of  the  skin  rapidly  disappear.  The  exact  nature  of 
many  of  the  cases  in  the  literature  is  uncertain. 

Lymphosarcoma  of  the  tongue  has  been  reported  by  several  observers,  but 
Schleinzer  was  able  to  collect  only  4  cases  which  could  be  regarded  as  genuine, 
2  of  which  recovered  after  operations.  In  i  case  the  tumor  distended  the 
buccal  cavity  after  12  years'  growth,  and  recurred  after  operation.  In  3 
cases  the  tumors  early  became  ulcerated  and  invaded  the  cervical  and  once 
he  abdominal  nodes.  Fripp  and  Iwan  have  collected  cases  of  round-cell 
sarcoma  of  the  tongue,  the  exact  nature  of  which  it  is  difficult  to  determine. 
Some  of  the  difficulties  of  diagnosis  in  this  field  are  illustrated  in  the  case  of 
pseudosarcoma  described  by  Foote,  in  which  the  very  chronic  lesion  con- 


388 


NEOPLASTIC  DISEASES 


sisted  of  a  diffuse  ilfiltration  of  large  mononuclear  cells  somewhat  resembling 
plasma  cells.  In  this  case  there  were  also  anal  lesions. 

Lymphosarcoma  of  the  testis  has  been  a  common  diagnosis,  especially 
among  French  writers,  but  Chevassu  has  pointed  out  that  many  of  these 
cases  were  probably  embryonal  carcinoma.  Yet  true  lymphosarcoma  has 
been  described  by  Malassez,  Ehrendorfer,  and  Debarnardi.  I  have  studied 
2  cases  which  seem  to  be  genuine. 

The  disease  occurs  chiefly  in  young  subjects,  usually  involves  both  testes, 
develops  cutaneous  and  internal  metastases,  and  runs  a  rapid  course  with 
fever.  The  exact  origin  of  this  tumor  is  uncertain.  The  testicle  is  some- 
times the  seat  of  metastatic  lymphosarcoma. 

The  kidney  is  a  favorite  seat  of  metastatic  lymphosarcoma  in  the  form  of 
minute  foci,  diffuse  infiltrations,  or  bulky  masses.  In  Turner's  case  both 
kidneys  reached  an  enormous  size  from  diffuse  infiltration  and  much  of  the 
renal  tissue  was  destroyed.  The  existence  of  primary  lymphosarcoma  of 
the  kidney  is  uncertain.  In  a  case  of  Dowd's  I  found  the  organ  largely  re- 


&W^*SSS 


^f^^^M 

FIG.  156. — Malignant  lymphocytoma.     Invasion  of  venule  in  retroperitoneal  fat. 

placed  and  moderately  enlarged  by  many  round  masses  of  tumor  tissue 
composed  of  atypical  lymphocytes  with  hyperchromatic  nuclei. 

Extramedullary  Plasma-cell  Tumors. — In  a  rather  numerous  group  of 
tumors  of  mucous  membranes  and  lymph-nodes  the  growth  is  composed 
exclusively  of  plasma-cells.  Considering  their  comparative  frequency  and 
rather  peculiar  clinical  course,  they  have  received  inadequate  attention 
(Kusunoki,  Frank,  Lit.).  The  growths  occur  chiefly  in  the  nasopharynx, 
alveolar  borders,  tongue,  lips,  and  cervical  lymph-nodes,  but  they  have  been 
observed  in  many  other  regions.  The  course  is  relatively  slow,  but  they 
may  recur  after  extirpation,  and  become  associated  with  a  chronic  cachexia. 
They  are  commonly  classed  as  lymphosarcoma,  but  being  as  a  rule  benign 
processes  with  very  indistinct  neoplastic  properties,  it  is  highly  important 
that  they  should  be  separated  from  the  malignant  lymphosarcoma.  The 
structure  presents  a  diffuse  growth  of  more  or  less  typical  plasma-cells. 

Etiology. — Lymphosarcoma,  representing  a  lawless  proliferation  of 
reticulum  cells  and  their  derivatives,  may  be  attributed,  a  priori,  to  any 


LYMPHOMA  AND  LYMPHOSARCOMA 


389 


irritant  which  influences  these  unstable  cells  over  a  considerable  period  or  in 
a  specific  manner.  There  is  no  urgent  necessity  for  assuming  the  existence 
of  any  unknown  micro-organism  or  any  other  occult  factors  in  the  origin 
of  this  process,  for  when  the  above  principle  is  applied  in  the  study  of  cases 
a  large  proportion  of  lymphosarcomas  are  reasonably  accounted  for. 

Thus  Birch-Hirschfeld  observed  a  rapidly  fatal  case  which  was  practi- 
cally a  continuation  of  typhoid  hyperplasia.  The  older  observers  were  in  the 
habit  of  attributing  many  of  these  cases  to  syphilis,  but  the  grounds  for  this 
assumption  have  not  been  strengthened  in  recent  years. 

The  more  generalized  forms  of  lymphosarcoma  are  not  infrequently  the 
sequel  of  pseudoleukemia  or  leukemia,  for  which  an  infectious  origin  is  prob- 
able. The  usual  type  of  sarcoma  following  Hodgkin's  granuloma  has  a  specific 
structure  which  differs  from  that  of  lymphosarcoma  and  has  been  separately 
described. 


FIG.  157. — Malignant  lymphocytoma  of  groin,  infiltrating  fat  tissue,  walls  of  vessels,  and 

lumina  of  small  veins. 

Tuberculosis  occupies  a  prominent  position  as  an  excitant  of  lympho- 
sarcoma. In  fact,  many  observers,  finding  frank  tuberculosis  so  intimately 
associated  with  lymphosarcoma,  have  been  willing  to  identify  the  two  con- 
ditions. Since  the  discovery  of  tubercle  bacilli  in  pseudoleukemic  tissue  by 
Weigert,  in  pure  lymphoid  hyperplasia  by  Brentano  and  Tangl,  and  in 
generalized  lymphomas  of  nodes,  spleen,  liver,  and  serious  membranes  by 
Sabrazes,  only  a  slight  difference  has  separated  lymphosarcoma  from  the 
immediate  or  distant  presence  of  tubercle  bacilli  or  their  toxins.  Frank 
tuberculosis  associated  with  lymphosarcoma  is  reported  by  Ricker  in  a  case 
terminating  after  14  years  with  sarcomatous  infiltration  of  neck,  lung, 
adrenals,  spinal  canal,  and  wide-spread  caseous  areas,  with  giant-cells  and 
tubercle  bacilli.  Yet  the  structure  of  the  sarcomatous  tissue  in  this  case 
suggests  Hodgkin's  granuloma.  Miiller,  however,  saw  general  sarcomatosis 
from  a  primary  tumor  of  breast  in  which  miliary  tubercles  were  nearly  co- 
extensive with  large  sarcomatous  masses.  A  significant  case  is  that  of  Brandt's 
in  which,  with  tuberculosis  of  left  apex  of  lung,  there  was  sarcomatous  inva- 


390  NEOPLASTIC  DISEASES 

sion  of  ileocecal  region,  many  lymph-nodes,  pharynx,  Eustachian  tube,  parotid, 
middle  ear,  adrenal,  and  ovary.  Inoculation  of  the  pure  sarcomatous  tissue 
yielded  only  lymphoid  hyperplasia  of  intestinal  follicles  in  guinea-pigs,  but 
inoculation  of  the  tissue  of  these  follicles  gave  frank  tuberculosis  in  a  second 
series  of  pigs. 

Gastro-intestinal  lymphosarcoma  is  especially  difficult  to  separate  from 
tuberculosis  or  some  form  of  infectious  granuloma.  These  lesions  often 
exhibit  lymphocytes,  plasma-cells,  eosinophile  cells,  and  necrosis,  and  cases 
in  which  tubercle  bacilli  are  missing  may  closely  resemble  hyperplastic 
tuberculosis  in  which  acid-fast  bacilli  are  present,  but  scanty.  Tuberculous 
intestinal  ulcers  closely  associated  with  wide-spread  sarcomatous  lesions  in 
mesentery  or  retroperitoneal  nodes  are  described  by  Nothnagel,  Freudweiler, 
Munk,  and  others.  Thus  it  seems  highly  probable  that  many  cases  of  lym- 
phosarcoma arise  on  a  tuberculous  basis  and  that  the  process  thus  established 
progresses  of  its  own  momentum  and  eventually  apart  from  the  presence  of 
any  bacilli  or  their  toxins. 

That  tuberculosis  is  not  always  the  exciting  factor  must  be  granted. 
Kundrat  stated  that  tuberculosis  is  not  commonly  implicated  in  lympho- 
sarcomatosis.  Lubarsch  assumes  that  any  infectious  agent  may  serve  as 
the  exciting  cause,  and  chiefly  because  of  the  close  dependence  of  the 
process  upon  microorganisms  and  their  products  he  would  separate  lym- 
phosarcoma from  other  or  true  neoplasms.  For  the  same  reasons  Borst 
anticipates  the  ultimate  identification  of  lymphosarcoma  with  infectious 
granulomas.  It  may  here  be  noted  that  the  local  aggressive  quality  which 
chiefly  distinguishes  lymphosarcoma  from  pseudoleukemia  fails  entirely  to 
separate  this  process  from  the  infectious  granulomas,  which  also  infiltrate 
and  destroy  tissues. 

Not  a  few  lymphosarcomas  arise  in  infants  and  appear  to  have  a  con- 
genital basis.  The  testicular  cases  are  often  of  this  character.  The  dis- 
covery of  epithelial  elements  in  the  tumor  masses  indicates  an  origin  from 
misplaced  tissue  masses  (Finkler,  Martland). 

Ribbert  assumes  that  all  true  lymphosarcomas  arise  from  aberrant  and 
undifferentiated  cell  groups,  and  that  tuberculosis  often  serves  as  the  neces- 
sary incitant  to  growth.  Such  a  view  seems  reasonable  for  very  malignant 
localized  tumors,  less  so  for  the  generalized  forms  resembling  pseudoleukemia. 

SARCOMA  OF  SPLEEN 

While  primary  sarcoma  of  the  spleen  is  rare,  several  varieties  of  this  tumor 
have  been  reported  (Jepson,  Albert,  Foix,  Roemmele,  Lit.).  Three  varieties 
of  splenic  sarcoma  were  briefly  described  by  Weichselbaum  in  1881,  spindle- 
cell  sarcoma,  endothelial  sarcoma,  and  lymphosarcoma,  and  although  it  is 
impossible  to  determine  the  exact  nature  of  many  cases  in  the  literature, 
most  of  them  seem  to  fall  in  one  of  the  above  groups. 

1.  Spindle-cell  sarcoma  occurs  as  a  small  or  bulky  circumscribed  tumor. 
The  case  of  Jepson  and  Albert  stands  as  a  typical  example  of  this  rarest  of 
types.     The  structure  showed  spindle-  and  round  cells  with  trabeculse  and 
solid   areas   of   fibrous   tissue.      This   tumor   is   comparatively   benign.     A 
capsular  sarcoma  has  been  described  by  Heinricus,  and  angiosarcomas  by 
Langhans,  Theile,  and  Jores. 

2.  The  endothelial  sarcoma  is  the  most  frequent  variety.     As  a  rule  it 
produces  multiple  nodules  in  a  greatly  enlarged  organ,  and  many  of  these 
nodules  may  fuse  into  larger   diffuse  masses.     Metastases  are  commonly 
present,  having  been  observed  by  Bunting  in  liver,  pancreas,  and  skin,  and 


LYMPHOMA  AND  LYMPHOSARCOMA 


391 


by  Foix  and  Roemmele  about  the  adrenal.  This  tumor  is,  therefore,  quite 
malignant. 

The  structure  consists  of  large  cells  with  single  or  multiple  vesicular  nuclei 
and  pale  cytoplasm.  They  are  round  or  elongated  or  polyhedral,  and  giant- 
cells  may  form.  The  arrangement  may  be  diffuse  or  alveolar.  Bunting, 
in  an  alveolar  tumor,  concluded  that  the  cells  arose  from  the  endothelium 
of  the  splenic  tissue. 

Foix  and  Roemmele  in  an  elaborate  analysis  trace  the  origin  to  the  reticulum 
cells  of  the  splenic  follicles.  They  liken  the  process  to  a  neoplasm  arising 
on  an  inflammatory  hyperplasia  of  these  follicles  and  are  prepared  to  accept 
an  infectious  agent  or  an  irritant  of  endogenous  origin  as  the  ultimate  cause 
of  the  proliferation.  Their  designation  of  the  tumor  as  "reticulosplenome 


FIG.  158. — Structure  of  a  primary  diffuse  sarcoma  of  the  spleen. 

nodulaire"  is  non-committal  on  the  endothelial  origin  of  the  growth.  Many 
of  these  cases  resemble  the  endothelial  sarcoma  arising  in  Hodgkin's  granuloma. 
A  relation  to  "splenomegalie  primitive,  Gaudier"  has  not  been  indicated  by 
any  transitional  cases  so  far  described. 

3.  Primary  lymphosarcoma  of  the  spleen,  derived  from  the  lymphoid 
cells  of  pulp  or  follicles,  has  been  described  by  several  observers,  but  it  is 
difficult  to  determine  which  of  the  recorded  cases  belong  in  this  group. 
This  tumor  produces  diffuse  enlargement  of  the  spleen,  as  in  the  cases  of 
Kocher,  Grohe,  Clarke,  and  Kocher,  or  it  may  appear  in  the  form  of  one  or 
more  large  discrete  masses  (Warren,  Herczel).  Regional  metastases  are 
common,  but  not  invariable.  The  normal  structure  of  the  spleen  is  largely 
destroyed  by  diffuse  growth  of  small  or  large  round  cells  of  the  type  of  lym- 


392  NEOPLASTIC  DISEASES 

phocytes.  Menetrier  designates  the  tumors  with  small  cells  as  lymphocy- 
toma,  and  those  with  large  cells  as  splenoma.  I  have  studied  one  case  of  the 
latter  type,  reported  by  Janvrin,  in  which  the  entire  organ,  much  enlarged 
but  with  capsule  intact,  was  composed  of  somewhat  peculiar,  large  round 
cells  resembling  the  splenic  lymphocytes.  On  account  of  the  partial  pres- 
ervation of  sinuses  and  follicles  the  truly  neoplastic  nature  of  the  process 
appeared  doubtful.  Grohe's  case,  which  appears  to  belong  in  this  group, 
gave  extensive  metastases. 


CHAPTER  XXII 
TUMORS  OF  THE  BRAIN 

General  Considerations. — Occurrence. — The  frequency  of  occurrence  of 
brain  tumors  cannot  be  accurately  stated.  Probably  about  i  per  cent,  of 
deaths  are  from  this  cause.  Bruns  saw  210  cases  among  11,500  nervous 
patients,  but  Hirsch  saw  only  14  brain  tumors  among  8000  nervous  cases. 
Tooth  collected  500  cases  in  the  service  of  the  National  Hospital,  London, 
during  10  years.  Among  14,005  autopsies  at  Munich  and  Heidelberg,  135 
brain  tumors  were  recorded  by  Seydel  and  Beck.  In  Gurlt's  tables  covering 
14,630  tumors,  218  of  the  brain  are  included. 

Sex. — Including  a  small  proportion  of  tubercle,  males  were  affected  in 
744  cases,  and  females  in  428,  in  the  series  collected  by  Gowers,  Bruns,  and 
Tooth. 

Age  Incidence. — Of  Tooth's  500  tumors,  excluding  tubercle,  139  occurred 
between  i  and  20  years  (27.8  per  cent.) ;  123  from  21  to  30  years  (26  per  cent.) ; 
137  from  31  to  40  years  (27.4  per  cent.);  65  from  41  to  50  years  (13  per  cent.); 
33  from  51  to  60  years  (6.6  per  cent.);  and  3  after  61  years. 

Starr  shows  that  cerebellar  tumors  are  relatively  frequent  in  children. 
Of  45  cortical  tumors,  3  occurred  under  19  years,  while  of  29  cerebellar  growths 
ii  were  found  under  19  years.  The  gliomas,  endotheliomas,  and  sarcomas 
show  much  the  same  age  incidence.  Gliomas,  cholesteatomas,  and  dermoids 
are  rarely  congenital.  Gowers  found  only  the  first  5  months  immune. 

Heredity  was  a  negligible  factor  in  Tooth's  analysis,  a  cancerous  family 
history  being  obtained  in  only  37  cases  (7.2  per  cent.).  In  no  case  was  a 
history  of  brain  tumor  noted.  There  are,  however,  occasional  exceptions 
to  this  rule. 

Trauma. — The  frequency  of  the  traumatic  origin  of  brain  tumors  has 
been  variously  estimated  by  different  observers,  but  as  a  rule  the  estimates 
are  notably  high.  Gerhardt  accepted  the  traumatic  origin  of  10  among  60 
reported  cases  of  glioma,  and  in  4  of  n  cases  of  his  own.  Bruns  holds  that  a 
direct  traumatic  origin  is  rare.  Adler  collected  1986  cases,  accepting  a  rela- 
tion to  trauma  in  8.8  per  cent.  He  details  118  cases  of  various  types,  illus- 
trating many  possible  relations  to  trauma,  some  of  them  quite  direct. 
Lowenthal  found  n  gliomas  which  on  somewhat  uncertain  evidence  he  re- 
ferred to  trauma.  A  traumatic  origin  of  certain  sarcomas  resembling  granu- 
lation tissue  is  more  acceptable  than  with  gliomas. 

The  trauma  may  have  no  influence  whatever  on  the  tumor.  This  rela- 
tion must  be  assumed  to  exist  in  the  cases  in  which  the  trauma  is  incapable 
of  producing  a  lesion  of  the  brain  tissue,  and  may  be  assumed  as  probable 
when  a  long  interval  elapses  between  the  injury  and  the  appearance  of  symp- 
toms. 

The  trauma  may  cause  the  outbreak  of  symptoms  of  a  previously  existing 
latent  tumor.  Such  cases  are  observed  when  an  unsuspected  glioma  causes 
epileptic  attacks  with  head  injury  in  falling  (Bruns). 

The  trauma  may  accelerate  the  growth  of  a  previously  existing  tumor. 
Burns  refers  to  the  rapid  growth  after  trauma  of  mildly  indicated  gliomas,  and 
supposes  that  the  trauma  produces  hemorrhage  in  the  vascular  tumor.  Oppen- 
heim  states  that  trauma  may  indirectly  excite  tumor  growth  by  establishing 

393 


394 


NEOPLASTIC  DISEASES 


a  condition  of  epilepsy  which  eventually  induces  the  neoplastic  proliferation 
of  glia-tissue.    Such  cases  are  reported  also  by  P.  Knapp  and  Osier. 

Trauma  may  be  the  direct  exciting  cause  of  the  tumor.  In  order  to  prove 
such  a  relation  it  is  necessary  to  show  that  a  sufficient  injury  has  caused  a 
lesion  of  the  dura  or  pia  with  affection  of  the  brain  tissue.  Evidences  of 
old  hemorrhage,  with  adhesions  of  brain  to  membranes  beneath  the  point 
of  injury,  are  the  only  satisfactory  data  that  can  be  offered  as  proof.  Such 
cases  have  been  fully  reported  by  Hitzig,  Eppinger,  Thomas  and  Bartlett, 
Keen,  Annandale,  Adler,  Carara,  and  others.  Both  sarcoma  and  glioma  are 
observed  under  such  conditions.  Somewhat  less  satisfactory  and  more 
numerous  are  the  cases  in  which  the  tumor  does  not  appear  at  the  point  of 
injury,  but  owing  to  the  influence  of  contrecoup  the  brain  lesion  may  be  far 
removed  from  the  point  of  the  blow.  Additional  evidence  may  appear  in  the 
clinical  history,  when  it  is  shown  that  the  tumor  symptoms  were  continuous 
with  or  appeared  shortly  after  the  injury.  With  increasing  intervals  between 


FIG.  159. — Location  of  a  series  of  brain  tumors,      (v.  Eiselsberg.) 

trauma  and  tumor  the  relation  must  be  regarded  as  less  direct.  Starr's  as- 
sumption that  a  cerebral  hemorrhage  or  contusion  may  pass  directly  into  a 
tumor  process  is  rejected  by  Oppenheim  and  Bruns,  but  such  an  interpre- 
tation is  fujly  in  accord  with  histological  findings  as  well  as  clinical  history. 
In  the  organization  of  a  cerebral  blood-clot  the  growth  of  capillaries  and  glia- 
tissue  may  be  very  active. 

The  relative  frequency  of  the  different  types  of  tumors  may  be  judged 
by  Tooth's  analysis  of  258  cases  verified  at  operation  or  postmortem  as 
follows: 

Glioma,  132  (55  per  cent.);  endothelioma,  37  (14.3  per  cent.);  sarcoma, 
21  (8.1  per  cent.);  carcinoma,  15  (5.8  per  cent.);  tubercle,  14  (5.4  per  cent.); 
fibroma,  13  (5  per  cent.);  cysts,  5  (1.9  per  cent.);  ventricular  papilloma, 
3  (i.i  per  cent.);  cholesteatoma,  2  (0.7  per  cent.);  pituitary,  2  (0.7  per  cent.); 
pineal,  4  (1.5  per  cent.). 

Fibrogliomas  and  fibromas  belonged  to  the  cerebellum.     The  endothe- 


TUMORS  OF  THE  BRAIN 


395 


liomas  were  confined  to  the  anterior  portion  of  the  falx  in  35  of  the  37  cases. 
Of  the  carcinomas  only  one  was  certainly  primary. 

The  general  distribution  of  brain  tumors  is  indicated  in  the  following  table, 
in  which  are  included  the  series  of  cases  of  J.  Collier  and  Tooth,  together 
with  those  of  Stern: 


Frontal 129 

Parietal 73 

Temporosphenoidal 63 

Occipital 17 

Corpus  callosum 34 

Mesencephalon 57 

Lateral  ventricles 3 

Third  and  fourth  ventricles 5 


Optic  thalamus 6 

Pons 65 

Medulla i 

Base 9 

Pituitary 14 

Pineal 4 

Cerebellum 112 

Extracerebellar 40 

632 


Including  tubercle  and  gumma  the  following  table  of  incidence  results 
from  combining  the  figures  of  Birch-Hirschfeld  and  Bernhardt: 


Tubercle. 

Gumma. 

Sarcoma. 

Glioma. 

Osteoma. 

Cholestea- 
toma. 

Cortex.  . 

SO 

I  c 

16 

12 

o 

Lobes  

18 

8 

-2Q 

AA 

o 

Basal  ganglia  . 

17 

7 

IA 

I  j 

I 

Corpora  quadrigemina 
Pons  

2 
^O 

0 

6 

2 

8 

6 

12 

I 

Medulla  

o 

2 

c 

1  1 

Cerebellum 

cy 

22 

12 

2 

Hypophysis  

o 

•7 

-3 

o 

o 

Pineal  

o 

o 

A 

o 

o 

183 

45 

US 

128 

4 

2 

Multiple  brain  tumors  are  not  infrequently  observed.  In  the  same  case 
Hanel  saw  a  cystic  round-cell  sarcoma,  a  ganglionic  neuroma,  a  spindle- 
cell  sarcoma,  several  lymphangiomas,  and  a  tumor-like  thickening  of  the 
dura  vessels. 

Operability. — Conclusions  regarding  operability  of  brain  tumors  have 
not  greatly  changed  in  recent  years,  notwithstanding  isolated  reports  of 
brilliant  successes.  In  1889  Starr  concluded  that  of  300  brain  tumors  in 
children  only  19  cases  warranted  operation,  and  only  16  could  have  been 
successfully  removed,  of  which  10  were  tubercle. 

In  1914  Kuttner  reports  that  in  100  clinical  cases  30  tumors  were  removed 
and  34  others  were  later  demonstrated  to  exist,  45  died  from  the  operation, 
14  died  in  i  to  3  months,  and  5  in  4  to  5  months.  In  13  cases  it  was  later 
shown  that  no  tumor  existed.  Four  blind  cases  recovered  sight,  and  n  cases 
remained  well  for  6  months  to  6  years. 

Henschen  reports  that  of  205  operations,  48  patients  died  from  the  opera- 
tion and  88  more  in  one  month,  while  after  2  years  all  but  14  were  dead. 
Bergmann  and  v.  Eiselsberg  both  report  operative  mortalities  of  38  per  cent., 
while  among  371  cases  Bergmann  reports  in  not  improved  and  88  (23  per 
cent.)  improved.  Eichelberg  concludes  that  70  to  80  per  cent,  of  brain  tumors 
can  be  localized,  and  of  these  5  per  cent,  are  enucleable.  Among  33  cases 
of  brain  tumor  Cramer  and  Hippel  found  only  4  suitable  for  operation,  3 
of  which  were  cysts.  Duret  analyzed  400  operative  cases,  finding  that  78 


396  NEOPLASTIC  DISEASES 

(19.5  per  cent.)  died  immediately,  20  very  soon  from  meningitis,  and  47 
within  one  month,  so  that  a  total  of  145  (36  per  cent.)  received  no  benefit. 
Improvement  in  varying  degree  followed  in  258  cases,  among  which  there 
were  41  recurrences  of  the  tumor.  The  surgical  possibilities  in  favorable 
cases  are  well  illustrated  in  the  report  of  Alexander  and  linger  who  located 
a  calcine  subpial  endothelioma,  7X7X5  cm.,  by  means  of  the  x- ray  and 
removed  it  under  cocain  with  complete  cure,  although  the  lateral  ventricle 
had  been  opened. 

Miscellaneous  statistics  are  of  practically  no  value  in  determining  the 
probable  outcome  of  any  given  case,  whereas  a  very  thorough  clinical  study 
of  every  feature  of  the  condition,  accurate  localization,  rate  of  growth  of  the 
tumor,  age  of  the  patient,  a  knowledge  of  the  natural  history  of  the  different 
types  of  tumors,  and  of  their  pathological  anatomy  may  together  yield  a 
comparatively  reliable  prognosis. 

All  of  these  subjects  form  a  very  extensive  department  of  our  knowledge 
of  brain  tumors  and  furnish  the  chief  topic  of  several  comprehensive  works, 
such  as  those  of  Oppenheim,  Bruns,  Duret,  Henschen,  Stern,  Starr,  F.  Krause, 
and  many  others. 

The  duration  of  brain  tumors  without  operation  was  found  by  Tooth 
as  follows:  Glioma  10.1  months  for  21  cases,  extremes  9  years  and  24  days. 
Endothelioma,  20.2  months  for  6  cases  unoperated.  In  31  cases  operated 
upon  the  average  duration  was  4  years,  extremes  20  years  and  2  months. 
Sarcoma,  5  cases  survived  11.2  months,  or,  omitting  one  which  lasted  4  years, 
the  average  was  5.1  months.  Of  7  cases  diagnosed  as  pituitary  the  average 
survival  period  was  7.5  years.  A  notable  fact  was  the  long  survival  period 
of  6.5  years  of  51  cases  not  localized. 

Secondary  Effects  of  Brain  Tumors. — The  continued  growth  of  an  intra- 
cranial  tumor  usually  induces  secondary  changes  in  many  intracranial  struc- 
tures, giving  rise  to  complex  and  confusing  cerebral  symptoms  and  compli- 
cating the  anatomic  relations  of  the  tumor.  These  effects  are  the  result  of 
many  factors,  including  the  pressure  of  the  tumor  mass,  circulatory  disturb- 
ances in  the  vicinity  of  the  tumor  and  in  the  whole  cranial  cavity,  interference 
with  the  paths  of  ventricular  fluids,  and  local  invasion  and  dissemination  of 
the  tumor. 

(a)  On  the  brain  tissue.  The  tumor  may  act  on  the  brain  tissue  by  com- 
pression, by  irritation,  or  by  actual  destruction  of  cells  and  fibers.  Simple 
compression  is  best  observed  with  tumors  of  the  meninges,  or  encapsulated 
growths  which  displace  the  adjoining  brain  substance.  Pressure  atrophy 
gradually  follows  with  loss  of  cells  and  myelin  sheaths,  but  complete  loss  of 
functional  capacity  of  the  affected  region  is  generally  slow  to  appear.  Exten- 
sive displacement  of  affected  parts  may  result,  especially  in  the  cerebellum. 
Here  bulky  tumors  have  been  known  to  force  the  medulla  or  even  the  cere- 
bellum tightly  into  the  foramen  magnum  or  spinal  canal.  Compression 
effects  are  often  observed  at  a  distance,  as  when  a  tumor  of  one  side  com- 
presses the  structures  of  the  opposite  cerebral  hemisphere  with  convulsions. 
Cerebral  tumors  may  even  compress  the  cerebellum,  although  the  tentorium 
usually  limits  such  effects  in  both  directions. 

Very  extensive  hernial  protrusion  of  the  brain  may  follow  opening  the 
skull.  In  some  cases  the  relief  of  pressure  accelerates  the  growth  of  an  un- 
derlying or  distant  glioma  or  sarcoma  which  forces  brain  tissue  or  tumor 
tissue,  or  both,  through  the  opening.  Eichelberg  describes  a  hernial  protrusion 
almost  as  large  as  the  brain  itself.  Compression  of  the  cranial  nerves  yields 
some  of  the  most  reliable  of  localizing  symptoms.  These  nerves  may  be 
directly  compressed  by  the  tumor,  or  displacement  of  portions  of  the  brain 


TUMORS  OF  THE  BRAIN 


397 


may  strangle  the  blood-vessels  or  the  nerve-fibers  or  actually  sever  the  nerve 
trunk  (Wernicke). 

The  imperfectly  formed  blood-vessels  of  gliomas  are  especially  susceptible 
to  intermittent  distention,  producing  intermittent  pressure  symptoms.  Or, 
after  rupture,  extensive  hemorrhage  in  or  about  the  tumor  may  come  from 
these  vessels.  Irritation  of  brain  tissue  usually  precedes  the  pronounced 
stages  of  compression.  The  mechanism  of  the  resulting  spasms  and  par- 
esthesias  is  not  clear,  but  probably  consists  of  local  vascular  disturbances 
with  edema  and  exudation. 

Destruction  of  brain  tissue  follows  prolonged  pressure,  results  from  the 
gradual  extension  of  glioma,  and  is  rapidly  effected  by  infiltrating  sarcomas 
and  especially  by  carcinomas.  Inflammatory  reaction  about  the  tumor  or 
extending  over  considerable  portions  of  the  brain  is  frequently  observed  and 
may  greatly  complicate  accurate  localization  of  the  original  growth.  Collier 


FIG.  160. — Acute  edema  of  brain  in  region  surrounding  a  hard,  slowly  growing  tumor. 

(After  J.  Collier.') 

analyzed  false  localizing  signs  occurring  in  20  of  161  cases,  finding,  as  the 
source  of  the  symptoms,  extensive  edema  about  slowly  growing  tumors, 
thrombosis  or  hemorrhage  at  a  distance  from  the  tumor,  areas  of  softening, 
ventricular  hydrops,  and  distortion  of  cranial  nerves.  These  signs  were  en- 
countered in  13  per  cent,  of  supratentorial  growths  and  only  twice  in  cerebellar 
tumors.  In  two  fibrosarcomas  the  false  signs  resulted  from  intracranial 
metastases. 

General  edema  about  small  gliomas  may  involve  an  entire  hemisphere 
and  lead  to  rapidly  deepening  coma,  convulsions,  and  paralysis.  About  a  pial 
sarcoma  invading  the  brain  tissue  Merzbacher  observed  very  marked  pro- 
liferation of  glia-cells  which  he  interpreted  as  a  reactive  glioma.  In  a  series 
of  12  cases  he  found  no  reaction  of  the  glia- tissue  against  carcinoma,  but  con- 
siderable reaction  in  the  presence  of  sarcoma. 

The  disappearance  of  localizing  symptoms,  which  is  a  well-known  feature 


398  NEOPLASTIC  DISEASES 

of  brain  tumors,  may  result  from  a  change  in  anatomical  relations,  with  relief 
of  pressure  and  subsidence  of  edema  and  exudate.  Interesting  cases  of  relief 
from  symptoms  of  brain  tumor  are  recorded  by  Hawthorne.  In  many  brain 
tumors,  especially  gliomas,  the  entire  brain  tissue  may  be  the  seat  of  struc- 
tural changes  resulting  probably  from  general  disturbance  of  circulation. 
They  consist  in  increase  of  glia  nuclei,  especially  in  the  deep  cell  layers,  dis- 
turbed polarity  of  the  cells,  partial  or  complete  tigrolysis,  shrinkage  or  com- 
plete atrophy  of  cells,  pyknosis,  karyolysis,  or  homogenization  of  nuclei,  and 
marked  increase  of  pericellular  nuclei  (Stern). 

(b)  Disturbance  of   the  circulation  of  blood,  lymph,  and  cerebrospinal 
fluid  becomes  pronounced  in  the  late  stages  of  most  brain  tumors  and  leads 
to  general  cerebral  compression,  with  symptoms  of  headache,  increasing  dul- 
ness,  coma,  slowing  of  pulse  and  respiration,  and  choked  disk.    On  exposing 
the  brain  the  convolutions  may  appear  flattened  and  pulsation  is  absent. 
The  essential  feature  of  general  cerebral  compression  appears  to  be  capillary 
anemia.    In  nearly  all  cases  there  is  ventricular  hydrops,  and  this  condition 
develops  early  in  most  tumors  of  the  base,  cerebellum,  and  fourth  ventricle. 
It  is  generally  indicated  by  deep  coma  and  muscular  spasticity.    Secondary 
pressure  effects  of  ventricular  hydrops  may  be  traced  in  several  directions: 
as  upon  the  plexus  veins,  vena  Galeni,  and  the  great  sinuses;  upon  the  sur- 
rounding brain  tissue  with  atrophy;  and  upon  the  chiasm  and  cranial  nerves 
with  false  localizing  symptoms. 

Choked  disk  may  be  referred  chiefly  to  the  mechanical  effects  of  general 
cerebral  compression.  The  fluid  in  the  arachnoid  spaces  passes  directly 
into  the  lymph  sheath  of  the  optic  nerve,  distends  the  sheath  and  the  lymph 
vessels  of  the  nerve,  obstructs  the  blood  flow  of  the  central  vein  with  vari- 
cosities  in  the  retinal  veins,  and  edema,  hemorrhages,  and  eventual  atrophy 
of  the  optic  cusp.  Secondary  exudative  and  degenerative  changes  may  fol- 
low and  have  led  to  the  assumption  that  the  changes  are  of  toxic  origin  (Elsch- 
nig).  The  essential  dependence  of  choked  disk  upon  mechanical  edema  best 
explains  the  sudden  changes  which  this  condition  may  exhibit.  A  similar 
edema  of  the  auditory  labyrinth  is  also  observed  (Schwalbe). 

(c)  Spinal  cord  degeneration,  affecting  the  posterior  columns  and  ganglia, 
results  from  distention  of  the  spinal  arachnoid  with  stretching,  tearing,  and 
compression  of  nerve  roots.    Batten  and  Collier  found  such  changes  in  20  of 
29  cases.    The  cervical  cord  was  chiefly  affected,  the  condition  was  especially 
common  with  cerebellar  tumors,  and  the  chief  symptom  was  loss  of  knee- 
jerks. 

(d}  Meningeal  complications  consist  chiefly  in  local  or  diffuse  invasion 
by  the  tumor  process.  While  very  pronounced  conditions  of  this  type  belong 
to  pial  malanoma  and  rare  forms  of  pial  sarcoma,  Verdun  was  able  to  collect 
28  cases  of  more  or  less  extensive  invasion  of  the  pia  by  various  types  of  tumors. 
In  one  glioma  of  the  pons  he  observed  extensive  pial  thrombophlebitis. 

(e)  Changes  in  the  skull.  The  bones  of  the  skull  may  suffer  absorption 
from  local  pressure  or  thinning  from  general  cerebral  pressure.  Bony  changes 
are  most  common  with  tumors  of  the  base  and  in  children,  and  by  means  of 
the  #-ray  they  form  an  important  class  of  localizing  symptoms.  Up  to  the 
age  of  puberty  intracranial  growths  may  separate  the  cranial  sutures  as  does 
hydrocephalus.  Perforation  of  the  skull  is  observed  with  hypophyseal  growths, 
which  may  discharge  into  the  nares,  and  with  sarcomas  which  penetrate  the 
orbit  or  pharynx. 

Anatomical  Classification. — Of  the  numerous  pathological  conditions  which 
fall  in  the  clinical  group  of  brain  tumors  several  may  for  the  present  purpose 
be  eliminated  from  the  category  of  intracranial  neoplasms.  Such  are  the  soli- 


TUMORS  OF  THE  BRAIN  399 

tary  tubercle,  gummas,  echinococcus  cysts,  and  simple  hydropic  cysts.    The 
remaining  list  of  true  tumors  includes: 

[  Astrocytoma, 
Glioma  j  Gliosarcoma, 

[  Neuro-epithelioma. 

Sarcoma,  derived  from  blood-vessels. 

Endothelioma  and  psammoma,  derived  from  endothelial  structures  of 
the  meninges. 

Papilloma  and  carcinoma  of  the  ventricles  and  choroid  plexus. 

Neurofibroma,  arising  from  cranial  nerve-trunks. 

Melanoma,  derived  from  misplaced  or  wandering  chromatophores. 

Fibroma  and  myxoma,  derived  from  the  dural  connective  tissue  or  repre- 
senting acellular  forms  of  glioma,  or  endothelioma. 

Osteoma. 

Lipoma. 

Cholesteatoma. 

Finally,  there  are  specific  tumors  of  the  pineal  gland  and  the  hypophysis. 

The  plan  adopted  for  the  discussion  of  these  tumors  recognizes  the  fact 
that  some,  especially  the  benign  tumors,  are  of  rare  occurrence  in  the  brain 
and  are  of  more  general  interest.  Fibroma,  osteoma,  lipoma,  endothelioma, 
and  melanoma  are  therefore  included  with  similar  growths  in  other  situations. 

Tumors  of  the  pineal  gland  and  hypophysis  are  treated  as  specific  diseases 
of  these  organs.  There  remain,  as  true  tumors  belonging  to  the  brain,  glioma, 
sarcoma,  and  tumors  of  the  ventricles.  Glioma,  the  chief  cerebral  tumor, 
occurs  in  other  situations  and  its  various  types  and  locations  will  be  con- 
sidered together. 

GLIOMA 

Glioma  is  the  characteristic  tumor  of  the  central  nervous  system  and 
consists  of  neoplastic  neuro-epithelium  or  its  adult  derivative  the  glia-cell. 
Three  structural  forms  of  this  tumor  may  be  distinguished : 

1 .  Astrocytoma,  typical  adult  glioma. 

2.  Gliosarcoma,  anaplastic,  cellular. 

3.  Neuro-epithelioma,  embryonal. 

The  typical  glioma  occurs  in  the  brain,  spinal  cord,  and  roots  of  cranial 
nerves,  while  atypical  forms  arise  both  in  these  organs  and  in  the  eye  and  in 
teratomas.  The  adult  form  of  glioma  consists  of  well-developed  glia-tissue, 
but  in  many  embryonal  tumors  undifferentiated  neural  epithelium  appears 
and  the  tumors  are  called  neuro-epithelioma.  There  are  considerable  varia- 
tions in  the  proportions  of  glia-cells  and  glia-fibers,  giving  rise  to  the  terms 
glioma  molle  and  durum,  and  the  great  predominance  of  round  or  spindle 
glia-cells  deficient  in  fibrils  produces  cellular  tumors  called  gliosarcoma. 
Some  would  limit  the  term  "gliosarcoma"  to  mixed  tumors  derived  from  glia- 
tissue  and  from  mesoblastic  elements  in  nervous  tissue,  but  it  is  doubtful 
if  such  tumors  exist,  and  in  a  morphological  sense  the  term  "gliosarcoma"  is 
admissible  for  cellular  and  malignant  gliomas.  Scanidi  argues  for  the  meso- 
blastic origin  of  a  portion  of  the  glia-cells.  Glia  tumor-cells  often  grow  to 
large  dimensions  and  resemble  ganglion-cells  in  tumors  which  may  be  called 
glioma  ganglionare  or  gangliocellulare. 

Gross  Anatomy. — Gliomas  appear  as  irregular  or  rounded  segments  of 
nervous  tissue  of  greater  or  less  density  than  the  normal  tissue,  but  often 
without  definite  enlargement  of  the  affected  part.  They  are  usually  more 
opaque  than  normal  brain  tissue  and  the  blood  content  is  increased  so  that  the 


400  NEOPLASTIC  DISEASES 

color  is  bluish.  Hemorrhage  or  excessive  development  of  blood-vessels,  glioma 
telangiectaticum,  may  render  them  especially  conspicuous.  Yet  the  borders 
grade  insensibly  into  the  surrounding  tissue  so  that  it  is  often  difficult  to 
determine  the  limits  or  even  the  existence  of  a  glioma  from  the  naked-eye 
inspection.  Gliomas  obliterate  the  normal  markings  of  the  brain,  some  are 
distinctly  nodular  and  quite  firm;  they  may  cause  flat  protrusions  of  the 
pia  and  a  diffuse  thickening  is  often  produced.  Ependymal  gliomas  occur 
in  the  form  of  projecting  nodules  or  larger  masses  which  may  become  pedun- 
culated  (Virchow,  Linck).  In  Bielschowski's  case  and  in  Pfeiffer's  the  tumors 
were  multiple  and  the  ventricles  dilated.  In  size  gliomas  vary  from  a  small 
focus  to  a  diffuse  involvement  of  nearly  a  whole  hemisphere,  with  distinct 
widening  of  the  convolutions.  They  are  seldom  multiple,  and  local  metastases 
•••"•• 


FIG.  161. — Glioma  cerebri. 

are  rare.  Retinal  gliomas  differ  from  the  cerebral  in  producing  bulky  fungat- 
ing  tumors.  In  the  spinal  cord  the  tumors  may  be  localized,  but  usually  they 
arise  in  the  region  of  the  central  canal  into  which  they  extend  in  the  form 
of  long  cords,  destroying  the  gray  matter,  and  sheathed  by  the  white  tissue. 
A  dilated  central  canal  may  persist  and  the  condition  resembles  syringo- 
myelia  (Miura,  Saxer,  Schlesinger) .  Neuro-epitheliomas  frequently  grow 
to  large  size  and  produce  metastases. 

Secondary  degenerations  in  gliomas  are  relatively  frequent.  Hemor- 
rhages, old,  with  formation  of  cysts  and  deposit  of  pigment,  or  recent  and 
diffuse,  belong  to  the  natural  course,  especially  of  the  cerebral  tumors.  Necro- 
sis of  large  central  areas  is  common.  Hyaline  degeneration  may  affect  the 
vessels  and  calcification  may  appear  in  such  vessels  or  in  old  necrotic  areas. 
Globular  myelin  droplets  may  be  very  numerous  and  may  become  calcified. 


TUMORS  OF  THE  BRAIN 


401 


Soft  gliomas  may  be  extensively  edematous,  strands  of  tissue  being  widely 
separated  by  collections  of  fluid.  Myxomatoid  changes  follow  edema  and 
have  led  to  the  use  of  the  term  "myxoglioma."  Cysts  form  from  absorbed 
necrotic  areas,  from  extensive  edema,  areas  of  hemorrhage,  and  dilated  canals. 
The  structure  of  glioma  presents  glia-cells  and  glia-fibers  in  their  various 
forms  and  in  varying  proportions.  In  many  cases  the  typical  spider-cell 
(astrocyte)  is  predominant.  This  cell  has  a  small  compact  nucleus  and 
scanty  cytoplasm,  from  which  radiate  very  numerous  comparatively  short 
fibers.  Golgi  believed  that  the  cells  with  short  fibers  characterize  tumors 


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FIG.  162. — Edematous  glioma  of  brain. 


of  the  outer  cortex  (astromas),  while  cells  with  long  fibers  are  found  chiefly 
in  the  deeper  or  central  gliomas,  but  this  relation  appears  to  be  inconstant. 
In  other  cases  the  cells  are  larger  and  the  fibers  less  numerous  and  much 
longer. 

In  certain  tumors  the  large  glia-cells  possess  cytoplasmic  processes,  large 
nuclei,  with  multiple  nucleoli,  and  closely  resemble  ganglion-cells.  Stroebe 
finds  such  cells  most  frequently  about  the  edges  of  spaces  lined  by  neuro- 
epithelium,  but  they  are  not  limited  to  such  situations,  and  in  some  tumors 
all  the  cells  may  be  of  this  type  (Borst) .  Occasionally  the  cells  contain  multiple 
nuclei,  so  that  Stroebe  speaks  of  giant-cell  glioma.  The  significance  of  these 
ganglionic  glia-cells  has  generally  been  interpreted  as  an  expression  of  the 
normal  developmental  tendency  of  the  originating  cells  of  the  tumor,  both 
glia-  and  ganglion-cells  being  derived  from  neural  epithelium.  Even  in  normal 
brain  tissue  Golgi  and  v.  Kolliker  find  glia-cells  approaching  the  form  of 
ganglion-cells,  and  Renaut's  view  that  glia-cells  functionate  as  conducting 
nerve-cells  is  being  regarded  with  increasing  favor.  Renaut  described  axis- 
26 


402 


N EOF LAST  1C  DISEASES 


FIG.  163. — Detailed  structure  of  glioma  (astrocytoma).      (After  Stroebe.) 


1 


FIG.  164. — Details  of  structure  of  a  glioma.    Astrocytes,  round  cells,  and  cavities  lined 
by  neuro-epithelium.     Muller's  fluid.     Mallory's  hematoxylon.     (After  Stroebe.) 


cylinder  processes  in  the  large  cells  of  glioma,  but  Storch  finds  by  means  of 
Weigert's  neuroglia  stain  that  these  processes  have  the  brush-like  ends  of 
glia-fibers  and  often  terminate  in  the  adventitia  of  blood-vessels.  Mallory 


TUMORS  OF  THE  BRAIN 


403 


finds  that  the  cells  in  many  gliomas  contain  from  2  to  30  of  the  glia  granules 
described  by  Weigert  in  ependymal  cells,  and  that  these  granules  form  a 
valuable  diagnostic  sign  of  glioma.  Pigmented  astrocytomas  of  optic  thalamus 
and  lateral  ventricle  with  ependymitis  granularis  occurred  in  a  case  described 
by  E.  J.  Kraus. 

Finally,  the  cells  in  glioma  may  assume  a  spindle  form,  and  when  they 
are  numerous  the  tumor  resembles  a  spindle-cell  sarcoma.  From  the  poles 
of  such  spindle-cells  the  radiating  fibers  may  usually  be  demonstrated,  and 
portions  of  such  tumors  may  show  more  typical  glia  structure. 

The  glia-fibers  are  the  most  characteristic  element  in  glioma.  Although 
Ranvier  and  Weigert  claimed  that  the  fibers  are  disconnected  from  the  cells, 
Golgi,  Kolliker,  Lenhossek,  and  many  later  observers  using  specific  staining 


FIG.  165. — Large  cell  glioma  of  brain  cortex. 

methods  have  shown  that  the  fibers  emanate  from  the  cells  and  under  ordi- 
nary conditions  retain  their  cellular  connection.  In  normal  tissue  the  great 
length  which  the  fibers  attain,  reaching  IOOO/JL  (Kolliker)  renders  very 
difficult  the  determination  of  their  origin,  and  in  glioses  where  fibers  increase 
and  predominate  over  cells,  solution  of  continuity  may  doubtless  occur. 
The  study  of  gliomas  emphasizes  the  essential  connection  of  fibers  and  the 
growing  glia-cells  into  which  they  are  readily  traced  (Stroebe,  Storch,  Borst). 
That  occasional  separation  of  fibers  from  cells  may  occur  and  that  this 
condition  is  prominent  in  hard  acellular  gliomas  can  at  the  same  time  be 
admitted  (Aschoff).  Ribbert  holds  that  the  relation  of  glia-fibers  and  cells 
is  much  the  same  as  that  between  fibroblastic  fibers  and  cells. 

The  glia-fibers  are  very  numerous,  fine  and  short  (astrocytes),  or  fewer, 


404  NEOPLASTIC  DISEASES 

thicker,  and  longer,  while  from  the  large  glioma-cells  there  may  pass  only  a 
few  coarse,  irregular,  protoplasmic  processes  which  later  assume  the  characters 
of  glia-fibers  and  break  up  into  a  terminal  brush.  Anastomoses  with  other 
fibers  or  connections  with  other  cells  are  not  observed.  Buchholz  and 
Storch  noted  a  striking  accumulation  of  fibrils  about  the  walls  of  blood- 
vessels, but  this  feature  is  not  invariable.  Mallory  finds  that  glia  fibrils 
may  fuse  together  in  a  sort  of  membrane  where  they  meet  connective-tissue 
structures.  Degenerating  fibrils  become  varicose,  fragmented,  and  granular. 
The  proportion  of  fibers  varies  extremely,  the  hard  gliomas  exhibiting  a 
predominance  of  them,  while  in  certain  round-  and  spindle-cell  tumors  they 
may  be  difficult  to  demonstrate.  Stroebe  claims  that  neuroglia  fibers  may 
always  be  demonstrated  in  gliomas,  but  this  criterion  cannot  be  demanded 
for  retinal  gliomas  and  it  is  supplied  with  difficulty  for  some  gliosarcomas. 
Special  stains  are  required  for  their  complete  demonstration,  the  best  of  which 
are  Weigert's  neuroglia  stain  and  especially  Mallory's  phosphotungstic 
acid  hematoxylon. 

In  a  somewhat  peculiar  form  of  cerebral  glioma  the  detritus  of  the  invaded 
tissue  becomes  inclosed  in  large  phagocytic  tumor  cells  in  the  form  of  homo- 
geneous globules  and  much  of  the  affected  area  is  composed  of  such  cells. 
Between  them  lie  many  small  cells  with  compact  nuclei  and  scanty  glia  fibrils 
besides  which  are  many  large  multinucleated  cells  of  uncertain  origin.  On 
the  edges  of  the  tumor  it  seems  possible  to  trace  the  ganglion-cells  of  the 
invaded  cortex  which  become  hypertrophied  with  hyperchromatic  nuclei 
and  are  gradually  lost  among  the  numerous  tumor  cells.  Their  ultimate 
fate  is  uncertain,  but  they  seem  to  participate  in  the  very  diffuse  tumor  process. 

In  many  gliomas  there  are  canals  lined  by  small  cuboidal  cells  which 
resemble  ependymal  epithelium.  The  lumen  is  minute  or  of  considerable 
dimensions  and  the  contents  are  watery  fluid  or  granular  detritus.  The 
external  borders  of  the  cells  merge  insensibly  into  the  surrounding  tissue, 
and  glia  fibrils  are  scanty  or  missing.  Canals  of  this  character  are  to  be  dis- 
tinguished from  rosettes  of  embryonal  and  often  cylindrical  neuro-epithe- 
lium  which  inclose  minute  spaces  and  form  large  cysts  in  neuro-epitheliomas. 
The  significance  of  the  ependyma-like  canals  has  been  variously  interpreted. 
Buchholz  believed  that  glia-cells  of  the  tumor  became  transformed  into 
ependyma-like  cells  with  which  they  are  genetically  related.  Stroebe  and 
many  others  have  concluded  that  the  canals  arise  from  sprouts  and  misplaced 
groups  of  ependymal  cells,  and  this  view  is  suggested  especially  by  the  abun- 
dance of  such  structures  in  tumors  of  the  basal  ganglia  and  spinal  cord.  Mis- 
placed islands  of  ependymal  epithelium  have  been  found  by  Arnold  in  a 
deformed  hemicephalic  brain,  by  Miura  in  syringomyelia,  and  by  Aschoff 
in  ependymitis  granularis.  A  third  origin  has  been  suggested  from  spaces 
lined  by  endothelium.  In  my  own  cases  it  has  been  possible  to  trace  the 
glia-cells  of  the  tumor  into  cubical  epithelium  lining  canals  and  spaces  usually 
of  considerable  size,  and  in  these  cases  the  cubical  cells  are  of  neoplastic  type. 
In  other  cases  canals  lined  by  cubical  epithelium  not  of  neoplastic  type  have 
appeared  on  the  outer  portions  of  the  tumor  and  these  I  believe  result  from 
transformation  of  glia-cells  of  the  invaded  tissue.  Similar  changes  may  be 
seen  in  other  pathological  conditions.  Borst  describes  them  both  in  glioma 
and  in  multiple  sclerosis.  In  central  and  spinal  gliomas  the  inclusion  of 
groups  of  ependymal  epithelium  probably  accounts  for  some  of  the  canals. 
The  participation  of  endothelial  cells  in  this  process  seems  very  doubtful, 
and  the  presence  of  the  canals  does  not  require  an  ependymal  element  in 
the  tumor  anlage,  as  urged  by  Stroebe,  since  any  of  the  glia-cells  may  appar- 
ently produce  the  cubical  cells  in  the  formation  of  the  canals. 


TUMORS  OF  THE  BRAIN  405 

Neuro-epithelioma. — In  a  numerous  group  of  cases  the  cells  greatly  exceed 
the  fibrils,  they  assume  a  polyhedral  or  spindle  form,  rosettes  of  low  cubical 
or  high  cylindrical  cells  surround  central  points  or  canals,  and  from  its  pre- 
dominant cellular  element  the  tumor  is  designated  as  neuro-epithelioma 
or  neurocytoma.  In  this  group  one  has  to  deal  with  a  more  embryonal  form 
of  glioma  in  which  the  cells  develop  but  slightly  from  the  original  form  of 
embryonal  neural  epithelium.  The  essentially  gliomatous  character  of  these 
tumors  appears  in  the  presence  of  very  many  well-formed  neuroglia  fibrils, 
which  with  specific  stains  are  nearly  always  demonstrable  and  often  form  a 
very  prominent  structural  feature.  In  edematous,  degenerating,  and  spindle- 
cell  growths  the  fibrils,  which  are  a  highly  important  diagnostic  feature, 
may  be  scanty  and  difficult  to  identify. 

Neuro-epitheliomas  are  of  wide  distribution,  occurring  in  the  cortex, 
basal  ganglia,  arachnoid,  eye,  spinal  cord,  abdominal  sympathetic,  adrenal, 


**•.'.*»*  A.*,  «e*»«M 


FIG.  1 66. — Structure  of  neurocytoma.     (After  Landau.) 

and  in  teratomas  in  many  situations.  The  retinal  gliomas  are  often  of  this 
type.  Many  of  them  are  very  cellular  and  in  this  class  fall  most  of  the  tumors 
to  which  the  term  "gliosarcoma"  has  been  applied.  It  is  probable  that  the 
gliomatous  nature  of  many  sarcomas  connected  with  the  nervous  system  has 
been  overlooked. 

The  blood-vessels  in  gliomas  are  usually  abundant.  They  appear  as 
medium-sized  arterioles  with  well-developed  walls,  or  as  capacious  venules 
with  thin  walls,  or  as  large  sinuses.  Areas  of  cavernous  blood-vessels  may 
displace  the  tumor-tissue,  and  varicosities  are  common.  The  walls  may 
undergo  a  peculiar  thickening  and  hyalinosis  which  may  terminate  in  occlu- 
sion and  formation  of  lamellated  homogeneous,  or  partly  calcified  masses. 
Proliferation  of  the  cells  in  the  walls  of  vessels  may  be  considerable,  but  a 
true  neoplastic  character  I  have  not  observed  in  this  process.  The  capacity 
of  the  blood-vessels  is  very  great  and  the  blood  content  is  subject  to  wide 


406  NEOPLASTIC  DISEASES 

variations.  Hence  the  course  of  glioma  is  marked  by  intermittent  symptoms 
dependent  on  variations  in  the  blood  content,  and  hemorrhage  with  apo- 
plectic symptoms  is  frequent.  Several  observers  have  noted  an  accumulation 
of  glia  fibrils  about  the  blood-vessels,  a  feature  which  I  have  seen,  especially 
in  neuro-epithelioma.  Small  vessels  may  form  the  nodal  points  of  neuro- 
epithelial  rosettes  and  the  entire  tumor  may  consist  of  thick  perivascular 
cell  sheaths,  an  arrangement  determined  by  the  demands  for  nutrition. 

The  growth  of  gliomas  is  one  of  the  best  examples  of  tumors  of  the  infil- 
trative  type.  The  edge  of  the  tumor  often  merges  insensibly  into  the  sur- 
rounding tissue  and  usually  fails  of  demarcation  by  vascular  reaction  or 
cellular  exudate  or  signs  of  compression.  Yet  the  hard  gliomas  and  the 
neuro-epitheliomas  may  be  sharply  circumscribed  from  the  surrounding  tissue 
by  virtue  of  expansive  growth.  Pressure  symptoms  are  slowly  established 
with  all  varieties  of  glioma,  infiltrative  or  expansive,  but  these  symptoms 
are  partly  dependent  on  the  blood  content  and  may  therefore  be  intermittent. 
Flattening  of  convolutions  often  occurs  and  demonstrates  the  existence  of  a 
permanent  mechanical  element  in  the  pressure  symptoms.  On  the  edges  of 
infiltrating  tumors  one  finds  a  zone  of  round  cells  with  few  or  no  fibrils,  and 


FIG.  167. — Detail  of  fibril  formation  in  a  neurocytoma.      (After  Landau.) 

Ribbert  points  out  that  it  is  only  such  cells  without  fibrils  which  are  capable  of 
explaining  the  infiltration.  Just  within  the  growing  edge  the  cells  develop 
fibrils  which  permanently  fix  their  location.  Hence  the  growth  of  typical 
glioma  is  slow.  Cell-division  by  mitosis,  symmetrical  or  multipolar,  and  by 
amitosis  has  repeatedly  been  observed. 

The  fate  of  the  invaded  tissue  is  gradual  atrophy  and  absorption,  but 
ganglion-cells  may  persist  for  some  time  on  the  edges  of  the  tumor,  and 
Stroebe  finds  in  all  cerebral  gliomas  traces  of  medullated  or  naked  nerve- 
fibers  derived  from  the  original  tissue.  Large  vacuolated  phagocytic  cells 
containing  fatty  detritus  and  pigment  may  appear  on  the  edges  of  the  tumor 
or  throughout  its  substance. 

The  possibility  that  the  normal  glia-cells  are  partly  transformed  into 
tumor  cells  while  actively  opposed  by  Ribbert,  is  considered  as  uncertain 
by  Stroebe  and  others.  It  is  not  yet  clear  what  relation  is  borne  by  certain 
structural  anomalies  observed  in  the  central  nervous  system  and  the  occur- 
rence of  very  diffuse  forms  of  glioma  and  the  uncertain  criteria  which  separate 
glioma  from  certain  glioses  render  somewhat  hazardous  a  definite  opinion 
on  this  point.  In  a  peculiar  form  of  diffuse  cerebral  glioma  I  find  that  the 


TUMORS  OF  THE  BRAIN  407 

ganglion-cells  seem  to  become  hypertrophied,  they  acquire  multiple  pyknotic 
nuclei,  and  become  merged  with  the  numerous  glia-cells  of  the  tumor. 

Resistant  structures  offer  a  rather  firm  barrier  to  the  advance  of  glioma 
even  to  the  most  cellular  varieties.  The  pia  mater  terminates  the  extension 
of  most  cortical  gliomas,  but  is  itself  often  split  up  by  strands  of  cells  which 
fill  the  natural  spaces  of  this  membrane,  leading  to  adhesions,  but  not  to 
metastases.  The  retinal  tumors,  however,  infiltrate  the  perivascular  sheaths. 
Spinal  tumors  also  may  extensively  infiltrate  the  pia  and  subdural  space. 

The  differential  diagnosis  of  glioma  from  sarcoma  may  offer  difficulties, 
especially  with  the  small  round-  or  spindle-cell  tumors.  According  to 
Stroebe  the  small  glia-cells  show  very  scanty  cell  body,  but  some  fine  fibrils 
are  always  attached  to  the  cells.  The  margin  of  the  glioma  shows  infiltra- 
tion by  tumor  cells,  but  lacks  the  sharp  demarcation  and  reactive  inflam- 
mation often  observed  with  sarcoma.  The  glia-cells  are  of  uniform  character 
throughout  the  tumor  and  fragments  of  medullated  nerve-fibers  or  myelin 
droplets  are  always  present.  Gliomas  do  not  infiltrate  the  vessel  sheaths 
and  they  either  stop  at  the  pia  or,  if  infiltrating  its  layers,  do  not  destroy  this 
structure  and  cause  its  fusion  with  the  tumor.  Yet  Pels-Leusden  saw  very 


FIG.  1 68. — A  solid  papillary  pedunculated  neuroblastoma  of  the  fourth  ventricle.     X  3 
(Case  of  Dr.  John  A.  Hart-well.) 

extensive  infiltration  of  the  pia  up  to  the  medulla  from  a  lumbar  glioma. 
A  fibrin  network  is  said  to  closely  simulate  glia  fibrils,  but  fibrin  fibrils  radiate 
from  nodal  points  and  are  not  connected  with  cells,  but  exhibit  numerous 
anastomoses. 

Sarcoma-cells  may  possess  fibrils,  but  they  are  less  numerous  and  more 
granular  than  glia-fibers.  Glioma  without  fibrils  probably  occurs  in  rare 
cases,  but  cellular  tumors  of  this  character  almost  always  prove  to  be  sar- 
comas. The  existence  of  glioma  with  sarcoma  of  the  vessels  of  the  central 
nervous  system  has  not  been  satisfactorily  demonstrated.  In  some  cases 
the  diagnosis  may  remain  in  doubt.  Borst  studied  two  sarcomas  of  the  brain 
which  showed  all  the  gliomatous  characters  except  abundant  fibrils,  and 
Stroebe  claims  to  have  observed  a  primary  infiltrating  round-cell  sarcoma 
of  the  supramarginal  gyrus  with  fatal  hemorrhage.  Such  tumors  suggest 
the  existence  of  glioma  without  fibrils.  In  a  tumor  of  the  lumbar  cord  Thiele 
saw  cellular  glioma  in  the  upper  portion  changing  to  spindle-cell  sarcoma 
below.  Henneberg  also  found  purely  sarcomatous  areas  without  fibrils  in 
a  glioma  of  the  brain.  It  is  therefore  highly  probable  that  anaplastic  gliomas 
occur  in  which  no  trace  of  fibrils  may  be  demonstrable.  Gowers  and  Bruns 


408 


NEOPLASTIC  DISEASES 


both  concluded  that  glioma-cells  frequently  resemble  sarcoma-cells  and  may 
exhibit  no  signs  of  specific  fibrils,  but  Borst  is  inclined  to  exclude  uncertain 
cases  from  the  category  of  glioma.  It  is  probable  that  the  careful  use  of 
modern  staining  methods  will  greatly  limit  the  number  of  doubtful  cases. 

Etiology  of  Glioma. — Although  occurring  at  any  age,  the  predominance 
of  gliomas  in  early  life,  their  frequency  in  childhood,  and  the  occurrence 
of  bilateral  congenital  gliomas  of  the  retina  indicate  that  the  tumor  usually 
results  from  an  embryogenic  disturbance  in  the  structure  of  the  nervous 
system,  v.  Rindfleisch  assumed  the  existence  of  superfluous  embryonal 
tissue  distributed  in  the  glia  structures  as  furnishing  the  cells  of  origin  of 
gliomas.  Lenhossek  conceived  that  these  embryonal  cells  must  take  the 


FIG.  169. — Neuroblastoma  of  fourth  ventricle.     Same  case  as  Fig.  168. 

form  of  indifferent  round  cells  without  fibers,  but  mitotic  figures  have  been 
observed  in  adult  glia-cells  in  forms  of  gliosis,  and  multiplication  of  glia- 
cells  and  especially  of  fibers  occurs  in  chronic  sclerosis.  It  is  quite  clear  that 
these  highly  differentiated  and  firmly  bound  cells  are  by  no  means  devoid 
of  regenerative  power. 

The  association  of  glioma  with  various  gross  deformities  is  further  evi- 
dence of  the  embryonal  origin.  Schule  observed  multiple  glioma  of  the  cord 
with  fissure  of  the  medulla.  Schmidt  interpreted  a  glioma  of  the  nasal  sinus 
as  a  form  of  encephalocele  and  referred  to  several  other  cases  of  the  same 
nature.  Hildebrand  collected  a  series  of  cases  of  glioma  associated  with 
gross  abnormalities  in  the  central  nervous  system. 

Heterotopia  or  local  malformations  of  the  cortex  have  been  observed 


TUMORS  OF  THE  BRAIN 


409 


which  suggest  a  probable  origin  for  some  cerebral  gliomas.  Ernst  described 
misplacement  of  circumscribed  foci  of  cerebellar  tissue  which  exhibited 
some  of  the  characters  of  incipient  glioma.  Baumann  observed  multiple 
thickened  areas  of  cerebral  gyri  in  which  there  were  groups  of  hypertrophic 
ganglion  cells.  Hartdegen  found  a  dozen  very  hard  areas  in  several  convo- 
lutions in  a  newborn  infant  with  spina  bifida.  These  areas  contained  numer- 
ous groups  of  large  polygonal  cells  resembling  large  ganglion-cells.  In  the 
ventricles  projected  several  nodular  swellings  of  the  same  structure. 

Schultze  observed  reduplication  of  the  central  canal  with  glioma  of  cere- 
bellum and  gliosis  of  the  cord.  In  cases  of  congenital  hydrocephalus  there 
may  appear  multiple  nodular  outgrowths  in  the  cortex  which  resemble 


FIG.   170. — Early  multiple  extramedullary  cylindrical  cell  tumors  of  ependyma  and 
spinal  arachnoid.     Section  of  cauda  equina.     (Pfeiffer's  case,  Z.  N,  5.) 

tumors.  They  consist  of  glia-tissue  rich  in  fibers  and  of  ganglion-cells 
and  they  are  associated  with  focal  sclerosis  and  hypertrophies  (Lubarsch, 
Borst).  Small  gliomas  probably  of  this  class  are  described  by  Simon  and 
Meschede. 

The  embryonal  character  and  eccentric  position  of  the  neuro-epitheliomas 
indicate  their  derivation  from  embryonal  and  misplaced  cells,  and  this  origin 
becomes  certain  in  the  numerous  group  of  gliomatous  teratomas  in  which 
the  structure  is  usually  that  of  neuro-epithelioma. 

On  the  other  hand,  the  embryogenic  disturbance  becomes  less  prominent 
and  less  essential  with  the  slowly  growing  and  diffuse  gliomas  of  the  brain 
which  may  exhibit  a  very  wide  distribution.  Such  cases  have  suggested  to 


410  NEOPLASTIC  DISEASES 

Rindfleisch  and  many  others  that  here  the  glioma  is  not  a  true  tumor,  but  a 
chronic,  proliferation  of  glia-tissue  resulting  from  a  disturbance  of  nutrition. 
Stroebe  was  much  impressed  with  this  view  and  even  went  so  far  as  to  describe 
protozob'n-like  structures  in  the  cells  of  old  gliomas.  In  the  cord  the  chronic 
gliosis  associated  with  syringomyelia  passes  through  many  gradations  up  to 
true  glioma  with  central  softening  (Saxer,  Schlesinger),  and  Miura  finds 
it  difficult  to  distinguish  between  central  gliosis  and  glioma.  Meyer  and 
Beyer  describe  focal  lesions  in  the  brain,  the  inflammatory  or  neoplastic 
nature  of  which  they  find  it  difficult  to  determine.  Hererotopia  of  ependy- 
mal  epithelium  seems  to  favor  both  the  gliosis  of  syringomyelia  and  ependymal 
glioma,  and  Schultze  and  Hoffmann  expressed  the  view  that  both  processes 
arise  in  superfluous  tissue  about  the  ventricles  and  central  canal. 

In  a  study  of  7  cases  of  ependymal  gliomatosis  Margulis  found  the  lesion 
distributed  over  the  ventricles,  especially  the  lateral,  and  affecting  also  the 
subcortical  tissues.  It  was  often  associated  with  other  proliferative  processes 
affecting  the  glia-tissue,  but  inflammatory  changes  in  the  vessels  were  missing. 
Many  stages  of  the  progress  terminating  in  sclerosis  may  usually  be  observed 
in  the  same  case.  He  interprets  the  condition  as  a  local  or  general  response 
of  the  glia-tissue  to  infectious  or  toxic  irritation.  The  symptomatology  was 
variable  and  not  specific. 

Pfeifer  found  the  entire  ventricular  system  covered  with  projecting  nodules 
from  which  extended  a  diffuse  infiltration  of  the  surrounding  brain  tissue. 
The  nodules  consisted  of  small  polymorphous  cells  with  fine,  short  processes, 
but  true  astrocytes  were  scanty.  Roccavilla  demonstrated  diffuse  glioma- 
tosis of  brain  and  medulla  in  a  child  with  spina  bifida  and  reduplication  of 
the  central  canal  of  the  cord.  He  regarded  the  gliosis  as  the  result  of  prolifera- 
tion of  congenitally  superfluous  glia-cells. 

All  of  these  observations  form  a  rather  broad  basis  for  the  conception  of  an 
anatomical  predisposition  as  an  essential  factor  in  the  etiology  of  glioma. 
The  formative  influence  of  misplaced  epithelium  may  be  a  factor  of  impor- 
tance in  such  cases,  and  the  etiological  inquiry  leads  back  to  the  influences 
which  cause  the  misplacement.  Here  structural  abnormalities,  chronic  in- 
flammation, and  possibly  trauma  all  claim  attention  (Henneberg). 

Thus  the  etiology  of  glioma  reveals  in  this  group  of  tumors  many  grades 
of  neoplastic  growth,  from  processes  which  are  difficult  to  distinguish  from 
replacement  or  slightly  formative  glioses,  up  to  highly  embryonal  tumors. 

The  relation  to  trauma  has  already  been  discussed. 

Clinical  Types  of  Gliomas. — (a)  Cerebral  gliomas  have  been  chiefly  con- 
sidered in  the  foregoing  general  discussion.  These  tumors  are  usually  soft 
and  hemorrhagic,  ill-defined  or  rarely  firm  and  nodular,  and  their  position 
is  subpial,  intermediate,  or  central.  Multiple  flat  or  nodular  growths  of 
variable  structure  project  into  the  ventricle.  The  cerebellum,  basal  ganglia 
and  medulla,  and  pons  furnish  the  majority  of  cerebral  cases.  The  centrum 
ovale  is  a  favorite  seat.  In  structure  the  great  majority  of  cerebral  gliomas 
fall  in  the  class  of  astrocytomas  with  small  cells  richly  provided  with  fibrils, 
but  gliomas  with  large  ganglionic  cells  are  not  infrequently  observed,  and 
there  are  many  other  variations  in  structure. 

The  histological  classification  includes  the  following  varieties  of  intra- 
cranial  gliomas: 

1.  Embryonal  heterotopias  of  small  segments  of  gray  and  white  matter, 
with  slight  hypertrophy  and  hyperplasia  of  cells  and  fibers. 

2.  Hard  gliomas  approaching  in  structure  simple  gliosis. 

3.  Typical  astrocytomas  with  or  without  canals  lined  with  low  or  high 
epithelium. 


TUMORS  OF  THE  BRAIN  411 

4.  Astrocytomas  with  many  large  ganglionic  glia-cells. 

5.  Neuro-epithelioma. 

6.  Diffuse  atypical  glioma,  with  many  imperfect  astrocytes  and  formation 
of  many  large  multimicleated  cells  and  phagocytic  cells  distended  with  myelin. 

7.  Gliosarcomas,  round-  or  spindle-cell  tumors  with  partial  or  complete 
loss  of  glia  fibrils. 

(b)  Nasal  Glioma. — A  peculiar  form  of  cerebral  glioma  appears  in  children 
as  a  swelling  at  the  base  or  tip  of  the  nose  or  in  the  nasal  sinus  (Schmidt). 
They  arise  as  a  form  of  encephalocele  and  Reid  and  Muhr  traced  the  origin 
through  the  foramen  cecum,  Meyer  through  the  cribriform  plate.    In  2  cases 
of  Clark's  large  ganglionic  glia-cells  were  well  represented,  but  other  cases 
have  shown  only  glia-tissue  with  scanty  evidence  of  progressive  growth. 

(c)  Glioma  of  the  spinal  cord  appears  in  several  widely  different  forms 
dependent  upon  the  origin,  location,  and  varying  grade  of  the  neoplastic 
character  of  the  process. 

1.  Solid  central  glioma  is  a  common  form  of  the  spinal  tumor  of  which 
Schlesinger  has  collected  18  cases.     The  growth  forms  a  cylindrical  mass 
inclosing  or  obliterating  the  central  canal  and  surrounded  by  a  sheath  of 
the  distended  white  matter  wrhich  in  places  may  be  entirely  destroyed.     It 
extends  over  several  segments  in  any  portion  of  the  cord  or  involves  almost 
the  entire  organ  (Daxenberger,  Miura).    A  tumor  limited  to  the  filum  termi- 
nale  was  observed  by  Lachmann,   and   an   irregularly  distributed  growth 
yielding  Brown-Sequard's  syndrome  was  studied  by  Volkmann.    The  tumor 
seldom  reaches  the  pia,  but  this  structure  may  become  involved,  and  in  a  case 
described  by  Pels-Leusden  the  arachnoid  was  diffusely  infiltrated  from  cauda 
to  medulla.    Grund  collected  several  similar  cases. 

The  structure  of  the  tumors  varies  considerably.  Not  a  few  belong  in 
the  group  of  neuro-epithelioma  with  the  predominance  of  polyhedral  or 
spindle-cells  with  spaces  lined  by  high  epithelium  and  comparatively  few 
astrocytes  and  glia-fibers.  Such  tumors  exhibit  expansive  growth,  but  Rib- 
bert  has  observed  both  types  of  growth  in  the  same  tumor.  In  others  the 
structure  is  that  of  the  usual  type  of  cellular  glioma.  Astrocytes  and  glia 
fibrils  are  abundant.  Large  glia-cells  are  also  present,  but  the  adult  characters 
are  prominent,  the  tumors  grow  slowly  and  they  infiltrate  the  surrounding 
tissue.  Canals  and  spaces  lined  by  ependyma-like  cells  and  compact  groups 
of  such  cells  are  present.  The  majority  of  spinal  gliomas  fall  in  this  latter 
class. 

2.  In  a  group  of  cases  a  definite  gliomatous  process  is  associated  with 
syringomyelia  at  one  or  both  poles  of  the  tumor,  which  itself  may  exhibit 
elongated  canals  lined  by  cubical  cells.    A  typical  case  is  that  of  Rosenthal  in 
which  the  tumor  was  composed  largely  of  a  series  of  canals  lined  by  embryonal 
ependymal  cells  lying  in  a  cellular  glioma  with  many  astrocytes.    Other  cases 
of  this  class  have  been  collected  by  Miura.     The  associated  syringomyelia 
has  been  referred  by  some  to  disturbance  in  circulation  caused  by  the  tumor, 
while  others  regard  the  tumor  as  an  advanced  stage  of  a  process  depend- 
ent on  developmental  anomalies  which  lead  also  to  the  syringomyelia.    There 
can  be  little  doubt  that  the  chief  factor  in  the  softening  which  produces  the 
canal  is  the  presence  of  fluid  under  pressure.    Saxer  describes  a  central  glioma 
with  syringomyelia  extending  far  beyond  the  ends  of  the  tumor.     In  the 
central  portions  of  the  tumor  the  canal  was  lined  by  neoplastic  epithelium, 
extensions  of  which  formed  a  part  of  the  growth.     Elsewhere  in  the  tumor 
the  canal  was  walled  by  softened  tumor  tissue.    Above  and  below  the  tumor 
the  canal  lay  in  an  area  of  simple  gliosis  which  Saxer  refers  to  disturbances 
in  circulation  caused  by  the  tumor.     In  a  case  studied  by  Strauss  in  this 


412 


N EOF LAST  1C  DISEASES 


laboratory  the  canal  extended  from  the  cauda  to  the  pons.  It  was  surrounded 
by  a  well-circumscribed  zone  of  dense  gliosis,  beyond  which  the  cord  was 
compressed  or  soft,  edematous,  and  contained  many  granule-cells.  The 
proportion  of  glia  fibrils  and  cells  varied  at  different  levels,  fibrils  greatly 
predominating,  but  ganglionic  glia-cells  were  occasionally  found.  Ependymal 
epithelium  was  entirely  missing  and  all  stages  of  central  softening  of  the 
tumor  could  be  seen.  Here  was  a  low-grade  but  definite  tumor  process  lead- 
ing to  syringomyelia  by  central  softening.  This  case  supports  Saxer's  view 
that  no  embryonal  anomaly  is  needed  for  the  development  of  central  glioma 


FIG.  171. — Miliary  glioma  of  spinal  gray  matter.     (From  a  specimen  of  Dr.  I.  Strauss.} 

with  syringomyelia,  and  that  there  is  no  essential  connection  between  these 
cases  of  glioma  and  the  central  canal  or  its  epithelium. 

3.  In  an  important  group  of  cases  a  pronounced  central  gliosis  is  asso- 
ciated with  extensive  syringomyelia.  The  new  glia- tissue  is  comparatively 
acellular,  but  its  dimensions  are  considerable  and  the  tracts  are  displaced 
and  the  cord  deformed.  Definite  histological  features  of  neoplastic  growth 
are  lacking,  but  not  more  so  than  in  some  slowly  growing  diffuse  gliomas  of 
the  brain.  The  central  space  is  wide  and  an  epithelial  lining  may  be  wanting, 
in  which  case  the  canal  seems  to  be  formed  by  progressive  softening  of  the 
new  tissue.  Or  the  canal  may  be  lined  by  epithelium  which  may  show  numer- 
ous imaginations  extending  into  the  new  tissue.  In  some  cases  the  canal 


TUMORS  OF  THE  BRAIN  413 

may  be  compressed  by  a  bulky  overgrowth  of  rather  cellular  glia  tissue 
(Hoffmann). 

The  significance  of  these  cases  of  syringomyelia  with  overgrowth  of  glia 
tissue  has  been  the  subject  of  much  discussion  by  observers  whose  views 
are  summarized  by  Saxer.  Some  regard  the  process  as  a  true  neoplasm,  while 
others  consider  it  as  a  form  of  inflammatory  gliosis.  In  favor  of  the  neo- 
plastic  theory  is  the  congenital  character  of  some  cases  in  which  the  syringo- 
myelia follows  hydromyelia  with  extensive  gliosis  and  secondary  degenera- 
tion (Saxer,  Schlesinger).  Lateral  invaginations  of  epithelium  occur  with 
hydromyelia  and  may  favor  the  gliosis.  In  certain  cases  without  hydro- 
myelia the  presence  of  outlying  groups  of  epithelial  cells  about  the  central 
canal  suggests  the  deposit  of  superfluous  material  in  this  locality.  Hence 
Hoffmann,  who  finds  considerable  proliferation  of  cells  in  the  new  tissue, 
regards  the  process  as  neoplastic.  Storck,  having  observed  angiomatous 
glioma  in  the  upper  cervical  cord  combined  with  syringomyelia  below,  in- 


FIG.  172. — Neurocytoma.     (From  a  section  of  Symmers'  case.) 

clines  to  the  same  view.  There  is  no  doubt  also  that  pronounced  glioma  is 
occasionally  associated  with  extensive  cavity  formation,  as  in  the  cases  of 
Pels-Leusden,  Saxer,  Strauss,  etc.  On  the  other  hand,  it  is  clear  that  syringo- 
myelia may  result  from  many  processes  not  connected  with  tumor  growth, 
as  in  myelitis,  meningomyelitis,  hematomyelia,  simple  regressive  tissue 
atrophy  (Chiari),  lymph  or  blood  stasis  (Langhans,  Storck)  and  various 
chronic  inflammatory  processes  (Saxer).  The  softening  and  solution  of 
tissue  about  the  central  canal  may  be  referable  to  changes  in  the  blood-vessels 
to  which  this  region  is  prone,  and  the  outgrowth  of  epithelium  is  probably 
often  a  natural  extension  of  the  lining  cells  of  the  canal  in  the  attempt  to 
cover  defects  thus  created  (Miiller,  Meder,  Miura).  Finally,  the  symptoms 
of  genuine  tumors  of  the  cord  are  pronounced  and  progressive,  while  those 
of  the  present  group  of  syringomyelia  are  suppressed  or  mild,  or  of  very  slow 
progress  (Baumler,  Simon). 

It  seems  necessary  therefore  to  exclude  most  of  the  present  group  of  cases 


414 


NEOPLASTIC  DISEASES 


from  the  class  of  true  glioma,  and  to  regard  them  as  representing  that  com- 
mon type  of  process  which  falls  into  an  intermediate  position  between  neo- 
plasms and  inflammatory  or  simple  tissue  hyperplasia.  Syringomyelia  occurs 
in  the  course  of  central  glioma,  but  unless  the  structure  of  the  process  is  clearly 
gliomatous  the  case  should  not  be  classed  in  that  category. 

(d)  Pial  glioma  occurs  as  a  secondary  invasion  of  this  structure  from 
central  tumors  (Pels-Leusden,  Grund),  or  as  a  primary  tumor  arising  from 
misplaced  glia  tissue.  Inglis  reports  a  pial  glioma  composed  of  scanty  astro- 
cytes  and  many  fibrils,  originating  from  the  root  of  the  seventh  dorsal  nerve 
and  forming  a  small  elongated  intradural  tumor.  In  the  numerous  cases 
of  extradural  tumors  collected  by  Leyden,  Goldscheider,  Grund,  and  others  it 
does  not  appear  that  any  uniform  effort  was  made  to  recognize  glioma,  so  that 


>x  -  v 
VJf 


FIG.  173. — Sacral  neurocytoma,  with  rich  development  of  fibrils.     (Mallory's  specimen 

and  stain.) 

the  frequency  of  extradural  glioma  cannot  at  present  be  stated.  Thus  in 
2  cases  recorded  by  Spiller  as  sarcoma,  the  author  later  states  his  impres- 
sion that  they  were  gliomatous.  That  many  supposed  multiple  gliomas  of 
the  cord  are  artefacts  was  shown  by  Van  Giesen. 

(e)  Neurocytoma. — Under  this  term  Wright  has  collected  a  series  of  tumors, 
chiefly  of  the  adrenal  with  metastases  in  the  liver,  but  also  occurring  in  the 
cranium  and  elsewhere.  They  have  the  structure  of  embryonal  neuro-epithe- 
lioma.  In  some  the  cells  exhibit  abundant  fibrils,  in  others  cells  greatly  pre- 
dominate over  fibrils  and  assume  the  rosette  arrangement.  Wright  believes 
that  certain  tumors  reported  as  sarcoma,  lymphoma,  and  lymphosarcoma 
are  in  reality  highly  embryonal  forms  of  neuro-epithelioma,  as  in  the  cases 
of  Pepper,  Tileston  and  Wolbach,  and  Hutchinson.  For  the  so-called  con- 


TUMORS  OF  THE  BRAIN  415 

genital  sarcomas  of  the  adrenal  and  liver  Kretz  has  expressed  the  view  that 
they  arise  from  the  formative  cells  of  the  sympathetic. 

(/)  Teratomatous  Glioma. — Nervous  tissue  occurs  in  a  considerable  pro- 
portion of  teratomas.  In  teratoma  testis,  besides  portions  of  brain,  retina, 
ganglia,  and  ependyma,  neuro-epithelial  cells  frequently  occur  and  may 
occasionally  form  a  considerable  portion  of  the  tumor  (Ohkubo,  Lit.).  In 
ovarian  teratoma  nervous  structures  are  rare. 

From  the  sacral  region  Mallory  has  described  a  large  neuro-epithelioma 
presenting  the  structure  of  carcinoma,  but  exhibiting  an  extensive  develop- 
ment of  neurofibrils.  The  origin  of  the  tumor  he  referred  to  remnants  of 
the  neural  canal  (Fig.  173). 

TUMORS  OF  THE  CHOROID  PLEXUS  AND  EPENDYMA 

A  considerable  variety  of  pathological  processes  occur  in  the  choroid 
plexus  and  ependyma,  many  of  which  have  a  relation  to  tumors  of  these 
structures. 

Pigmentation,  and  calcine,  fatty,  and  amyloid  degeneration  are  frequently 
observed  in  the  choroid  plexus  and  have  been  described  in  detail  by  E. 
Hackel.  Common  structural  changes  include  varicosity  and  overgrowth 
of  blood-vessels,  thickening,  induration,  and  mucoid  degeneration  of  the 
stroma.  Calcine  changes  in  the  vessel  walls  may  lead  to  the  formation  of 
angioliths,  which  are  commonly  observed  in  subjects  over  50  years.  A  diffuse 
overgrowth  of  stroma  and  lining  cells  with  well-marked  squamous  meta- 
plasia may  result  from  chronic  inflammation  (Delamarre,  Merle).  Cysts 
arising  from  mucoid  degeneration  of  the  stroma  occurred  in  15  of  23  cases 
studied  by  Loeper.  Rarely  such  cysts  reach  a  large  size,  and  in  the  case  of 
an  infant  observed  by  Cayley  and  Brown  there  was  protrusion  of  the  parietal 
bone  by  a  very  large  cyst.  In  the  infant  the  choroid  plexus  is  very  highly 
developed  and  the  abundance  of  lipoids,  pigment,  and  glycogen  have  led  to 
the  assumption  that  it  possesses  a  secretory  function.  Petit  and  Girard 
class  this  structure  with  the  hypophysis  and  other  glands  of  internal  secretion. 

The  ependymal  epithelium  is  also  capable  of  marked  proliferation  with 
changes  in  form  and  size  in  acute  and  chronic  simple  and  specific  inflam- 
mations (ependymitis  granularis).  In  several  conditions,  but  chiefly 
in  tumors,  close  relations  are  revealed  between  ependymal  and  glia-cells, 
the  one  readily  becoming  transformed  into  the  other.  Thus,  in  inflamed 
and  edematous  brain  tissue,  polyhedral  cells  often  inclosing  lumina  appear  in 
multiple  foci,  by  a  type  of  embryonal  reversion  of  glia-cells.  In  many  gliomas 
alveoli,  spaces,  and  cysts  form  with  a  lining  of  cubical  or  cylindrical  cells 
of  ependymal  form  (Saxer,  Muthmann,  Sauerbeck,  Lit.).  In  certain  multiple 
ependymal  gliomas  the  ependymal  and  the  modified  glia-cells  are  richly 
commingled  and  one  type  of  cell  passes  into  the  other  (Linck).  With  both 
ependymal  and  plexus  epithelium  nutritional  and  inflammatory  changes 
seem  to  pass  through  many  gradations  into  tumor  processes. 

The  excessive  pigmentation  observed  by  Virchow  in  the  pia-arachnoid, 
with  tumor-like  proliferation  of  cells,  appears  in  exaggerated  form  in  the 
melanomas  arising  from  these  cells  (Pick,  Esser,  Thorel).  Extensive  calci- 
fication of  the  plexus  may  apparently  lead  to  the  rare  osteoma  of  the  ventricle 
(Bonnet).  The  common  angioliths  appear  frequently  in  cellular  tumors  of 
the  plexus.  Myxomas  and  angiomas  recall  the  mucoid  stroma  and  varicosi- 
ties  of  the  chronically  inflamed  plexus.  Hypertrophy  of  the  plexus  may 
lead  to  extensive  overgrowth  of  this  structure,  and  Bruchanow  interpreted 
his  large  papillary  tumor  as  a  simple  hypertrophy  and  hyperplasia.  Ependy- 


416 


NEOPLASTIC  DISEASES 


mitis  granularis  involves  both  epithelium  and  subepithelial  glia  tissue,  and 
seems  to  present  a  frequent  preliminary  to  multiple  ependymal  gliomas  of  the 
ventricles  (Jeremias,  Saltykow). 

General  Etiology. — Tumors  of  this  entire  group  are  comparatively  rare. 
Boudet  and  Clunet  found  32  cases  on  which  to  base  their  study,  but  their  list 
does  not  include  many  recent  cases.  The  majority  of  subjects  are  children 
or  young  adults.  A  history  of  typhoid  fever,  or  coincident  tuberculosis,  has 
frequently  been  noted.  In  several  cases  trauma  had  recently  preceded  the 

outbreak  of  symptoms  (Muthmann,  Sauer- 
beck, Linck,  Saxer). 

The  chief  seats  are  the  fourth,  the  lateral, 
and  the  third  ventricles,  n,  n,  and  7  cases 
respectively  being  located  in  these  situa- 
tions by  Boudet  and  Clunet.  Four  cases 
were  extracerebral  and  in  the  region  of 
the  chiasm.  Cornil  described  two  papillary 
tumors  within  cortical  tissue.  Marchand's 
tumor  was  attached  to  the  oculomotor  nerve. 
Fauret  finds  that  tumors  of  the  fourth  ven- 
tricle are  chiefly  observed  in  children  and 
often  appear  to  follow  trauma.  They  are 
chiefly  astrocytomas  or  ependymal  gliomas. 
He  collected  12  gliomas,  i  gliosarcoma,  3 
sarcomas,  5  papillary  tumors  of  the  plexus, 
and  4  cysts,  all  involving  the  fourth  ven- 
tricle. Hunt  describes  2  congenital  cystic 
tumors  projecting  into  the  fourth  ventricle. 
Weisenburg  collected  30  tumors  of  the  third 
ventricle,  with  autopsy,  and  points  out  that 
the  symptoms  in  these  cases  are  caused  by 
pressure  or  by  hydrocephalus.  The  syn- 
drome is  ill-defined,  but  presents  ocular 
paralyses,  impaired  reaction  of  pupils,  ex- 
ophthalmos,  and  cerebellar  ataxia.  Bassoe 
reports  6  ependymal  gliomas  of  third  and 
fourth  ventricles. 

A  congenital  anatomical  predisposition 
has  often  been  assumed  to  favor  the  de- 
velopment of  tumors  of  the  plexus  and 
ependyma,  but  there  is  little  evidence  in 
favor  of  this  view.  Saxer's  large  congenital 
tridermal  teratoma  attached  to  the  plexus 
is  a  unique  observation. 

Gross  Appearance. — The  tumor  is  usually  single  except  in  the  case  of  the 
ependymal  glioma,  which  is  regularly  multiple.  While  several  small  growths 
have  given  rise  to  perplexing  cerebral  symptoms,  the  tumors  frequently 
reach  the  size  of  an  egg  or  an  orange  and  produce  definite  focal  symptoms. 
While  usually  circumscribed,  they  may  invade  the  brain  tissue.  The  ven- 
tricles are  frequently  distended.  The  papillary  conformation  predominates, 
but  some  growths  are  spongy  or  polycystic,  a  few  resemble  thyroid  gland 
tissue  (Mackay,  Bruce),  and  nearly  all  are  highly  vascular. 

Structure. — Tumors  of  the  ependymal  epithelium  vary  from  the  peri- 
vascular  neuro-epithelioma  toward  the  true  glioma  (astrocytoma)  with  spider- 
cells  and  glia  fibrils,  while  tumors  of  the  plexus  retain  a  papillary  adeno- 


FIG.  174. — Papillary  carcinoma 
of 'choroid  plexus  distending  lateral 
ventricle.  (After  Boudet  and 
Clunet.) 


TUMORS  OF  THE  BRAIN 


417 


carcinomatous  type  and  may  show  squamous  metaplasia.    Von  Wilier  points 
out  that  the  ependymal  epithelium  is  ciliated  at  birth  and  long  retains  the 


v   *A      '*':/  ;/%   •*':• 
%///\  ,'       :.. 


*'.vV 


FlG.    175. — ^Structure   of   papillary  carcinoma  of  choroid   plexus   in   lateral   ventricle. 

(After  Boudet  and  Clunet.) 


FlG.  176. — Papillary  adenocarcinoma  of  choroid  plexus  in  third  ventricle. 

condensed  border  and  intracellular  fibrils  of  ciliated  cells,  whereas  the  plexus 
epithelium  is  granular,  reticulated,  and  secretory  in  type.  These  original 
characters  may  assist  in  the  separation  of  the  two  types  of  tumors. 

27 


418 


NEOPLASTIC  DISEASES 


Three  main  structural  types  are  observed:  (i)  Papillary  adenocarcinoma, 
(2)  squamous-cell  carcinoma,  and  (3)  ependymal  glioma. 

i.  Papillary  adenocarcinoma  is  the  usual  form  of  tumor  of  the  choroid 
plexus.  The  papillary  axis  contains  a  well -developed  blood-vessel  supported 
by  scanty  connective  tissue  which  often  undergoes  mucoid  degeneration. 
Rare  fibromyxomas  probably  represent  a  predominance  of  this  structure. 
The  blood-vessels  are  thin  walled,  often  varicose,  and  subject  to  hemorrhage. 
Calcification  of  the  walls  often  leads  to  complete  occlusion  by  angioliths. 
The  lining  cells  present  one  or  more  rows,  the  first  usually  cylindrical,  the 
others  cubical.  Numerous  capillary  blood-vessels  surrounded  by  a  single 
layer  of  cubical  cells  are  a  common  picture.  In  cellular  growths  adjoining 
papillae  fuse,  the  epithelium  may  grow  diffusely,  and  an  angiosarcomatous 


FIG.  177. — Structure  of  a  papillary  carcinoma  of  choroid  plexus  in  the  third  ventricle. 


structure  may  result.  In  one  case  I  found  all  the  cells  very  small,  cubical, 
consisting  chiefly  of  nuclei,  and  suggesting  a  gliomatous  tendency  (cf.  Boudet). 
Cysts  form  by  mucous  degeneration  of  the  stroma  and  they  are  usually  bounded 
by  palisade  cells. 

Malignant  tumors  yielding  multiple  metastases  in  the  pia  or  brain  tissue 
have  been  observed.  Spat  found  a  primary  tumor  of  the  plexus  or  ependyma 
of  the  lateral  ventricle  with  small  multiple  metastases  in  the  brain  substance. 
Bielschowsky  and  Unger  describe  a  large  vascular  papillary  growth  arising 
from  the  plexus  of  the  lateral  ventricle.  A  second  tumor  developed  in  the 
lateral  horn  of  the  fourth  ventricle  and  14  metastatic  nodules  appeared  in  the 
pia  over  both  hemispheres.  The  structure  presented  capillary  vessels  sur- 
rounded by  radiating  high  cylindrical  cells.  E.  Meyer  found  a  tumor  in  the 


TUMORS  OF  THE  BRAIN 


419 


third  ventricle  composed  of  numerous  hyaline  blood-vessels  surrounded  by 
small  closely  packed  round  cells,  while  two  small  nodules  of  similar  structure 
appeared  in  the  fourth  ventricle.  Although  this  tumor  was  described  as  a 
sarcoma,  a  relation  to  the  small-cell  epithelial  tumors  of  ependyma  or  plexus 
is  suggested.  Kaufmann  also  pictures  round-cell  sarcoma  of  the  pia  with 
hyaline  blood-vessels. 

2.  Squamous-cell  carcinoma  is  the  type  presented  by  certain  tumors  of  the 
choroid  plexus.  Occurring  in  the  third  ventricle  they  may  be  difficult  to 
distinguish  from  acanthoma  of  the  hypophyseal  duct,  but  similar  growths 
are  observed  in  the  fourth  and  lateral  ventricles  and  without  relation  to  the 
hypophysis  (Cornil,  Boudet,  Clunet). 


FIG.  178.  —  Papillary  adenocarcinoma  of  choroid  plexus. 

cells.     (From  Saxer.) 


A  specific  tumor  of  ependymal 


The  structure  is  essentially  a  duplicate  of  the  adenocarcinoma.  The 
squamous  cells  appear  in  scanty  groups  or  diffusely  and  they  form  pearls  or 
diffuse  sheets  usually  surrounded  by  cylindrical  cells. 

Boudet  and  Clunet  collected  7  cases  in  which  keratinization  was  present,  but 
the  origin  of  some  of  their  cases  is  doubtful.  Mott  and  Barrat  in  a  tumor  attached  to 
the  choroid  plexus  observed  intercellular  bridges  between  flat  cells.  E.  Wagner  described 
a  villous  papillary  tumor  near  the  chiasm  without  involvement  of  the  hypophysis.  It 
was  covered  externally  with  many  long  papillae  lined  in  places  by  cylindrical  cells,  in 
other  places  by  flat  stratified  cells.  Selke's  case  has  been  variously  interpreted.  It  was 
a  large  tumor  of  the  third  ventricle  passing  by  the  foramen  of  Monro  into  the  lateral 
ventricles.  The  hypophysis  was  intact.  The  ependyma  about  the  base  of  the  papillary 
tumor  was  represented  by  layers  of  squamous  cells  lying  on  connective  tissue  and  the 
entire  tumor  contained  flat  stratified  cells.  Selke  regarded  the  growth  as  originating 
from  the  ependyma  of  the  third  ventricle,  while  Erdheim  considers  it  a  cystic  tumor  of 
the  hypophyseal  duct.  Saxer  has  described  a  papillary  tumor  of  the  choroid  plexus  of 
the  third  ventricle,  a  compact  papillary  adenocarcinoma  of  the  fourth  ventricle,  and  a 
papillary  squamous  cell  growth  from  the  hypophyseal  duct,  all  of  which  form  in  struc- 
ture comparative  types  of  these  tumors. 


420 


NEOPLASTIC  DISEASES 


3.  Ependymal  glioma  is  a  rare,  but  well-defined  tumor.  Linck  collected 
6  fully  described  cases  and  to  these  may  be  added  those  of  Saxer  (Wunscheim) 
and  Mallory.  Cimbal  refers  to  many  fragmentary  reports.  Its  chief  seat  is  in 
the  fourth  ventricle,  where  it  commonly  produces  a  bulky,  solid,  rather  firm 
but  vascular  tumor  which  produces  marked  pressure  symptoms.  Cimbal's 
tumor  showed  extensive  central  necrosis  and  Henneberg  described  a  gelatinous 
growth  as  large  as  a  hen's  egg.  The  ependyma  of  the  ventricle  is  usually  the 
seat  of  multiple  or  diffuse,  granular  or  papillary  outgrowths,  and  from  such 
lesions  the  tumors  probably  originate.  The  structure  varies  chiefly  in  the 
relative  proportions  of  ependymal  epithelium  and  astrocytes  with  their 
fibers.  At  one  extreme  the  tumors  approach  the  ependymal  adenocarci- 
nomas  (Saxer's  case),  and  at  the  other  they  may  be  chiefly  gliomatous  (Linck's 
case).  Alveolar  groups  of  neural  epithelium  are  regularly  present  in  the  form 
of  cubical  or  cylindrical  cells  inclosing  ill-defined  lumina  or  surrounding  cap- 
illary blood-vessels.  In  some  cases  the  cells  are  very  long  and  cylindrical. 
By  suitable  stains  (Mallory)  neuroglia  fibrils  derived  from)  the  cells  may  be 


FIG.  179. — Characteristic  fibrils  and  granules  of  ependymal  cells.     (After  Mallory.) 

demonstrated.  In  very  cellular  tumors  the  cells  become  more  numerous,  of 
small  size,  round  or  spindle,  the  fibrils  diminish,  and  a  picture  resembling  round- 
cell  sarcoma  may  result.  That  gliosarcoma  in  the  vicinity  of  the  ventricles 
may  develop  in  this  way  may  safely  be  assumed.  The  prominence  of  blood- 
vessels may  suggest  an  angiosarcoma,  or  very  cellular  sheaths  about  blood- 
vessels may  yield  a  peritheliomatous  structure. 

The  origin  of  these  tumors  has  been  traced  satisfactorily  to  the  ependymal 
epithelium  and  the  underlying  glia  tissue.  In  ependymitis  granularis  the 
erosion  of  segments  of  ependymal  cells  permits  minute  extrusions  of  the 
underlying  glia  layer,  forming  the  characteristic  granules  of  ependymitis 
(Jererriias).  Proliferation  of  the  glia  tissue  and  the  neighboring  ependymal 
cells  follows  and  the  tumor  develops  with  varying  proportions  of  these  ele- 
ments (Linck).  A  transformation  of  ependymal  cells  into  astrocytes  probably 
occurs  in  some  tumors,  but  mitotic  figures  are  limited  to  the  rounded  or  cubical 
epithelium  (Saxer). 

Tumors  of  the  Infundibular  Ependyma. — The  hypophyseal  region  and 
the  third  ventricle  are  the  seat  of  a  group  of  papillary  cystic  tumors  which 


TUMORS  OF  THE  BRAIN  421 

strongly  suggest  an  origin  from  ependymal  epithelium.  These  tumors  lie 
outside  of  the  brain  tissue,  but  within  the  dura.  In  advanced  cases  it  may  be 
difficult  to  determine  their  original  relations.  They  are  composed  of  a  loose 
edematous  meshwork  of  connective  tissue  covered  by  one  or  more  layers 
of  small  cubical  epithelium  which  may  be  gathered  into  broad  sheets  or  thrown 
up  into  papillary  projections.  The  great  vascularity  and  the  perivascular 
arrangement  of  the  cells  often  recalls  the  structure  of  the  choroid  plexus. 
Saxer,  Hart,  and  others  have  attributed  such  tumors  to  the  ependymal  epi- 
thelium and  their  occurrence  largely  beneath  the  base  of  the  brain  and  in  close 
relation  to  the  pedicle  of  the  hypophysis  indicates  that  they  may  arise  from 
the  ependymal  prolongation  of  the  infundibulum.  I  have  studied  such  a  tumor 
in  a  young  girl  with  a  long  history  of  cerebral  compression.  The  growth  was 
cystic,  4  cm.  in  diameter,  lay  above  the  hypophyseal  lobes,  had  destroyed 
the  pedicle,  was  separated  by  a  thin  partition  from  the  distended  ventricle, 
and  the  structure  resembled  Saxer's  (Case  I)  ependymal  carcinoma.  A  some- 
what similar  case  is  described  by  Mullaly. 

GLIOMA  OF  RETINA 

Characteristic  clinical  behavior  and  peculiar  structure  render  glioma 
retina  one  of  the  most  striking  examples  of  a  specific  tumor  process.  Many 
of  the  old  cases  of  fungous  hematodes  described  by  Wardrop  were  probably 
of  this  nature.  The  first  histological  descriptions  were  given  by  Robin  in 
1854,  since  which  time  the  interpretation  of  the  tumor  has  been  the  subject  of 
very  extensive  study  and  speculation,  which  have  not  yet  reached  a  final 
conclusion  (Parsons,  Lit.). 

These  tumors  are  soft  and  bluish  in  early  stages,  but  soon  become  milky 
or  gray  from  fatty  degeneration  and  focal  calcification.  They  are  very  sub- 
ject to  necrosis,  and  are  often  hemorrhagic;  23  per  cent,  are  bilateral, 
and  of  these  94  per  cent,  are  under  4  years  of  age.  The  involvement  of 
both  eyes  is  usually  noted  at  the  first  examination,  when  it  appears  that 
the  disease  is  less  advanced  in  one  eye.  Occasionally  the  involvement  of  the 
other  eye  is  noted  sometime  later;  and  in  a  few  cases  a  long  interval,  3,  4,  or 
even  13  years,  has  elapsed  between  the  enucleation  of  the  first  and  the  affec- 
tion of  the  second  eye  (A.  Knapp).  The  initial  growth  may  be  very  slow. 

The  tumors  arise  chiefly  from  the  ciliary  portion  or  from  the  posterior  seg- 
ment of  the  retina.  According  to  Wintersteiner  the  origin  is  often  multiple 
and  chiefly  from  the  posterior  pole.  The  origin  has  been  traced  in  different 
cases  with  considerable  certainty  to  the  internal  granular  layer  (Knapp, 
Hirschberg),  from  the  inner  side  of  external  granular  layer  (Delafield),  from 
the  external  granular  layer  (Schweiger,  Flexner),  from  the  fibrillar  layer 
(Iwanoff).  The  early  anatomic  and  ophthalmoscopic  appearances  are  tabu- 
lated by  Eisenlohr.  The  tumors  grow  expansively,  splitting  the  retina  and 
stripping  it  from  the  choroid  or  covering  it  with  a  mass  of  tissue  which  encircles 
the  vitreous  or  penetrates  it  in  dendritic  masses.  Invading  the  choroid  at  the 
papilla  it  may  form  a  discoid  mass  in  this  structure,  and  traveling  within  the 
optic  nerve  it  reaches  the  base  of  the  brain  (Knapp).  In  the  eyeball  it  later 
replaces  the  vitreous,  invades  all  portions  of  the  bulb,  perforates  the  sclerotic 
or  cornea  by  way  of  the  vessels,  invades  the  orbit,  from  which  in  advanced  cases 
it  protrudes  as  a  vascular  necrosing  tumor  of  large  dimensions.  Metastases  are 
late  or  absent,  but  recurrence  is  common,  and  secondary  growths  appear  in 
brain,  skull,  spinal  cord,  regional  lymph-nodes,  and  internal  organs.  Most 
cases  have  proved  fatal  (66  per  cent.,  Wintersteiner),  but  Collins  reports  four 
recoveries  (?)  from  bilateral  tumors  after  double  enucleation.  Regressive 


422 


NEOPLASTIC  DISEASES 


changes  rather  frequently  occur  in  eyes  that  retain  vision,  especially  in  the 
second  eye,  and  in  a  few  instances  the  regression  appears  to  have  rendered  the 
tumor  quescent,  as  in  Meller's  case.  Renewed  growth  may  begin  after  con- 
siderable periods.  Regression  of  the  tumor  may  follow  rupture  of  the  eyeball, 
with  phthisis  bulbi,  necrosis  of  the  tumor,  and  calcine  or  bony  deposits. 

The  ophthalmoscopic  appearances  of  regressing  glioma  consists  in  irreg- 
ular atrophic  areas  in  the  choroid  and  about  the  macula  and  optic  nerve,  with 
detachment  of  the  retina  by  whitish  masses. 

Glioma  retinae  is  considerably  influenced  by  applications  of  heavily  filtered 
radium  over  the  eyeball,  but  the  regression  produced  is  usually  temporary. 

The  structure  of  glioma  retinae  was  recognized  by  Virchow  as  recalling  that 
of  many  cerebral  gliomas.  The  tumor  is  composed  of  small  round  cells  appear- 
ing often  as  naked  compact  nuclei,  but  exhibiting  a  scanty  cytoplasm  from 
which,  as  a  rule,  no  definite  fibrils  can  be  traced.  The  cells  lie  usually  in  peri- 
vascular  groups  between  which  there  may  be  diffuse  cellular  tissue  or  more 


FIG.  180. — Glioma  of  retina. 

often  necrotic  detritus.  Besides  the  perivascular  groups  two  other  features 
are  revealed  on  close  inspection. 

(i)  The  cells  may  assume  a  low  cuboidal  form  and  be  arranged  in  small 
alveoli  or  rosettes  after  the  manner  of  neuro-epithelial  rosettes  (Flexner, 
Becker).  Such  structures  were  observed  in  n  of  32  cases  by  Wintersteiner, 
and  in  several  cases  I  have  found  them  the  predominating  feature.  By  means 
of  serial  sections  Steinhaus  showed  that  these  rosettes  are  spheroidal  and 
not  tubular  bodies.  On  account  of  this  structure  Flexner  applied  the  term 
"neuro-epithelioma  retinae."  Eisenlohr  also  described  occasional  very  minute 
canals  lined  by  a  thin  membrane,  but  not  bounded  by  cylindrical  cells. 

The  inner  border  of  the  typical  rosettes  is  lined  by  a  thin  membrane  which 
has  been  interpreted  as  a  reproduction  of  the  membrana  limitans  externa, 
while  the  cells  of  the  rosettes  are  believed  to  be  derivatives  of  the  rods  and 
cones.  Similar  structures  have  been  found  in  malformed  eyes  and  in  inflam- 
matory conditions  (Parsons,  Lit.). 

2.  Even  when  the  rosettes  are  not  prominent  the  small  cells  are  not  dif- 
fusely distributed,  but  are  arranged  in  rows  or  indistinct  circles  which  indicate 


TUMORS  OF  THE  BRAIN  423 

traces  of  the  same  tendency  which  produces  the  complete  rosettes.  This 
appearance  is  observed  even  in  the  perivascular  cell  mantles,  but  in  old  tumors 
it  is  gradually  obliterated  (Steinhaus).  In  the  local  extensions  of  the  tumor 
through  the  choroid,  in  the  orbit  or  into  the  brain,  all  traces  of  structure  are 
commonly  missing  and  the  tumor  is  composed  of  small  round-  or  spindle-cells 
which  tend  to  travel  along  the  perivascular  lymph-sheaths.  Yet  Greef  found 
that  in  extrabulbar  extensions  the  tumor  cells  might  show  more  of  the  char- 
acters of  ordinary  glioma-cells. 

The  demonstration  of  glia  fibrils  in  retinal  glioma  requires  special  technic. 
Ordinary  staining  methods  usually  fail  to  reveal  any  trace  of  fibrils  and 
Scaffidi  and  others  have  been  unsuccessful  with  Weigert's  and  Mallory's 
stains.  Greef,  however,  using  the  Golgi-Cajal  silver  impregnation,  found 
many  cells  with  scanty  fibrils,  resembling  the  embryonal  spider-cells  of  the 
optic  nerve,  and  in  some  areas  these  fibrils  were  very  numerous.  Borst  pic- 
tures the  fibers  as  short  and  rudimentary  and  he  finds  them  only  on  the  cyl- 
ndrical  cells  forming  rosettes.  Greef  also  demonstrated  large  ganglionic 
cells  with  many  branching  processes  and  more  numerous  medium-sized  tri- 
polar  cells.  These  observations  have  been  verified  by  Hertel,  de  Gama  Pinto, 
and  others.  Yet  Scaffidi  believes  that  these  large  cells  are  persistent  rem- 
nants of  the  original  retina.  It  may  be  urged  that  the  silver  method  is  not  a 
reliable  means  of  distinguishing  ganglion-cells  from  large  multipolar  glia-cells. 

From  the  descriptions  of  many  authors  it  is  evident  that  the  structure 
varies  considerably.  In  one  group  of  cases  the  perivascular  arrangement  is 
most  prominent,  in  another  the  rosettes  are  the  most  striking  feature,  and  in 
still  others  the  tumors  are  diffuse  and  large  and  small  glia-cells  are  demon- 
strable. These  variations  do  not  warrant  the  assumption  that  the  tumors 
may  be  of  different  nature,  but  they  have  formed  the  basis  of  much  difference 
of  interpretation. 

Etiology. — Glioma  of  the  retina  appears  almost  exclusively  in  infants  and 
two-thirds  of  the  cases  occur  before  the  fourth  year.  The  congenital  char- 
acter is  most  remarkable.  Newton  reports  a  family  of  16  children,  10  of  whom 
died 'of  retinal  glioma,  in  7  of  which  the  disease  was  bilateral.  Wilson  saw  8 
children  in  one  family  affected  and  several  other  similar  reports  have  been  col- 
lected by  Williams.  An  hereditary  element  may  possibly  be  traced  in  the 
cases  of  Steinhaus  and  of  Feinstein  in  which  several  first  cousins  were  victims 
of  the  disease. 

The  tumor  has  several  times  been  associated  with  ocular  deformities, 
as  microphthalmos  (Helfreich,  Ginzberg,  Salzmann),  or  persistent  embryonal 
vessels  in  the  lens  (Eisenlohr).  The  embryonal  structure  accords  with  the 
congenital  origin.  Although  there  has  been  much  discussion  as  to  the  nature 
of  the  growth,  the  general  resemblance  to  other  gliomas  in  which  fibrils  are 
demonstrated  with  difficulty  and  the  demonstration  of  spindle-cells  by  Greef 
and  others,  are  satisfactory  evidence  of  the  embryonal  gliomatous  nature. 
The  exact  nature  of  the  embryogenic  disturbance  can  only  be  surmised,  while 
its  cause  is  entirely  obscure.  The  tumor  bears  a  strong  resemblance  to  the 
outer  granule  layer  of  the  retina  to  which  its  early  stages  have  been  traced, 
so  that  one  may  assume  the  existence  in  this  locality  of  superfluous  or  mis- 
placed tissue  material.  Wintersteiner  concludes  that  the  tumor  arises  from 
misplaced  elements  of  the  outer  retinal  layers  which  have  been  found  as 
rosettes  in  a  series  of  malformed  inflamed  eyes.  He  assumes  that  the  dis- 
turbance must  occur  late  in  the  development  of  the  retina,  but  the  highly 
embryonal  structure  of  the  growth  and  its  association  with  gross  abnormali- 
ties favor  an  earlier  origin  (Greef,  Axenfeld,  Emanuel).  Trauma  has  been  held 
responsible  for  the  outbreak  of  many  cases,  but  usually  on  uncertain  evidence. 


424  NEOPLASTIC  DISEASES 

SARCOMA  OF  BRAIN  AND  MENINGES 

The  only  well-defined  form  of  sarcoma  of  the  brain  and  meninges  is  de- 
rived from  the  walls  of  blood-vessels,  and  since  these  tumors  are  often  quite 
vascular  they  may  be  regarded  as  essentially  angiosarcomas.  Very  cellular 
tumors  composed  of  round  cells  arise  from  the  glia-tissue  and  are  best  desig- 
nated as  gliosarcomas  or  malignant  gliomas.  Cellular  endotheliomas  also 
present  many  features  of  spindle-cell  sarcoma,  but  in  all  but  rare  instances 
they  may  be  identified  on  minute  structural  features,  such  as  the  presence 
of  areas  of  flat  cells  and  a  concentric  arrangement  around  small  canals.  Owing 
to  the  general  similarity  of  structure  it  is  probable  that  the  sarcomas  recorded 
in  the  literature  include  tumors  of  each  of  the  three  above  groups.  There  has 
been  much  controversy  over  the  use  of  the  term  "gliosarcoma."  Strictly  speak- 
ing, this  word  signifies  a  mixed  tumor  of  glia-cells  and  some  mesodermal  cell. 
It  is  not  clear  that  any  such  mixed  tumor  exists,  although  Stroebe  describes  a 
rare  growth  with  commingling  of  glia  and  mesodermal  cells,  and  Merzbacher 
saw  reactive  proliferation  of  glia  about  invading  pial  sarcoma.  Wohlwill  also 
describes  as  true  gliosarcoma  a  tumor  composed  of  glia-cells  in  one  portion  and 
mesoblastic  cells  in  another.  Entirely  separate  glioma  and  sarcoma  in  the  same 
brain  are  recorded  by  Hanel. 

Gross  Anatomy. — (i)  Sarcoma  arises  chiefly  from  the  dura  and  pia  and 
probably  some  deeply  placed  tumors  develop  from  the  blood-vessels  of  the 
brain.  Their  position  is,  therefore,  extra-  or  intracerebral,  and  about  equally 
frequent  in  all  parts  of  the  brain.  They  produce  firm  or  soft  opaque  cellular 
well-circumscribed  tumors  which  may  attain  large  dimensions.  Putnam 
describes  one  case  in  which  the  tumor  replaced  nearly  one-half  of  the  cere- 
brum. It  was  successfully  removed,  but  recurred  after  some  months.  Hen- 
schen's  series  includes  a  large  cystic  sarcoma  replacing  a  parietal  lobe,  one 
involving  vertex,  dura,  and  base,  one  arising  from  the  occipital  portion  of  the 
falx,  and  one  involving  both  hemispheres.  Stern  saw  the  entire  corpus  callosum 
destroyed,  while  a  very  large  tumor  of  chronic  course  occupied  most  of  the 
frontal  region.  Many  of  the  large  tumors  are  soft,  cystic,  or  hemorrhagic. 
Arising  from  the  membranes  they  at  first  displace  but  eventually  tend  to 
invade  the  brain  tissue.  At  all  times  they  are  rather  sharply  defined  from  the 
surrounding  brain  tissue,  occasionally  by  a  capsule. 

Perforating  dural  sarcomas  are  rarely  observed  and  most  of  these  tumors 
probably  arise  from  the  bone.  In  certain  instances  an  intradural  tumor 
has  forced  its  way  through  the  dura,  eroded  the  skull,  and  appeared  beneath 
or  even  on  the  scalp  (Bruns). 

Arising  from  the  outer  side  of  the  dura  they  may  perforate  the  bone  and 
appear  externally,  or  most  of  the  growth  may  remain  in  the  skull  at  the 
expense  of  the  brain  tissue.  Weisewange  has  collected  a  series  of  perforating 
tumors,  a  few  with  the  structure  of  alveolar  sarcoma,  which  he  traces  to  dura, 
diploe,  or  periosteum.  The  typical  osteosarcomas  of  bone  also  perforate  the 
skull  in  either  direction. 

Osteochrondrosarcoma  arising  within  the  cerebellum  and  extending  into 
the  spinal  canal  is  described  by  Jacobson  and  Jamane. 

2.  Diffuse  Sarcoma  of  Cerebral  Meninges. — While  local  invasion  of  the 
meninges  by  malignant  tumors  is  not  uncommon,  a  wide-spread  extension 
over  meninges,  ependyma,  nerve  roots,  and  down  the  spinal  cord  is  observed 
in  a  limited  number  of  characteristic  cases  which  include  glioma,  sarcoma,  en- 
dothelioma,  melanoma,  and  one  tumor  of  the  pituitary  gland  (Schlesinger's). 
Verdun  has  collected  28  cases  of  this  group  of  sarcomas,  to  which  may  be 
added  several  others  from  the  reports  of  Nonne  and  M.  Rindfleisch,  as  well  as 


TUMORS  OF  THE  BRAIN  425 

recent  cases  of  Markus  and  Almecrona.  The  same  condition  usually  involves 
both  brain  and  spinal  cord,  but  in  many  cases  only  one  of  the  regions  was 
examined.  Occasionally  the  brain  alone  or  the  cord  alone  is  affected. 

The  anatomical  conditions  vary.  In  some  cases  there  is  a  large  primary 
tumor  from  which  the  diffuse  invasion  spreads  through  the  arachnoid  space 
(Weaver).  Or  small  multiple  tumors  may  appear  at  several  points  connected 
by  diffuse  invasion  of  the  pia.  This  condition  is  observed  chiefly  with  sub- 
ependymal  gliomas  of  the  ventricles  (Martens,  Seiffer,  Verdun). 

No  definite  tumor  mass  may  be  present  anywhere,  but  the  meninges 
exhibit  a  moderate  diffuse  opacity.  To  this  form  Orith's  term,  pachymen- 
ingitis  internet,  sarcomatosa,  best  applies.  In  such  a  case  Marcus  found  the 
changes  to  consist  of  proliferation  of  large  hyperchromatic  cells  in  the  walls  of 
blood-vessels  occluding  the  lumen.  Almecrona  described  a  very  similar  case 
as  endothelioma.  It  was  complicated  by  invasion  of  the  brain  tissue  and 
metastases  in  the  liver. 

In  other  cases  of  this  group  the  structure  has  been  described  as  large 
round-cell  sarcoma  (Weaver),  spindle-cell  sarcoma  (Carnot-Bougle),  glio- 
sarcoma  (Fischer),  ependymal  glioma  (Verdun). 

While  it  is  thus  evident  that  diffusion  in  the  pia  is  not  peculiar  to  any 
one  form  of  sarcoma,  yet  the  cases  without  any  localized  tumor  stand  out 
from  the  others  as  a  disease  sui  generis  for  which  a  special  etiology  must 
probably  be  found.  Many  of  the  patients  are  young.  The  clinical  course  is 
that  of  chronic  meningitis. 

Structure. — The  structure  of  the  typical  angiosarcoma  of  the  brain  is 
often  an  exact  duplicate  of  that  observed  for  this  tumor  in  other  regions. 
There  are  many  blood-vessels  lined  by  endothelium  and  supported  by  a  thin 
layer  of  connective  tissue,  beyond  which  lies  a  broad  sheath  of  polyhedral, 
rounded,  or  spindle-cells.  The  unit  of  the  vessel  and  its  cell  sheath  is  very 
prominent.  The  vessels  may  be  widened,  the  walls  imperfect,-  and  the  tissue 
infiltrated  with  blood.  Areas  of  necrosis  and  cyst  formation  may  greatly 
alter  the  appearance.  Oppenheim  describes  pigmentation  of  these  and  of  less 
vascular  sarcomas.  In  fact,  not  a  few  diffuse  melanomas  of  the  pia  closely 
resemble  the  non-pigmented  sarcomas,  differing  chiefly  in  the  presence  of 
pigment.  A  possible  relation  between  these  processes  may  well  be  considered. 
Berblinger  found  perithelial  sarcoma  associated  with  diffuse  melanoma,  but 
he  regarded  the  two  processes  as  distinct. 

Very  cellular  forms  of  this  tumor  probably  give  rise  to  diffuse  large  round- 
cell  or  giant-cell  sarcoma.  Coste  and  Levy  describe  both  these  structures 
in  the  rapidly  growing  recurrence  of  an  original  typical  perithelioma  which 
was  possibly  of  traumatic  origin.  In  another  group  of  cases  the  abundant 
sheaths  of  perithelial  cells  are  not  prominent,  the  vessels  are  more  numer- 
ous and  smaller,  and  the  tumor  cells  are  arranged  concentrically  about  the 
vessel,  forming  a  thickened  wall  lined  by  tumor  cells  or  a  single  layer  of  endo- 
thelium. These  tumors  resemble  very  cellular  granulation  tissue.  With 
increasing  proliferation  of  tumor  cells  and  loss  of  vessels  they  pass  into  spindle- 
cell  sarcoma.  Such  tumors  develop  both  in  the  pia  and  in  the  substance 
of  the  brain.  The  great  difference  in  the  structure  of  these  two  forms  of 
sarcoma  suggests  a  difference  in  origin.  One  is  embryonal  or  anaplastic  in 
type,  the  other  more  adult.  In  neither  case  has  the  origin  been  traced. 

Myxomatous  changes  occur  in  vascular  sarcomas  as  well  as  in  glioma 
and  endothelioma,  and  the  exact  origin  of  the  growths  which  are  largely 
myxomatous  is  not  clear.  Oppenheim  described  a  calcified  chondromyxo- 
angioma  as  large  as  the  fist  developing  in  the  frontal  region  of  a  boy  of  16 
years,  8  years  after  trauma. 


426  NEOPLASTIC  DISEASES 

The  malignancy  of  most  brain  sarcomas  is  considerable  and  some  show 
extremely  active  growth,  especially  after  operative  interference.  The  peri- 
thelioma  of  Coste  and  Levy  recurred  promptly  and  reached  a  very  large 
size  with  a  change  to  a  diffuse  structure.  Putnam's  large  tumor  recurred 
only  after  an  interval  of  several  months.  Boettiger  examined  the  site  of  a 
sarcoma  10  years  after  its  removal  and  found  only  a  cyst  and  a  scar,  but  he 
failed  to  describe  the  original  growth.  Not  a  few  of  the  successful  operative 
results  appear  to  be  with  angiosarcoma  or  perithelioma.  The  prolonged 
course  (Stern)  as  well  as  the  successful  removal  of  some  of  these  tumors  indi- 
cate that  the  prognosis  may  not  be  entirely  unfavorable.  Yet  their  natural 
tendency  is  to  grow  rapidly  and  steadily  until  within  a  few  months  there 
is  extensive  destruction  of  brain  tissue,  and  a  fatal  outcome  is  assured.  General 
metastases  are  not  observed. 


CHAPTER  XXIII 
TUMORS  OF  NERVE  TRUNKS 

Neuroma  is  a  tumor  composed  of  nerve-cells  and  nerve-fibers,  in  which 
form  it  is  usually  designated  as  neuroma  ganglionare  or  ganglionic  neuroma. 
Extensive  overgrowth  of  nerve-fibers,  medullated  and  non-medullated,  occurs 
without  participation  of  ganglion-cells,  and  this  process  is  termed  neuroma 
myelinicum  or  amyelinicum. 

Although  ganglion-cells  and  their  process  stand  as  the  most  highly  dif- 
ferentiated and  immutable  of  the  soft  tissues,  yet  both  cells  and  processes 
occasionally  reveal  surprising  powers  of  growth,  the  cells  yielding  genuine 
neoplasms,  and  the  fibers  multiplying  or  sprouting  to  an  extent  which  closely 
approaches  the  nature  of  a  neoplasm. 

Intermediate  grades  of  proliferation  of  nerve-fibers  which  do  not  consti- 
tute genuine  tumors  are  rather  numerous. 

Traumatic  Neuroma. — In  amputation  stumps  and  after  severe  injuries 
to  peripheral  nerves  the  fibers  may  exhibit  protracted  and  excessive  pro- 
liferation, giving  local  thickenings  which  resemble  tumors.  The  connective 
tissue  of  the  severed  nerve  bundles  first  proliferates  and  forms  a  mass  of 
cellular  tissue  into  which  the  nerve-fibers  push  their  way.  The  axis-cylin- 
ders elongate,  divide,  and  sprout  into  the  surrounding  tissue  in  the  form 
of  twisted  bundles  in  which  medullary  sheaths  are  present  or  absent.  The 
nuclei  of  the  medullary  sheaths  multiply  and  provide  new  sheaths  for  the 
axis-cylinders.  The  result  is  a  marked  thickening  of  the  ends  of  the  nerves 
and  when  several  masses  join  with  each  other  and  with  the  thickened  fasciae 
and  scar  tissue  a  nodular  tumor  of  considerable  size  is  produced.  Since  very 
similar  changes  occur  in  the  simple  regeneration  of  nerve-trunks  (Bunger) 
the  amputation  neuroma  must  be  regarded  as  a  form  of  regenerative  over- 
growth comparable  to  proud  flesh  (Thoma).  Yet  Ziegler  holds  that  the  proc- 
ess may  exhibit  certain  neoplastic  characters. 

Plexiform  Neuroma. — While  in  most  cases  of  neurofibromatosis  the 
nerve-fibers  are  passive  and  gradually  atrophy,  there  are  rare  forms  of  over- 
growth of  nerve-trunks  and  ganglia  in  which  the  nervous  elements  take  part 
in  the  hyperplasia.  In  certain  plexiform  neuromas  of  neck,  back,  eyelid, 
and  face  the  elongated,  nodular,  and  contorted  nerve-trunks  show  preser- 
vation of  nerve-fibers,  and  Ziegler,  Birch-Hirschfeld,  and  Klebs  believe  there 
may  be  an  active  new  growth  of  nerve-fibers  (Bruns,  Lit.). 

In  the  cirsoid  neuroma,  which  consists  of  a  congeries  of  elongated  and 
irregularly  thickened  nerve-trunks,  Ziegler  points  out  that  the  bulk  of  nerve- 
tissue  is  greatly  in  excess  of  that  normally  provided  for  the  affected  part. 
These  processes  seem  to  stand  in  an  intermediate  position  between  genuine 
neuroma  and  neurofibroma.  Thoma  describes  neuroma  of  the  Pacinian 
bodies  of  the  skin,  producing  small  painful  tumors  which  are  chiefly  fibrous, 
but  may  show  overgrowth  of  nerve-fibers. 

True  Fibroneuroma. — Virchow  divided  tumors  of  nerve-trunks  into  true 
and  false  neuromas.  The  false  neuromas  arise  by  proliferation  of  connective 
tissue  and  endothelium  of  the  nerve-trunks  with  passive  atrophy  of  nerve- 
fibers,  and  this  group  is  numerously  represented  in  the  multiple  neurofibroma 
of  Recklinghausen.  Since  his  work  true  neuroma  of  peripheral  nerve-trunks 
has  nearly  disappeared  from  the  literature.  Yet  Virchow  gave  a  fullde- 

427 


428  X  EOF  LAST  1C  DISEASES 

scription  of  tumors  of  outlying  tissues  in  which  he  recognized  new  growth  of 
nerve-fibers  with,  and  more  often  without,  myelin  sheaths.  The  tumor  is 
composed  of  masses  of  long,  straight  running,  branching,  and  anastomosing 
nerve-fibers  in  which  lie  many  long  oval  nuclei.  These  fibers  he  identified 
as  naked  nerve-fibers,  and  in  some  tumors  he  traced  them  into  fibers  possess- 
ing myelin-sheaths.  The  amy clinic  tumors  he  regarded  as  an  undeveloped 
form  of  the  myelinic.  Virchow  collected  a  series  of  cases  of  this  class  in  all 
of  which  there  seemed  to  be  a  new  growth  of  atypical  nerve-fibers.  In  recent 
literature  this  group  of  tumors  seems  to  have  been  divided  among  the  neuro- 


FlG.  181. — Multiple  neuromata  of  the  peripheral  nerves:  A,  Nerves  of  the  right 
arm;  B,  the  left  sciatic  with  its  branches;  C,  the  left  anterior  crural  with  its  branches. 
(Pruden's  case.) 

fibromas  on  the  one  hand  and  the  ganglionic  neuromas  on  the  other.  The 
existence  of  true  fibroneuroma  has  been  emphasized  anew  by  Knauss,  but 
his  tumor  was  a  ganglionic  neuroma. 

Borst  and  Ribbert  are  quite  convinced  that  a  neoplastic  growth  of  nerve- 
fibers  apart  from  ganglion-cells  does  not  exist,  but  this  conclusion  does  not 
dispose  of  the  possibility  of  marked  overgrowth  of  peripheral  nerve-fibers 
without  corresponding  multiplication  of  ganglion-cells.  T  have  seen  several 
tumors  of  this  type  of  small  size  and  occurring  beneath  the  skin. 

Bruce  and  Dawson,  in  an  elaborate  study  of  a  remarkable  case  of  multiple 
miliary  myelinic  neuromas  of  medulla,  cord,  and  pia,  have  fully  disposed  of 


TUMORS  OF  NERVE  TRUNKS 

<*~?  '•' '     '"•' 


429 


FIG.  182. — Structure  of  a  true  neuroma  with  well-formed  medullated  nerve-fibers. 


FIG.  183. — Nerve  fibrils  in  a  true  neuroma.     (Stained  by  Weigert's  method.) 


430 


N  EOF  LA  STIC  DISEASES 


the  theory  that  medullated  nerve-fibers  cannot  develop  without  the  trophic 
or  functional  influence  of  ganglion-cells.  In  this  case  the  very  numerous 
neuromas  developed  from  indifferent  widely  scattered  cells  which  the 
authors  regarded  as  embryonic  residue.  They  clearly  traced  the  origin  of 
medullated  nerve-fibers  in  chains  of  peripheral  cells  of  the  above  type.  It  is 
interesting  to  note  that  these  cells  and  the  resulting  fibers  in  the  tumors 
showed  a  notable  tendency  to  develop  in  the  adventitia  of  blood-vessels. 
These  observations  may  have  an  important  bearing  on  the  histogenesis  of 
various  more  cellular  tumors  of  the  nervous  system,  in  which  myelinization 
does  not  occur,  especially  the  sarcomas  of  nerve-trunks  and  pia  mater. 

Ganglionic  Neuroma. — Tumors  composed  of  ganglion-cells  and  nerve- 
fibers,  while  rare  outside  of  the  central  nervous  system,  have  occurred  in  a 
small  group  of  cases  and  present  rather  notable  characteristics.  They  form 
small,  nodular,  and  multiple  growths,  or  bulky,  single  tumors  located  beneath 


FIG.  184. — Structure  of  myelinic  neuroma.     (Bruce  and  Damson.) 

the  skin  or  more  often  in  the  course  of  large  nerve-trunks  or  plexuses,  in  the 
adrenal,  gastro-intestinal  tract,  retroperitoneal  region,  skin,  and  about  the 
cerebral  and  spinal  dura.  They  seem  to  be  chiefly  or  exclusively  derived 
from  the  sympathetic  system  (Knauss,  Falk,  Lit.),  arising  usually  from  the 
thoracic  and  abdominal  sympathetic  trunks  and  ganglia  and  from  the  per- 
ipheral circumvascular  sympathetic  plexuses.  These  tumors  may  be  regarded 
as  the  counterpart  of  the  ganglionic  gliomas  of  the  central  nervous  system. 

In  the  gross  the  tumors  resemble  soft  fibromas,  with  radiating  markings 
which  correspond  to  the  bundles  of  nerve-fibers.  Their  position  may  suggest 
their  relation  to  the  sympathetic.  The  microscopical  structure  shows  bun- 
dles of  nerve-fibers  coursing  among  ganglion-cells  and  supported  by  connec- 
tive tissue  and  blood-vessels.  Fat-cells  may  also  be  present.  The  fibers 
may  be  chiefly  medullated  or  wholly  non-medullated.  The  ganglion-cells 
are  of  ordinary  characters  or  hypertrophied  to  giant  size,  but  deficient  in 


TUMORS  OF  NERVE  TRUNKS 


431 


chromatic  substance,  or  they  may  be  very  numerous  and  approach  the  form 
of  large  round  cells.  Falk  believes  that  the  connective  tissue  participates  in 
the  growth  and  that  the  neoplasms  are  mixed  tumors.  They  differ  in  com- 
position from  the  neuro-epithelioma  or  neurocytoma  which  Wright  described 
as  arising  from  the  sympathetic.  The  true  ganglionic  neuroma  may  be  diffi- 
cult to  distinguish  from  fibroma  of  ganglionic  nerve-trunks,  in  which  both 
cells  and  fibers  may  long  persist.  In  the  multiple  neurofibroma  of  stomach 
and  intestine  the  tumors  are  probably  derived  from  sympathetic  nerves  and 
ganglia  and  ganglion-cells  may  long  persist  (Askanazy).  The  ganglion  may 
become  greatly  distended  with  myelin-like  material.  Beneke  describes  mi- 
toses, and  many  forms  of  degeneration  and  atypical  cell  growth. 

The  adrenal  is  the  chief  seat  of  ganglionic  neuroma,  where  tumors  from 
the  size  of  a  cherry  to  that  of  a  man's  fist  have  been  observed  by  Weichsel- 
baum,  Bruchanow,  and  Ribbert.  In  a  case  of  Schmidt's  the  tumor  lay  be- 


FlG.    185.— Structure 


medullated   nerve-fibers   in    myelinic   neuroma. 
Daw  son.) 


tween  kidney  and  adrenal,  yet  the  suprarenal  plexus  was  normal.  A  com- 
bination of  suprarenal  tumor  with  multiple  growths  on  the  surface  of  the 
cerebellum,  cerebrum,  spinal  cord,  in  the  cauda  equina,  spinal  ganglia,  audi- 
tory nerve  roots,  and  axillary  plexus,  and  sciatic  nerve  occurred  in  a  remark- 
able case  described  by  Soyka.  In  the  thorax  Loretz  and  Borst  have  described 
subpleural  tumors  lying  near  the  spinal  column  and  doubtless  derived  from 
the  thoracic  plexus.  Multiple,  subcutaneous  tumors  probably  originating 
from  perivascular  plexuses,  recurrent  or  associated  ,with  internal  tumors,  are 
recorded  by  Soyka  and  by  Knauss.  In  Kredel's  case  scores  of  small  and 
large  tumors  were  scattered  over  the  body  of  a  5-year-old  child.  Chiari, 
Busse,  and  Beneke  found  unusually  large  tumors  arising  from  the  abdominal 
or  pelvic  plexuses. 

Malignant  neuroma  occurred  in  a  remarkable  case  of  Beneke's. 

In  a  child  of  10  years  a  tumor  the  size  of  a  man's  head,  of  seven  years'  duration,  orig- 
inating in  the  region  of  the  celiac  axis,  was  found  to  consist  largely  of  typical  ganglionic 


432 


NEOPLASTIC  DISEASES 


neuroma,  but  in  some  wide  areas  the  ganglionic  cells  could  be  traced  into  smaller  rounded 
cells  without  processes  and  arranged  in  the  form  of  alveolar  sarcoma,  which  structure 
also  appeared  in  much  enlarged  lymph-nodes.  A  much  less  cellular  tumor  with  sec- 
ondary growths  in  neighboring  lymph-nodes  is  described  by  Miller.  These  cases  form  a 
transition  group  between  ganglionic  neuroma  and  malignant  neuroblastoma,  which  will 
be  described  under  the  tumors  of  the  adrenal,  from  which  organ  they  chiefly  arise.  The 
entire  group  has  been  systematically  discussed  by  Wahl  and  by  Dunn. 

In  the  etiology  of  ganglionic  neuroma  one  must  assume  an  embryonal 
disturbance  of  the  structure  of  the  sympathetic  nervous  system  with  the 
presence  of  superfluous  undifferentiated  tissue  in  localities  giving  origin  to 
the  tumors.  This  view  is  favored  by  the  congenital  or  early  appearance  of 
the  tumors,  by  the  undeveloped  character  of  their  component  structures, 
by  their  wide  and  multiple  distribution.  As  to  the  nature  and  cause  of  this 


FlG.  1 86. — Advancing  edge  of  infiltrating  neurofibrosarcoma. 


disturbance  nothing  is  known,  but  congenital  variations  in  the  size  of  various 
nerve- trunks  and  ganglia  have  frequently  been  observed  (Virchow). 

Acoustic  Neurofibroma. — Intracranial  tumors  of  the  nerve-trunks  affect 
chiefly  the  acoustic,  rarely  the  trigeminus  nerves,  and  form  a  relatively  fre- 
quent and  characteristic  group  of  brain  tumors  (Henneburg  and  Koch; 
Fraenkel  and  Hunt,  Lit.).  They  are  usually  single,  rarely  bilateral,  and  may 
form  a  part  of  general  neurofibromatosis.  Neuromas  of  the  other  cranial 
nerves  are  regularly  extracranial.  The  condition  was  reported  by  Forster 
in  1862  and  fully  described  by  Monakow  in  1900. 

The  tumors  occur  usually  before  the  5oth  year,  and  often  in  young  per- 
sons. They  may  be  associated  with  other  abnormalities  of  the  brain,  as 
hyperplasia  and  hypertrophy  of  the  glia-cells  of  the  cortex  (Henneberg. 
Koch),  endothelioma  and  psammoma  of  the  dura,  sarcoma  of  brain,  multiple 
hernias  of  brain  tissue  through  the  dura  (Fraenkel,  Hunt).  These  abnor- 


TUMORS  OF  NERVE  TRUNKS 


433 


malities  suggest  an  underlying  anatomical  predisposition  to  tumor  growth. 
In  one  of  Henneberg's  cases  there  were  neuroma  of  the  acoustic,  fibroma  of 
the  falx,  fibrosarcoma  in  right  ventricle,  3  small  tumors  in  the  medulla,  and 
multiple  psammomas  of  pia  and  dura.  The  comparative  frequency  with 
which  isolated  brain  tumors,  fibroma,  sarcoma,  and  glioma  are  observed  with 
peripheral  neurofibroma  has  an  obvious  bearing  on  the  origin  of  many  solitary 
intracranial  neoplasms. 

The  tumors  begin  in  a  portion  or  involve  the  whole  of  the  nerve-trunk, 
producing  a  fusiform  or  round  swelling  which  has  been  encountered  when  as 
small  as  a  cherry  or  as  large  as  a  hen's  egg.  They  are  firm,  lobulated,  and 
encapsulated,  but  often  adherent.  They  compress  the  cerebellum,  medulla, 
and  adjoining  nerves.  The  diffuse  swelling  of  the  nerve  may  penetrate  the 
internal  auditory  meatus. 


FIG.  187. — -Structure  of  a  malignant  neurosarcoma. 

The  structure  is  usually  that  of  simple  neurofibroma,  but  some  very 
cellular  growths  approach  the  type  of  neurosarcoma.  Glia-tissue  has  several 
times  been  demonstrated,  and  from  this  element  a  sarcomatous  process  may 
be  derived.  Regressive  changes  include  fibrosis  and  cyst  formation. 

Sternberg  points  out  that  the  trigeminus,  acoustic,  facial,  glossopharyngeal, 
and  vagus  arise  from  the  neural  ridge  which  appears  at  an  early  date  when 
the  tissues  are  comparatively  undifferentiated,  while  the  other  cranial 
nerves  develop  from  the  cerebral  vesicles.  Hence  the  former  nerves  may 
readily  include  embryonal  cell  groups  which  explain  the  complex  structure 
of  their  tumors. 

The  clinical  course  is  of  a  slowly  growing  tumor  of  the  posterior  fossa, 
preceded  by  symptoms  referable  to  the  fifth  or  eighth  nerves.  The  ^slow 
course  and  encapsulation  place  them  among  the  operable  cases,  but  the  inac- 
cessibility, adhesions,  destruction  of  neighboring  vital  tissues,  and  occasional 
malignancy  yield  an  unfavorable  prognosis. 
28 


434  NEOPLASTIC  DISEASES 

Neuromyxoma  of  the  Optic  Nerve. — The  optic  nerve  is  the  seat  of  a 
characteristic  neuromyxoma  which  has  been  described  by  Collins,  Marshall, 
Reese,  and  others,  and  which  presents  quite  uniform  anatomical  and  clinical 
features.  Through  the  kindness  of  Drs.  Knapp,  Krug,  and  Reese  I  have  had 
the  opportunity  of  studying  several  cases.  The  tumors  occur  in  children  and 
young  persons,  they  grow  slowly  until  the  whole  nerve  is  destroyed,  but 
they  do  not  invade  the  eyeball  or  orbital  tissues  until  very  late.  They  form 
soft  elastic  fusiform  swellings  of  the  entire  nerve.  The  central  portions  at 
first  reveal  the  nerve  trunk  surrounded  by  tumor  tissue,  but  eventually  the 
tissue  softens  and  the  nerve-fibers  are  destroyed.  The  structure  presents 
numerous  small  groups  of  cells  of  the  type  of  glia-cells  without  fibrils  lying 
in  compact  foci  or  scattered  in  a  mucinous  matrix.  Remnants  of  nerve-fibers 
in  various  stages  of  degeneration  may  be  found  in  the  softened  matrix.  Small 
blood-vessels  may  be  abundant.  The  location  of  the  tumor  in  early  stages, 
surrounding  the  nerve  trunk,  suggests  that  it  arises  from  the  peripheral  por- 
tions of  the  nerve  or  from  the  endothelial  sheath,  but  this  peculiarity  may 


FIG.  1 88. — Benign  myxoglioma  of  optic  nerve  ensheating  the  nerve,  but  arising  from 
another  segment  and  extending  along  the  sheath.     (Case  of  Dr.  R.  G.  Reese.) 

also  be  referred  to  an  origin  from  one  end  of  the  nerve,  the  tumor  growing 
forward  about  the  trunk.  The  nerve  trunk  shows  definite  neoplastic  changes, 
as  in  Reese's  case.  Some  of  the  tumors  are  very  cellular,  in  some  the  mucinous 
stroma  is  prominent,  and  others  show  excess  of  blood-vessels.  They  are 
usually  removed  successfully  without  disturbing  the  eyeball,  and  recurrence 
of  encapsulated  growths  is  not  to  be  anticipated. 

Tumors  of  the  Gasserian  ganglion  are  of  considerable  surgical  interest, 
and  form  a  definite  pathological  basis  in  one  type  of  trigeminal  neuralgia, 
which  is  their  chief  clinical  symptoms.  Sachs  collected  21  cases,  and  the 
conditions  have  been  reviewed  in  detail  by  Spiller  and  by  Giana.  The  pain 
in  these  cases  usually  becomes  continuous,  the  results  of  surgical  treatment 
have  been  very  unfavorable,  and  the  disease  terminates  fatally  in  i  to  3  years. 
The  tumors  involve  and  destroy  the  ganglion  or  arise  in  the  capsule  and 
compress  the  ganglion.  They  reach  the  size  of  a  marble  or  pigeon  egg.  Several 
cases  appear  to  have  had  an  inflammatory  origin  and  were  associated  with 
tuberculosis  (Giana),  or  extensive  plasma-cell  overgrowth  (Hoffmeister, 


TUMORS  OF  NERVE  TRUNKS 


435 


Meyer).  The  structure  has  varied  from  fibrous  to  very  cellular  growths, 
the  latter  presenting  alveoli  surrounded  by  several  layers  of  polyhedral  cells. 
In  some  the  structure  resembles  perivascular  endothelioma.  In  others  glio- 


<*$ys^i 

*'£j£?$^r?>'§' 

^  i$££*«  4*'^i  >  A:  -  **»*^^ 

.-  •**.***<*•< 


^^ 


FIG.  189. — Structure  of  a  benign  myxoglioma  of  optic  nerve. 

matous  features  were  noted.  Marchand  believed  that  they  represented 
various  types  of  neurocytoma.  Others  have  derived  their  tumors  from  the 
pericellular  lymph-sheaths. 


CHAPTER  XXIV 
TUMORS  OF  SPINAL  CORD  AND  MEMBRANES 

General  Etiology. — All  tumors  of  the  spinal  cord  or  membranes  that 
compress  the  cord  fall  in  a  single  clinical  group  which  can  be  differentiated 
only  after  "Complete  study.  They  include  gummas,  tubercle,  and  parasitic 
cysts,  as  well  as  neoplasms. 

Statistical  studies  of  Schlesinger  give  151  such  tumors  among  35,000 
autopsies  at  Vienna  (0.43  per  cent.).  Of  400  cases  collected  by  this  author, 
302  were  intradural  and  88  extradural.  The  sarcomas  head  the  list  with 
107  cases;  followed  by  tubercle,  64;  echinococcus,  44;  neurofibroma,  37; 
gumma,  28;  glioma  and  gliosarcoma,  27;  psammoma,  18;  myxoma  and 
lipoma,  each,  n;  endothelioma,  6.  Excluding  144  cases  of  tubercle,  gumma, 
and  parasitic  cysts,  the  proportion  of  sarcomas  becomes  even  more 
prominent. 

Practically,  the  spinal  tumors  are  chiefly  sarcomas,  of  which  a  consider- 
able proportion  are  extradural,  31  of  107  cases;  glioma  and  gliosarcoma,  which 
are  always  intradural,  27  cases;  neurofibroma,  37  cases;  and  psammoma 
with  its  congener  endothelioma,  24  cases.  Lipoma  and  myxoma  are  distinctly 
rare,  and  some  of  the  latter  are  probably  degenerating  forms  of  growths 
originating  in  glia-tissue  or  nerve-trunks. 

It  is  of  interest  to  note  that  tumors  of  the  spinal  column  in  the  Vienna 
series  of  35,000  autopsies  were  far  more  frequent  than  in  the  meninges  and 
cord  (107  cases  to  44) ;  while  brain-tumors  of  all  types  were  six  times  as  com- 
mon (994  cases)  as  the  spinal  cord  growths  (151  cases).  Primary  tumors 
of  the  spinal  meninges  were  twice  as  common  as  the  secondary  metastatic 
growths.  During  this  same  period  427  cases  of  tuberculous  spondylitis  were 
observed. 

Trauma. — Less  frequently  than  in  the  brain,  severe  trauma  has  appeared 
to  be  the  direct  exciting  cause  of  spinal  cord  tumors,  usually  of  the  gliomatous 
type.  Severe  injury  capable  of  reaching  the  meninges  and  followed  by  symp- 
toms continuing  until  the  existence  of  a  tumor  at  the  injured  point  was  estab- 
lished, occurred  in  the  gliomas  of  Silberkuhl,  Wichmann,  Schuppel,  Schlapp, 
and  others. 

Sarcomas  appeared  to  develop  on  a  traumatic  basis  in  reports  of  Traube, 
Forster,  Ollivier,  Hunt  and  Woolsey,  and  myxomas  in  the  cases  of  Gowers, 
Bruce,  and  Mott.  Very  similar  histories  have  appeared  in  cases  of  fibroma 
(Marshall)  and  psammoma  (Oustaniol).  Gaupp's  angiofibroma  appeared 
many  years  after  a  severe  spinal  injury. 

In  many  instances  symptoms  proved  to  result  from  tubercle,  gumma, 
or  echinococcus  cyst  have  followed  immediately  or  soon  after  trauma 
(Schlesinger,  Lit.). 

It  thus  appears  that  trauma  may  be  the  direct  exciting  factor,  or 
may  accelerate  the  growth,  or  reveal  or  intensify  the  symptoms  of  spinal 
tumors,  or  may  have  no  connection  whatever  with  an  accidentally  associated 
lesion. 

Hereditary  influences  have  been  suggested  in  some  interesting  cases. 
Two  sisters  of  Huppel's  patient  with  multiple  sarcoma  suffered  from  the 

436 


TUMORS  OF  SPINAL  CORD  AND  MEMBRANES 


437 


same  symptoms.     A  brother  of  Hunt's  case  of  traumatic  sarcoma  died  of 
the  same  lesion,  also  of  traumatic  onset. 

AGE  INCIDENCE  OF  187  SPINAL  CORD  TUMORS 


Sarcoma. 

PI*   ma 

p 

»-,., 

Years. 

Intradural. 

Extradural. 

Diffuse. 

i-9 

I 

I 

7 

3 

o 

I 

lO-IQ 

0 

3 

4 

6 

o 

3 

20-29 

16 

o 

5 

13 

o 

3 

30-39 

13 

7 

2 

10 

2 

3 

40-49 

13 

10 

i 

6 

7 

4 

50-59 

6 

9 

i 

5 

4 

3 

60-69 

I 

i 

o 

2 

8 

3 

50 

3i 

20 

45 

21 

20 

The  above  table  includes  81  cases  tabulated  by  Schlesinger  in  1898,  many 
of  the  cases  collected  by  Collins,  and  some  recent  reports  up  to  1915. 

The  main  conclusions  from  these  data  are  as  follows:  Solitary  sarcoma 
occurs  chiefly  in  young  adults  between  20  and  40  years.  Diffuse  sarcomas 
are  practically  limited  to  children  or  young  adults  under  30  years  of  age. 
Gliomas  are  well  distributed  in  the  age  periods.  Psammoma  is  not  reported 
under  30  years.  Among  extremes  are  Anderseck's  sarcoma  of  the  cord  in 
a  newborn  infant  and  Duseberg's  angiosarcoma  in  a  man  of  79  years. 

The  great  majority  of  lipomas  occur  in  children  under  5  years.  Neuro- 
fibromas  occur  at  all  ages. 

In  children  under  10  years  a  spinal  cord  tumor  is  in  order  of  frequency 
a  solitary  tubercle,  a  diffuse  or  unfavorable  form  of  sarcoma,  or  rarely  a 
lipoma.  After  40  years  the  benign  tumors  and  favorable  forms  of  circum- 
scribed sarcomas  become  more  frequent.  Tubercle  is  distributed,  over  all 
periods,  but  gummas  are  rare  before  30  years. 

While  customary  subdivisions  of  spinal  tumors  are  numerous  it  is  probable 
that  they  arise  from  three  main  structures:  (i)  glia-cells  and  neural  epithelium, 
(2)  blood-  and  lymph-vessels  and  their  endothelial  lining,  and  (3)  the  nerve- 
trunks.  From  this  histogenetic  standpoint  they  may  be  classified  as  follows: 

Glia-tissue — Glioma,  gliosarcoma. 

Neural  epithelium — Neuro-epithelioma.    Some  so-called  angiosarcomas. 

Blood-vessels — Angioma,  angiosarcoma,  sarcoma. 

Lymphatics — Lymphangioma,  endothelioma,  psammoma,  sarcoma. 

Nerve-trunks — Neurofibroma,  fibroma,  myxoma. 

Spinal  fat  tissue — Lipoma. 

Only  the  spinal  sarcomas  will  here  be  considered  in  detail,  the  others 
being  considered  elsewhere. 

Sarcoma  of  Cord  and  Meninges. — Sarcoma  of  the  cord  or  meninges 
occurs  in  several  anatomical  forms: 

1.  A  solitary  tumor. 

2.  Multiple,  large,  small,  or  miliary  tumors. 
This  form  merges  into 

3.  A  diffuse  infiltration  which  results  from:    (a)  Extension  from  a  single 
large  primary  meningeal  growth,  or  (6)  as  a  diffuse  infiltration  without  local- 
ized primary  tumor,  and  (c)  as  a  secondary  invasion  from  extramedullary 
growths. 

Extradural  tumors  of  a  variety  of  types  arising  from  the  bone,  connective 


438  NEOPLASTIC  DISEASES 

tissue,  fat  tissue,  and  nerve  trunks  are  commonly  included  in  this  clinical 
group.  Of  6 1  sarcomas  in  the  vertebral  canal  Schlesinger  found  18  extra - 
dural.  Of  42  primary  intradural  sarcomas  16  arose  from  the  dura,  14  from 
pia,  6  from  arachnoid,  4  from  nerve  roots,  and  2  from  the  ligamentum  den- 
ticulatum. 

1.  The  solitary  sarcoma  is  a  relatively  frequent  form  of  cerebral  and  spinal 
tumor.    It  arises  from  the  dura,  pia,  or  nerve  roots,  and  extends  in  elongated 
form  along  the  cord  with  local  compression  if  firm  and  encapsulated  or  adapt- 
ing itself  to  the  spinal  canal  if  soft.    The  hard  tumors  remain  permanently 
encapsulated  or  become  pedunculated  and  do  not  invade  the  cord.     They 
are  composed  of  closely  packed  spindle-cells,  with  few  vessels  which  escape 
the  calcification  of  psammoma.    They  are  probably  related  in  origin  to  the 
neurofibromas  and  neurosarcomas,  but  lack  the  specific  structure  of  these 
tumors. 

Myxosarcoma  is  a  rare  but  characteristic  form  of  spinal  tumor  of  which 
Oustaniol  collected  9  cases.  The  cauda  is  a  favorite  site.  They  are  occa- 
sionally extradural  and  here  the  frequent  admixture  with  fat  indicates  an 
origin  from  misplaced  mesodermal  tissue.  Berthelot  and  Merklen  described 
multiple  myxomas  of  the  cord. 

Round-cell  sarcomas  form  soft,  vascular  growths  which  are  prone  to 
hemorrhage  and  cystic  degeneration  and  while  long  remaining  encapsu- 
lated they  may  eventually  invade  the  cord  or  produce  metastases.  Their 
sources  have  not  been  traced.  The  great  abundance  of  blood-vessels  in  cer- 
tain cases  suggests  a  perivascular  origin  (Schlesinger,  30).  As  a  rule  the 
cellular  tumors  are  difficult  to  distinguish  from  endotheliomas,  and  when  the 
cells  are  quite  round  and  very  numerous  the  separation  from  gliosarcoma 
is  required. 

2,  3.  Multiple  and  Diffuse  Sarcomatosis  of  Meninges. — This  remarkable 
and  highly  specific  neoplasm  appears  in  the  form  of  multiple  nodules  or  plates 
or  a  diffuse  infiltration  of  the  pia-arachnoid.    It  may  extend  over  many  seg- 
ments of  the  cord,  or  over  the  entire  cord  from  medulla  to  cauda,  or  may 
cover  the  cerebral  pia  over  the  base  and  even  extend  into  the  ventricles 
(Nonne,    Schroder).      The   nervous   tissue    usually   escapes  infiltration,  but 
may  be  involved  in  the  later  stages.     A  localized  primary  tumor  of  the 
meninges  is  occasionally  present  and  rarely  the  tumor  appears  to  originate 
in  the  nervous  tissue  or  its  sulci. 

The  alteration  in  the  exposed  cord  may  be  so  slight  as  to  escape  the  naked 
eye  (Nonne),  but  usually  there  is  a  nodular  or  diffuse  thickening  or  opacity 
from  grayish-red  tumor  tissue  which  appears  first  on  the  posterior  aspect 
of  the  cord,  encircles  it  more  or  less  completely,  and  passes  along  the  nerve 
roots. 

In  R.  Schulz's  case  the  entire  cord  was  surrounded  by  a  layer  of  new  tissue 
^  cm.  in  thickness,  and  in  the  cases  of  Schataloff  and  Nikoforoff  the  investing 
layer  was  i  cm.  deep.  Bausch  found  a  uniform  tumor  sheath  extending  from 
cauda  to  brain,  irregularly  over  the  cerebral  pia,  and  into  the  ventricles  along 
the  choroid  plexus.  When  a  localized  primary  tumor  appears  as  the  source 
of  the  diffuse  infiltration  it  usually  lies  in  the  cerebellum  or  base  (Hippel, 
Nonne),  or  in  the  substance  of  the  cord  (Westphal).  Of  18  cases  collected 
by  Schlesinger,  14  were  associated  with  large  tumors,  12  of  the  cerebellum, 
and  3  of  the  medulla.  The  occurrence  of  miliary  nodules  over  the  peripheral 
areas  indicates  that  the  tumor  advances  by  transfer  of  cell  groups  along  the 
arachnoid,  but  in  many  cases  the  advancing  edge  merges  gradually  into  healthy 
tissue.  Cerebral  involvement  often  leads  to  hydrocephalus. 

The  structure  of  the  diffuse  sarcoma  is  somewhat  uniform,  but  owing  to 


TUMORS  OF  SPINAL  CORD  AND  MEMBRANES 


439 


the  activity  of  growth  the  exact  origin  of  the  tumor  has  never  been  satis- 
factorily determined  and,  in  fact,  the  exact  nature  of  the  process  in  some  cases 
is  obscure. 

In  most  cases  the  tumors  contain  many  fine  blood-vessels  sheathed  by 
round  or  polyhedral  or  spindle-cells.  When  the  vessels  are  very  numerous 
the  tumor  has  been  called  angiosarcoma 
or  perithelioma  (Nonne,  Busch).  Hya- 
line changes  in  the  vessel  walls  led 
Kramer  to  designate  his  tumor  as 
cylindroma.  In  2  cases  W.  Rindfleisch 
found  the  vessels  overgrown  or  obliter- 
ated by  a  diffuse  growth  of  large  and 
small  round  cells.  Lenz  analyzes  the 
process  as  an  angioblastic  sarcoma  to 
which  is  added  a  marked  proliferation 
of  the  pial  endothelium,  yielding  many 
large  cells  in  alveolar  arrangement. 
In  his  case  a  cerebral  extension  was 
purely  sarcomatous  and  failed  to  show 
the  secondary  endothelial  overgrowth. 
Other  cases  of  this  type  are  the  original 
observation  of  Ollivier,  2  cases  of 
Coupland,  and  that  of  Westphal. 
Cramer  and  Lowenfeld  described  mul- 
tiple nodules  of  the  same  structure 
which  probably  represent  an  early  stage 
of  the  process.  Marked  regressive 
changes  were  observed  by  Cramer  and 
Ganguillet. 

The  main  histological  features  in 
this  group  point  to  an  origin  from  the 
adventitial  cells  of  the  blood-vessels, 
so  that  the  recognition  of  a  specific 
form  of  diffuse  angioblastic  meningeal 
sarcoma  seems  warranted. 

In  a  second  group  of  cases  endo- 
thelial characters  are  more  prominent 
and  the  tumor  appears  as  an  alveolar 
sarcoma.  Schulz's  bulky  growth  con- 
tained large  endothelial  cells  in  alveolar 
arrangement. 

Diffuse  melanoma  of  the  meninges 
has  been  observed  in  a  considerable 
series  of  cases.  In  many  of  these  the 
perivascular  arrangement  of  the  cells 
was  prominent  (Schopper,  Lua). 

The  clinical  course  of  diffuse  men- 
ingeal sarcoma  presents  certain  features 
of  special  interest.     Most  cases  occur 
in  children  or  young  adults,  but  Rind- 
fleisch reports  the  condition  at  49  years.     When  there  is  a  large  primary 
tumor  the  symptoms  are  usually  dominated  by  local  pressure  phenomena, 
while  the  infiltration  reveals  its  course  by  increasing  spinal   disturbance. 
Rindfleisch  established  a  diagnosis  during  life  by  the  presence  of  many  large 


FIG.  190.- 
mater. 


-Diffuse  sarcoma  of  spinal  pia 
(After  Schulz.     A.P.,i6.) 


440 


NEOPLASTIC  DISEASES 


cells  in  the  spinal  fluid.  Many  cases  are  very  acute  and  resemble  tuber- 
culous or  syphilitic  meningitis.  In  fact,  it  is  not  always  possible  to  distinguish 
the  disease  from  cellular  meningitis.  Thus,  Grund  found  rather  typical 
gross  lesions  of  tuberculous  meningitis  with  miliary  tubercles  in  liver  and 
kidney  in  a  child  of  n  years,  with  a  duration  of  4  months.  Under  such  condi- 
tions his  diagnosis  of  multiple  miliary  gliosarcoma  suggests  at  least  that  a 
tuberculous  element  was  concerned  in  the  meningeal  process. 

Central  spinal  sarcoma  has  occurred  in  a  series  of  cases  of  which 
Schlesinger  has  collected  13.  Gliomas  and  gliosarcomas  are  much  more 
frequent  in  this  region.  The  upper  portions  of  the  cord  as  chiefly  involved 
and  in  3  cases  the  entire  cord  was  affected  (Forster,  Glaser,  Schultze).  The 
tumor  mass  forms  a  narrow  cylinder  or  an  irregular  mass  \  to  i  cm.  in  thick- 
ness. Schiff  found  a  minute  spindle-cell  sarcoma  in  the  anterior  horn. 
Elongated  cavities  filled  with  serum  or  bloody  fluid  may  form  within  the 


FlG.  191. — Central  glioma  of  spinal  cord  with  syringomyelia :  fa,  Anterior  fissure;  ca, 
anterior  horn;  g,  tumor.     (After  Saxer.) 


Jt  '-'I"  J* 

tumor*  (Glaser j ;'Seebohm).  The  central  canal  is  usually  obliterated,  but  in 
some  cag.es;  beyond  or^within  the  tumor  mass  the  canal  may  be  dilated  and 
the  wall  softened  and  eroded.  Sharp  encapsulation  from  the  compressed 
nerve  tissue  is  usually  noted  (Fenger,  Adamkiewicz).  The  gliosarcomas, 
on  the  contrary,  begin  with  central  gliosis  and  gradually  invade  the  cord 
with  central  softening.  The  structure  of  the  more  specific  forms  of  these 
tumors  is  that  of  round-  or  spindle-cell  angiosarcoma.  They  are  not  always 
clearly  distinguishable  from  glioma  or  neurofibroma,  which  are  often  highly 
vascular.  Nonne  noted  the  resemblance  of  his  round-cell  tumors  to  glio- 
myxosarcomas,  from  which  he  separates  them  chiefly  on  gross  characters. 
In  Glazer's  case  the  structure  resembled  neuro-epithelioma.  The  true  sarcomas 
appear  to  originate  exclusively  from  the  vessels  of  the  gray  matter. 

Psammoma  arises  from  the  spinal  dura  or  arachnoid  and  usually  pro- 
duces a  single,  firm,  well-encapsulated  growth  compressing  the  cord.     Its 


TUMORS  OF  SPINAL  CORD  AND  MEMBRANES  441 

progress  is  slow  and  several  years  are  commonly  required  to  reach  rather 
limited  dimensions  which  seldom  exceed  2X4  cm.  Pressure  on  the  cord 
begins  early,  motor  and  sensory  symptoms  are  prominent,  and  extensive 
secondary  degenerations  are  commonly  established.  In  Steudener's  case 
the  cord  was  completely  severed  in  the  course  of  2  years'  growth.  The  tumors 
usually  lie  on  the  dorsal  and  lateral  aspects  of  the  cord,  and  chiefly  in  the 
lower  half.  The  structure  presents  either  a  cellular  and  vascular  form  of 
sarcoma  or  a  less  cellular  sclerosed  tumor  with  much  calcification.  In  the 
cellular  forms  there  are  many  small  canals  surrounded  by  concentric  layers 
of  spindle-  or  polygonal  cells.  Calcification  of  the  walls  of  these  small  vessels 
may  appear  early  when  the  tumors  are  cellular,  yielding  the  sarcome  angio- 
lithique  of  Cornil  and  Ranvier.  Very  cellular  forms  of  this  tumor  differ  from 
the  common  spindle-cell  sarcoma,  chiefly  in  the  presence  of  these  calcific 
vessels.  In  late  forms  the  growth  may  be  largely  composed  of  calcific  granules 
and  hyaline  tissue. 

Multiple  neurofibroma  of  the  spinal  cord  is  relatively  frequent.  Schles- 
inger  collected  15  cases,  of  which  10  were  intradural,  while  7  sprang  from 
the  membranes  and  3  from  the  nerve  roots.  All  portions  of  the  cord  are 
about  equally  affected,  but  the  cauda  is  a  somewhat  favorite  seat.  They 
are  frequently  a  part  of  general  neurofibromatosis  (Hunt),  and  in  Vast's 
case  both  cerebral  and  spinal  nerve-trunks  were  involved.  Schlesinger  ob- 
served 3  large  tumors  compressing  the  medulla  and  very  numerous  small 
nodules  throughout  cerebral  and  spinal  meninges  and  in  the  cauda. 

The  solitary  fibroma  is  probably  in  most  cases  a  hard  neurofibroma. 
While  usually  appearing  as  small,  hard  masses  attached  to  dura  or  pia,  they 
are  occasionally  cystic,  and  at  times  rather  cellular  and  vascular.  Merz- 
bacher  found  a  trilobed  cervical  intradural  fibroma  n  cm.  in  length  and  of 
1 8  years'  duration  in  a  man  of  55  years.  Heurtaux  traced  to  an  intraspinal 
origin  a  very  large  congenital  fibroma  projecting  from  the  neck. 

Endothelioma  of  the  spinal  meninges  appears  in  the  form  of  a  large  solitary 
tumor  or  as  multiple  nodules. 

Spinal  lipoma  occurs  in  solitary,  multiple,  and  diffuse  forms.  It  is  usually 
extradural,  and  extravertebral  tumors  may  grow  between  the  vertebrae  into 
the  canal  (Holmes,  Temoin);  or  an  extradural  growth  may  perforate  the 
dura  (Johnson);  while  others  originate  in  the  arachnoid  (Obre).  The  extra- 
vertebral  forms  may  be  connected  with  spina  bifida.  Braubach's  intradural 
tumor  in  a  child  of  5  years  extended  from  the  fourth  cervical  to  fourth  dorsal 
segment.  Multiple  lipomas  extending  over  much  of  the  lower  dura  and  the 
posterior  nerve  sheaths  are  described  by  K.  Hoffmann.  Multiple  angio- 
lipoma  is  described  by  Berenbuch,  and  multiple  malignant  myxolipoma  by 
Virchow.  Wolbach  reports  diffuse  lipomatosis  of  the  cord  in  an  infant. 
Gowers  saw  striated  muscle-fibers  in  caudal  lipoma. 

Spinal  angiomas  present  a  benign  illustration  of  the  proliferative  capacity 
of  the  meningeal  blood-  and  lymph-vessels.  They  show  many  gradations  up 
to  angioblastic  sarcoma  and  endothelioma.  Gaupp  pictures  a  cavernous 
angioma  of  the  pia,  and  a  cellular  capillary  angioma,  occurring  in  the  same 
cord  with  central  glioma  and  2  fibromas.  Barenbruch  found  12  cm.  of  the 
cord  partly  replaced  by  a  coarse  angiomatous  structure.  Angiomatous  tumors 
of  the  cauda  have  been  described  as  cylindroma,  owing  to  the  hyaline  de- 
generation of  the  vessel  walls  (Ganguillet).  Cobb  collected  several  cases  of 
cavernous  angioma  of  spinal  meninges  and  cord,  and  points  out  the  associa- 
tion with  cutaneous  nevi  in  the  same  regions. 

Zanda  describes  multiple  osteomas  arising  from  the  calcified  walls  of 
blood-vessels.  Cavernous  and  cystic  lymphangiomas  are  reported  by  Laquer 


442 


NEOPLASTIC  DISEASES 


and  by  Taube.    A  dermoid  cyst  of  the  dorsal  cord  is  reported  by  H.  White. 

Trachtenberg  has  described  a  remarkable  case  of  multiple  dermoids  of  cerebral 

and  spinal  meninges. 

Metastatic    sarcoma   may   extend   over   considerable   segments   of   the 

cerebral  or  spinal  meninges.    Such  cases  are  reported  with  renal  sarcoma  by 

L.  Muller  and  after  ovarian  sarcoma  by  Hensen.    The  entire  spinal  meninges 

was  found  microscopically  to  be  diffusely  infiltrated 
_  from  a  primary  intestinal  lymphosarcoma,  in  a  case 

described  by  Stursberg.  Schlesinger  describes  a 
glioma  and  endothelioma  of  the  pituitary  gland 
with  diffuse  infiltration  of  the  spinal  meninges. 

Secondary  changes  in  the  cord,  meninges, 
and  canal,  following  tumor  growth,  are  of  much 
practical  importance. 

Simple  compression  without  destruction  of 
nerve-tissue  may  greatly  narrow  the  cord  directly 
opposite  the  tumor.  About  the  compressed  area 
the  cord  is  swollen  and  hyperemic  and  there  may 
be  much  accumulation  of  fluid  in  the  central  canal, 
in  the  arachnoid,  or  in  a  cystic  compartment  which 
often  forms  about  the  tumor.  Upon  removal  of 
the  tumor  all  the  changes  may  rapidly  disappear, 
even  during  the  operation  (Kummel).  Func- 
tional recovery  may  be  almost  immediate.  That 
long-standing  compression  is  not  necessarily  ac- 
companied by  irreparable  damage  is  shown  by 
the  recovery  from  complete  paralysis  after  such 
duration  as  8  months  (Lichtheim),  13  months 
(Schultze),  1 8  months  (Macewen).  Eventually 
there  may  be  complete  atrophy  of  nerve  tissue 
and  fusion  of  the  envelopes  in  a  fibrous  cord  to 
which  the  tumor  may  adhere.  Acute  degenerative 
changes  may  supervene  in  the  course  of  the  com- 
pression and  seem  to  be  referable  not  merely  to 
pressure  but  also  to  an  inflammatory  process  ac- 
companying the  growth.  These  changes  may 
appear  suddenly  in  the  course  of  benign,  slowly 
growing  tumors,  as  psammoma,  and  are  espe- 
cially frequent  when  the  pia  is  invaded  by  locally 
aggressive  tumors.  The  nervous  tissue  is  then 
found  infiltrated  with  blood,  softened,  and  dif- 
fluent. The  hemorrhage  may  extend  far  from  the 
tumor  along  the  tracts  or  canal  and  the  myelin 
sheaths  of  the  fibers  are  swollen  and  degenerated. 
Above  and  below  the  main  lesion  Schlesinger  de- 
scribes focal  areas  of  swollen  axis-cylinders  and 

myelin  sheaths  which  he  refers  to  a  local  inflammatory  process.     Following 

the  early  lesions  the  usual  forms  of  secondary  degeneration  of  the  tracts 

become  established,  but  in  very  variable  degree. 

The  spinal  column  itself  may  suffer  from  local  absorption  of  vertebral 

bodies  and  at  the  weakened  point  scoliosis  and  sharp  kyphosis  may  develop. 
The  changes  in  the  lumbar  spinal  fluid  have  been  extensively  pursued. 

The  presence  of   increased  albumin  in  a  fluid  of  distinctly  yellowish  tinge 

(xanthochromia)  is  frequently  observed  in  spinal  cord  tumors,  but  is  by  no 


FIG.  192. — -Multiple  der- 
moids of  spinal  meninges. 
(Trachtenberg1  s  case.  V.  A., 

I54-) 


TUMORS  OF  SPINAL  CORD  AND  MEMBRANES  443 

means  pathognomonic  (Froin,  Nonne).  The  yellowish  color  is  probably  de- 
rived from  altered  blood-pigment.  The  onset  of  meningitis  is  indicated  by 
admixture  of  fibrin  and  many  round  cells.  Rindfleisch  found  many  tumor 
cells  in  the  aspirated  fluid. 

Meningeal  Pseudoneoplasms. — Aside  from  parasitic  cysts,  meningeal 
neoplasms  may  be  simulated,  in  both  clinical  and  anatomical  features,  by 
tuberculous,  syphilitic,  and  traumatic  meningitis. 

Spinal  tuberculosis  occurs  in  several  forms  which  resemble  extra-  or  in- 
tradural  tumors  with  or  without  bone  involvement.  It  produces  grayish, 
vascular,  or  partly  necrotic  plates  or  masses  extending  over  several  segments 
on  either  side  of  dura  or  in  the  pia-arachnoid.  The  structure  is  that  of  hyper- 
plastic  granulation  tissue  in  which  the  overgrowth  of  endothelial  cells  in 
and  about  the  vessels  is  very  marked.  Giant-cells  may  be  absent  and  lympho- 
cytes abundant,  so  that  the  tissue  may  resemble  round-cell  sarcoma.  Fungous 
masses  of  tuberculous  granulation  tissue  arising  from  carious  bone  foci  may 
penetrate  the  subdural  space  in  much  the  same  manner  as  sarcoma  (Schles- 
inger).  The  nerve  roots  in  the  lumbar  and  cauda  region  have  been  found 
agglutinated  by  tuberculous  tissue  in  a  tumor-like  mass  (Schamaschin,  Fischer, 
Schlesinger). 

Meningitis  (arachnitis)  serosa  circumscripta  in  both  brain  and  cord  may 
give  rise  to  cystic  accumulations  of  serous  or  milky  fluid  which  cause  symptoms 
of  tumors  (Adler,  Spiller,  Lit.).  The  cysts  form  in  the  thickened  arachnoid, 
extend  over  a  segment  \  cm.,  incompletely  encircling  the  cord,  distending 
the  dura  and  effectively  compressing  the  cord  of  convolutions.  The  ad- 
joining meninges  may  be  normal  or  adhesions  may  extend  over  a  wide  area. 
The  hydrops  may  involve  also  the  central  canal,  and  in  Schwartz's  case  there 
were  cavities  in  the  anterior  horns,  and  considerable  myelomalacia.  Sec- 
ondary degenerations  emanating  from  the  central  lesion  may  be  extensive. 
The  disease  occurs  at  all  ages,  chiefly  in  middle  life,  and  many  of  the  subjects 
are  luetic  or  tuberculous.  Trauma,  infectious  diseases,  and  vertebral  caries 
have  been  charged  with  other  cases.  It  is  relatively  frequent,  having  occurred 
in  6  of  21  laminectomies  by  Oppenheim  and  Krause  for  supposed  spinal  tumor. 
Quincke  has  described  cerebral  cases.  The  symptoms  are  those  of  a  mildly 
progressive  tumor  (Horsley). 

Hodgkin's  granuloma  may  produce  well-circumscribed  tumors  in  or  about 
the  meninges.  A  supposed  dural  sarcoma  recently  submitted  to  me  proved 
to  be  of  this  nature  and  mediastinal  and  cervical  tumors  developed  later. 
In  Welch's  case  of  Hodgkin's  disease  terminating  in  sarcoma  a  paraplegia 
of  many  months'  duration  was  found  at  autopsy  to  have  resulted  from  a 
large  intradural  mass.  Nonne  also  mentions  a  case  of  spinal  granuloma 
malignum. 

Pachymeningitis  cervicalis  hyperlrophica,  often  of  luetic  origin,  produces 
a  diffuse  thickening  of  the  spinal  envelope  which  may  approach  the  character 
of  an  angiofibroma,  but  apart  from  the  abundance  of  vessels  the  structure  is 
quite  different  from  any  tumor  (Charcot,  Koeppen,  Wieting).  While  ordi- 
nary gummas  are  readily  distinguished  from  tumors,  the  scope  of  structures 
in  tertiary  lesions  of  the  meninges  is  as  yet  imperfectly  defined. 

Trauma  following  spinal  fracture  in  i  case  and  sharp  scoliosis  in  2  cases 
led  to  diffuse  fibromatoid  growths,  as  reported  by  MacEwen. 

Symptomatology  of  Spinal  Cord  Tumors. — Elaborate  analysis  of  the 
symptoms  of  spinal  cord  tumors  has  been  required  as  a  guide  to  the  surgical 
treatment  of  these  growths  (Bruns,  Starr,  Malaise,  Nonne).  Its  main  features 
may  be  briefly  outlined. 

Level  of  the  Tumor. — Bruns  formulated  the  law  that  root  pains  should 


444  NEOPLASTIC  DISEASES 

be  referred  to  the  segment  from  which  the  root  arises  and  not  to  pressure  on 
the  root  in  its  intraspinal  course.  They  may  persist  for  years  before  medul- 
lary symptoms  appear  or  may  fail  entirely,  especially  in  ventral  growths. 
They  are  usually  very  severe  and  persistent,  continue  for  a  long  period, 
especially  in  extradural  growths,  but  may  eventually  disappear  when  the 
nerve-trunks  are  destroyed.  Widely  disseminated  pains  point  to  a  medullary 
lesion.  A  zone  of  hyperesthesia  extending  somewhat  above  the  tumor  is  often 
present  in  both  meningeal  and  medullary  growths.  Vertebral  symptoms, 
pain  and  tenderness,  are  more  characteristic  of  vertebral  than  of  cord  tumors, 
but  may  be  present  in  both.  Sharp  kyphosis  has  once  followed  bone  ab- 
sorption by  dural  growths.  Girdle  sensations  have  little  localizing  value, 
and  Hunt  finds  the  root  symptoms  more  reliable  than  local  tenderness. 
Motor  paresis  or  paralysis  appear  later  than  the  pains,  and  a  more  extensive 
lesion  involving  two  or  three  roots  is  required  before  paralysis  occurs.  Pain- 
ful cramps  may  denote  the  onset  of  anterior  root  or  horn  lesions.  Brown- 
Sequard's  paralysis,  usually  continuing  for  a  limited  period  only,  may  result 
from  unilateral  pressure  and  is  rather  more  frequent  in  extramedullary 
tumors,  especially  in  the  dorsal  region,  yet  it  occurs  also  with  intramedullary 
growths.  The  location  of  the  tumor  is  generally  found  to  be  two  to  four 
inches  above  the  level  of  the  anesthesia.  This  rule  is  based  on  the  fact  that 
with  small  tumors  the  pains,  anesthesia,  and  pareses  may  be  due  not  to  root 
pressure,  but  to  compression  of  cord  well  below  the  roots  adjacent  to  the 
tumor. 

Relation  to  Cord,  Membranes,  and  Vertebra. — A  spinal  tumor  may  be  in- 
tramedullary, intradural,  extradural,  or  vertebral,  and  a  somewhat  different 
prognosis  attaches  to  each  location. 

Intramedullary  tumors,  usually  gliomas,  present  as  cardinal  symptoms, 
loss  of  pain  and  temperature  sense  with  preservation  of  tactile  sense  due  to 
destruction  of  the  intermediate  gray  matter  and  the  commissure.  Yet  this 
symptom-complex  occurs  usually  in  unilateral  and  transitory  form  in  com- 
pression of  the  cord  from  without  (Schlesinger).  Invasion  of  the  posterior 
horns  eventually  destroys  the  tactile  sense.  An  initial  neuralgic  period  is 
usually  wanting,  or  brief  and  mild,  while  bilateral  motor  paresis  appears 
early.  Irregularities  in  course,  remissions,  and  eventually  a  wide  extent 
of  the  symptoms  accord  with  the  cellular  nature  of  gliomas.  Yet  meningitis 
may  give  pronounced  root  pains,  and  Kurtz  observed  continuous  neuralgia  for 
3  years  with  multiple  gliomas  of  the  cord.  Vasomotor  and  atrophic  disturb- 
ances frequently  occur,  and  spinal  deformity  without  pain  or  tenderness  is 
sometimes  observed.  In  many  cases  the  symptoms  are  those  of  transverse 
myelitis. 

Extramedullary  tumors  almost  always  begin  with  neuralgic  pains.  Ma- 
laise found  them  absent  in  only  5  per  cent,  of  the  cases.  Absence  of  pain  may 
be  due  to  a  location  away  from  the  roots,  to  the  resistance  of  the  roots  to 
pressure  from  soft  sarcomas  or  to  compression  of  cord  above  the  involved 
roots  (Schultze).  The  posterior  roots  have  been  found  incased  in  tumor,  but 
without  pain  (Quensel,  Sailer).  Neuralgia  was  the  only  symptom  for  8  years 
in  a  case  of  Schultze,  and  for  18  months  in  Sach's  caudal  sarcoma.  Following 
the  neuralgic  period  come  progressive  motor  disturbances. 

An  extradural  position  is  indicated  especially  by  long-continued  Brown- 
Sequard's  paralysis  with  unilateral  root  symptoms,  followed  by  unilateral 
medullary  symptoms  (Malaise).  Because  of  the  elongated  form  of  many  extra- 
dural tumors  muscular  cramps  and  paralysis  are  relatively  commoner  than 
with  intradural  growths,  but  owing  to  the  protection  of  the  dura,  medullary 
symptoms  may  be  long  delayed. 


TUMORS  OF  SPINAL  CORD  AND  MEMBRANES  445 

Vertebral  tumors  are  suggested  by  diffuse  or  local  spinal  pain  and  tender- 
ness and  by  sharp  kyphosis  or  marked  degrees  of  vertebral  disturbance  which 
may  be  determined  by  the  radiograph. 

The  duration  of  spinal  tumors  varies  widely.  Malignant  vertebral  tumors 
are  the  most  rapid  (average  8.5  months);  20  extradural  sarcomas  gave  an 
average  duration  of  12.7  months;  10  intramedullary  sarcomas,  16.8  months; 
18  intramedullary  gliomas,  23  months;  and  20  intradural  sarcomas,  24.2 
months  (Schlesinger).  The  extremes  for  tumors  diagnosed  as  sarcoma  vary 
from  i  month  to  25  years.  Of  prognostic  import  is  the  rule  that  a  tumor 
of  more  than  3  years'  duration  is  usually  intradural.  The  slowest  courses 
are  those  of  the  benign  fibroma  (31  to  38  months)  and  psammoma  (30  to 
36  months).  Yet  the  duration  of  symptoms  in  psammoma  has  varied  from 
a  few  weeks  to  14  years.  The  diffuse  sarcomas  may  clinically  resemble  men- 
ingitis. Tubercle  and  gummas  progress  slowly  (4  to  6  years). 


CHAPTER  XXV 
GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS 

PAPILLOMA;  ADENOMA;  CARCINOMA 
PAPILLOMA 

From  cutaneous,  mucous,  and  serous  surfaces  local  outgrowths  of  tissue 
composed  of  lining  cells  and  subjacent  connective  tissue  occur  in  many  por- 
tions of  the  body,  and  in  a  wide  variety  of  forms,  to  which  the  general  term 
papilloma  is  applied. 

A  papillary  structure  is  often  observed  in  tumors  of  glandular  organs 
which  pursue  the  course  of  adenoma  or  carcinoma  of  these  organs  and  are 


FIG.  193. — Topography  of  a  fibro-epithelial  papilloma  of  nares. 

therefore  properly  designated  as  papillary  adenoma  or  carcinoma.  They 
usually  develop  in  cysts  of  these  organs  where  the  conditions  nearly  duplicate 
those  obtaining  on  free  surfaces.  Pronounced  papillary  tendencies  appear  in 
papillary  adenoma  of  the  ovary  and  in  papillary  fibroma  of  the  breast,  etc., 
which,  however,  are  conveniently  discussed  with  other  adenomas  and  fibromas 
of  these  organs. 

446 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  447 

In  certain  cases  a  somewhat  specific  structure,  a  characteristic  clinical 
course  and  well-defined  etiological  factors,  combine  to  render  these  processes 
more  or  less  distinctive  diseases  and  demand  for  them  special  considera- 
tion. Otherwise  the  term  "papilloma"  might  well  be  abandoned  or  replaced 
by  the  adjective  "papillary"  attached  to  the  particular  inflammatory  or  tumor 
process  concerned. 

The  form  of  the  papilloma  is  chiefly  determined  by  the  local  conditions 
surrounding  the  tumor.  Outward  growth  of  hyperplastic  cells  is  in  the  line 
of  least  mechanical  resistance.  Irritation  leading  to  overgrowth  of  surface 
epithelium,  hyperemia,  dilatation,  and  elongation  of  blood-vessels,  and  cel- 
lular or  fluid  exudate,  give  rise  to  a  large  series  of  inflammatory  polyps,  es- 
pecially in  mucous  membranes,  and  these  lesions  pass  not  infrequently  into 
true  tumors. 

With  the  papillomas  of  true  neoplastic  type  it  has  long  been  questioned 
whether  the  initial  process  affects  epithelium  or  connective  tissue.  No 


FIG.  194. — Malignant  papillary  epidermoid  carcinoma  of  larynx. 

single  factor  covers  all  cases.  Growing  epithelium  reacts  on  the  underlying 
connective  tissue;  projecting  masses  of  stroma  demand  increase  of  epithe- 
lium for  their  covering;  mechanical  torsion  gradually  elongates  an  originally 
flat  wart;  and  inflammatory  changes  modify  the  contained  blood-  and  lymph- 
vessels.  Each  of  these  elements  becomes  prominent  in  different  papillomas, 
and  several  of  them  are  so  often  combined  that  the  bulk  of  a  papilloma  is 
usually  far  greater  than  would  ordinarily  result  from  any  neoplastic  element 
that  may  reside  in  it.  In  most  neoplastic  papillomas  both  epithelium  and 
connective  tissue  exhibit  the  tumor  tendency. 

While  the  majority  of  specific  papillomas  affect  cutaneous  and  mucous 
surfaces  the  same  processes  appear  in  the  ducts  and  parenchyma  of  glands, 
and  here  the  same  caution  must  be  exercised  in  judging  of  their  nature. 

The  clinical  course  of  papilloma  is  usually  benign,  and  in  most  instances 
the  growth  capacities  are  limited.  Exceptions  to  this  rule  result  from  per- 
sistence of  exciting  factors,  progressive  development  of  new  tumors,  and  ma- 
lignant changes.  The  natural  history  varies  with  each  locality.  In  the 


448  NEOPLASTIC  DISEASES 

skin  the  common  wart  has  a  transitory  life,  papillomas  of  the  bladder  and 
intestine  are  usually  multiple,  and  in  the  larynx  the  papilloma  is  often  ma- 
lignant from  its  inception. 

The  development  of  clinical  signs  of  malignancy  is  probably  much  more 
frequent  than  a  corresponding  change  in  the  growth  capacities  of  the  tumor. 
Such  a  change  may  be  simulated  when  an  original  carcinoma  is  associated 
with  secondary  simple  papillomas  on  the  surface  or  in  the  vicinity  which  mask 
the  malignant  character,  or  an  originally  malignant  process  may  for  a  time 
present  a  simple  papillomatous  appearance.  The  first  two  conditions  are 
exhibited  in  papillomatosis  of  the  intestine  and  the  last  in  some  malignant 
papillomas  of  the  larynx.  Nevertheless  the  gradual  transformation  of  a 
benign  papilloma  into  a  malignant  tumor  has  been  fully  demonstrated  in 
the  cervix  uteri,  bladder,  larynx,  and  other  locations,  and  has  usually 
followed  the  trauma  of  incomplete  operation,  or  prolonged  chronic  in- 
flammation. 

In  structure  the  papillary  tumor  may  fall  in  one  of  four  groups:  (i)  An 
inflammatory  hyperplasia  of  epithelium,  connective  tissue,  vessels,  and  tissue 
cells,  which  belongs  in  the  field  of  chronic  productive  inflammation  (nasal 
and  uterine  polyps,  condyloma  latum);  (2)  a  simple  overgrowth  of  histo- 
logically  normal  tissues,  for  which  a  congenital  origin  is  probable;  (3)  over- 
growth of  atypical  tissues  of  the  type  of  adenoma  (polypoid  adenoma  of 
mucous  membranes);  (4)  distinctly  atypical  and  malignant  epithelial  over- 
growth with  supporting  stroma  which  is  normal  or  neoplastic  (papillary 
carcinoma  of  bladder,  malignant  papilloma  of  larynx). 

All  papillomas  do  not  fall  readily  into  these  classes.  It  may  be  extremely 
difficult  to  determine  whether  a  mucous  polyp  is  purely  inflammatory  or 
partly  neoplastic.  Vesical  papilloma  often  appears  to  be  dependent  upon 
chronic  irritation,  as  of  uric-acid  crystals  or  of  excretory  products  in  anilin 
workers,  but  the  resulting  polyp  is  usually  distinctly  neoplastic.  Hence 
the  study  of  etiology  may  or  may  not  assist  in  the  classification.  The  bulk  of 
a  condyloma  latum  surpasses  that  of  many  papillary  epidermoid  carcinomas, 
and  the  hyperplastic  epithelium  of  cervical  polyps  may  exhibit  every  gra- 
dation from  normal  to  adenomatous  or  carcinomatous  cell  types.  In  many 
instances  the  transformation  of  clinically  benign  into  malignant  growth 
is  attended  with  few  demonstrable  changes  except  a  softening  of  the  under- 
lying tissue  and  a  downward  heterotopia  of  exactly  the  same  type  of  cell 
which  formed  the  polyp.  Abundant  mitoses  and  a  change  in  the  type  of  the 
misplaced  cells  are  to  be  regarded  as  suspicious  features.  Induration  and 
fixation  of  the  base  are  early  signs  of  the  desmoplastic  process  that  accom- 
panies beginning  carcinoma. 

Cutaneous  Warts. — Verruca  vulgaris,  the  common  wart  of  the  skirl, 
is  to  be  distinguished  from  papillary  fibroma  of  the  skin  and  from  the  pap- 
illary nevus.  It  is  a  specific  form  of  epithelial  overgrowth,  is  probably  of 
inflammatory  origin,  and  any  neoplastic  element  it  may  possess  reveals  itself 
in  ways  peculiar  to  this  process. 

It  occurs  on  exposed  regions  of  the  skin,  especially  on  fingers,  hands,  and 
face.  The  duration  is  very  variable,  some  disappearing  after  a  few  weeks, 
others  persisting  for  years.  A  tendency  to  recurrence  is  often  noted.  The 
characteristic  single  discrete  wart  may  become  multiple,  conglomerate,  and 
occasionally  bulky.  Rarely,  elongated  forms  develop  with  numerous  thin 
papillae.  In  young  subjects  very  numerous  small  flat  warts  may  appear 
on  the  backs  of  both  hands  (verruca  plana  juvenilis). 

The  structure  exhibits  an  overgrowth  of  the  entire  Malpighian  layer 
with  folds  and  projections  into  which  extend  thin  strands  of  stroma.  In 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS 


449 


some  cases  there  is  considerable  increase  of  blood-vessels  approaching  the 
type  of  the  papillary  nevus,  and  for  these  a  congenital  origin  is  probable. 

There  are  numerous  clinical  observations  suggesting  the  contagiousness 
of  warts,  but  on  analysis  they  can  be  dismissed  as  examples  of  the  transfer 


FlG.  195. — Topography  of  an  epithelial  papilloma  with  beginning  epidermoid  carcinoma 

of  peculiar  chemical  irritants,  or  exposure  to  the  same  irritant,  or  the  actual 
transfer  of  proliferating  epithelial  cells.  Payne  saw  three  warts  develop 
under  the  nail  of  his  thumb  which  he  had  used  to  separate  a  wart  from  its 


FlG.  196. — Structure  of  a  malignant  wart.     The  lesion  was  covered  with  many  long 
papillae  and  exfoliated  many  scales. 

base.    In  many  instances  warts  have  developed  on  the  skin  of  opposed  sur- 
faces.   Lanz  implanted  a  series  of  warts  on  the  back  of  his  gardener's  hand  by 
inserting  the  comminuted  fragments  under  the  epidermis.     From   74  in- 
29 


450  NEOPLASTIC  DISEASES 

oculations  from  warts  in  4  adults  Judassohn  secured  in  2  to  6  months  33 
warts.  Leale  successfully  employed  sections  of  warts  to  promote  healing  of 
ulcerated  surfaces.  The  etiological  importance  of  chemical  iriitants  appears 
in  the  cases  where  warts  develop  after  contact  with  irritating  substances. 
Many  of  the  observations  suggesting  the  contagiousness  of  cutaneous  warts 
have  been  duplicated  with  gonorrheal  condyloma  and  papilloma  of  the  larynx. 

Occasionally  warts  become  soft,  scaly,  and  inflamed,  they  develop  atypical 
cell  changes,  numerous  fine  pearls  form,  invasion  of  the  derma  follows,  and 
the  process  proves  malignant. 

Cornu  cutaneum  is  a  peculiar  form  of  cutaneous  wart  marked  by  excessive 
and  progressive  keratosis.  The  cutaneous  horn  occurs  chiefly  on  the  scalp, 
but  also  on  the  face,  eyelids,  buttock,  penis,  and  scrotum.  Lebert  collected 
104  cases  of  general  distribution.  Wilson  analyzed  90  cases.  Pick  reported 
10  cases  of  horns  on  the  penis.  Botge  observed  6  horns  on  the  face  of  one 
patient.  Multiple  horny  growths  approach  the  character  of  the  diffuse 
ichthyoses.  They  may  reach  a  length  of  several  inches.  Rodriquez  reported 
a  horn  of  the  scalp  14  inches  in  circumference. 

The  growth  is  slow  but  variable,  and  the  course  when  uninterrupted  con- 
tinues for  many  years.  Lebert  found  that  carcinoma  developed  in  12  per 
cent,  of  his  cases. 

The  growth  begins  as  a  wart  on  the  normal  skin  or  in  scars.  Some  horns 
take  origin  in  the  epithelium  of  sebaceous  cysts,  a  fact  which  suggests  that  the 
originating  cells  have  a  peculiar  functional  tendency  to  hornification.  The 
structure  presents  elongated  papillae  of  the  derma  covered  by  lamellae  com- 
posed chiefly  of  hornified  epithelium.  The  persistence  of  blood-vessels  in 
very  fine  papillae  coursing  through  the  horny  material  accounts  for  the  ex- 
tensive development  of  the  greatly  elongated  forms.  The  chief  oncological 
interest  centers  in  the  excessive  development  and  persistence  of  the  function 
of  keratosis.  The  process  may  be  interpreted  as  a  tumor  of  horny  substance 
(Dubreuilh). 

Condyloma  Acuminatum. — The  pointed  moist  venereal  wart  occurs  chiefly 
about  the  genitals,  but  also  on  the  thighs  and  abdomen,  whi'e  similar  growths 
are  occasionally  seen  in  the  axillae  and  on  the  face.  They  are  single,  mul- 
tiple or  conglomerate,  and  while  usually  elongated,  some  multiple  forms  are 
small  and  low.  They  are  composed  of  few  or  many  villous  projections  or 
tufts  which  commonly  spring  from  a  single  pedicle.  They  are  usually  moist 
and  bathed  in  rancid,  serous  or  mucinous  fluid,  the  irritation  of  which  is  be- 
lieved to  be  the  cause  of  the  overgrowth.  Yet  similar  warts  occur  in  posi- 
tions which  are  free  from  moisture.  While  commonly  associated  with  gonor- 
rhea, they  occur  in  children  and  the  aged.  In  the  irritating  fluid  many 
bacteria  are  found,  among  which  are  spirochetes  sometimes  in  enormous 
numbers.  The  growth  may  be  very  rapid,  especially  in  pregnancy,  but  they 
persist  for  long  periods,  and  may  reach  a  large  size  or  cover  a  widening  area. 
Hyde  mentions  a  compound  venereal  wart  of  the  penis  in  a  negro  which  was 
as  large  as  an  orange.  Contagiousness  is  often  observed  and  must  be  re- 
ferred to  the  transfer  of  peculiar  irritating  secretions  and  of  the  microorgan- 
isms which  find  in  such  fluids  a  suitable  habitat. 

The  structure  presents  a  central  core  which  is  more  vascular  than  in 
other  warts,  and  is  covered  by  a  variable  thickness  of  epithelium  in  which 
hornification  is  imperfect  or  absent.  Kuhneman  finds  the  chief  peculiarity 
in  a  thickening  of  the  granular  layer  and  an  imperfect  hornification  which 
leaves  the  epithelial  nuclei  still  visible  in  the  superficial  cells.  Through  this 
loose  epithelial  covering  there  is  a  slight  constant  exudation  of  serum.  In 
the  core  of  acuminate  condylomas  Herxheimer  found  varicose  nerve-fibers. 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS 


451 


Condyloma  latum  is  the  broad,  flat  wart  of  syphilis,  and  occurs  about 
the  genitals  and  especially  about  the  anus.  This  orifice  may  be  surrounded 
and  partially  occluded  by  a  luxuriant  fungating  mass  several  inches  in 
diameter  and  markedly  protuberant.  The  lesion  may  advance  within  the 
external  sphincter  and  over  a  considerable  portion  of  the  b'uttock.  It  is 
subject  to  fissuring,  infection,  and  ulceration,  and  in  some  cases  a  destructive 
form  of  carcinoma  develops  from  it. 

The  structure  shows  an  extensive  overgrowth  of  the  entire  Malpighian 
layer  which  becomes  greatly  thickened  and  much  convoluted.  The  cells  are 
hypertrophic,  but  otherwise  typical.  Hornification  may  be  defective.  The 
connective-tissue  papillae  are  thickened,  moderately  elongated  and  bifurcated, 
and  present  the  characteristic  changes  of  secondary  syphilis. 

Molluscum  contagiosum  is  a  peculiar,  contagious,  and  possibly  infectious 
disease  of  the  skin  which  produces  multiple,  wart-like,  projecting  nodules 


FIG.  197. — Intracellular  bodies  of  molluscum  contagiosum. 

distributed  over  the  hands,  face,  neck,  or  over  much  of  the  body.  The  dis- 
ease appears  chiefly  in  children,  continues  for  months  or  years,  but  eventually 
subsides.  A  somewhat  similar  condition  is  observed  in  chickens. 

The  nodules  are  single  or  conglomerate,  wax-like,  or  almost  transparent, 
as  large  as  a  pea  or  bean,  and  usually  present  a  central  depression.  On  sec- 
tion they  exhibit  a  series  of  swollen  rete  pegs  composed  of  a  moderately  in- 
creased number  of  markedly  hypertrophic  swollen  epithelial  cells  which 
produce  convolution  and  projection  of  the  Malpighian  layer.  Many  of  the 
lesions  develop  in  the  hair  or  sebaceous  follicles  of  the  skin  (Kaposi).  Be- 
tween opposed  layers  there  is  considerable  exfoliation  of  epithelium.  The 
structure  of  the  cells  is  quite  peculiar.  The  cytoreticulum  becomes  thickened 
and  coarse  at  the  expense  of  material  from  the  nucleus,  and  a  large  portion 
of  the  cytoplasm  thus  becomes  converted  into  a  well-defined  reticulated  struc- 


452  N  EOF  LA  STIC  DISEASES 

ture  imperfectly  separated  from  nucleus  and  cell-membrane  and  appearing 
as  a  foreign  body.  The  nucleus  eventually  shrinks  to  one  side  of  the  cell.  The 
variations  in  the  minute  structure  of  these  molluscum  bodies  are  quite  nu- 
merous. They  appear  to  form  in  much  the  same  manner  as  the  vaccine  bodies 
of  variola,  or  as  the  psorosperms  of  Darier,  and  similar  structures  appear  in 
ordinary  hyperkeratosis  (Petersen).  Lubarsch  finds  them  in  warts,  second- 
ary papillomas,  and  in  various  forms  of  epithelial  hypertrophy.  Many 
have  assumed  that  the  bodies  are  parasitic,  but  their  minute  analysis  has 
failed  to  support  this  view  (Kromayer).  Juliusberg  reports  that  the  virus 
of  human  molluscum  is  filterable. 

Papilloma  of  Tongue. — The  lingual  and  buccal  mucosa  is  frequently 
the  seat  of  papillomas,  which  present  peculiarities  in  structure,  origin,  and 
clinical  course. 

The  papillomas  occur  on  any  portion  of  the  tongue,  affecting  the  lateral 
borders,  under  surface,  and  dorsum.  The  median  raphe  of  the  dorsum  is  a 
frequent  site.  Many  are  of  congenital  origin.  Butlin  mentions  multiple 
papillomas  of  the  fungiform  papillae,  and  bulky,  warty  outgrowths  of  the 
dorsum  of  tongue  in  infants.  Riga's  disease  refers  to  multiple  papillomas 
on  either  side  of  the  frenum  caused  by  irritation  of  coughing  in  pertussis. 
In  adults  papilloma  arises  in  the  middle  line  of  the  dorsum  from  a  congenital 
basis,  from  leukoplakia  and  other  forms  of  syphilis,  from  simple  glossitis 
due  to  tobacco,  and  irritation  of  bad  teeth.  The  etiology,  therefore,  almost 
exactly  duplicates  that  of  lingual  carcinoma.  The  form  is  either  acuminate 
or  flat,  and  while  some  remain  single  and  small,  others  become  bulky  or  mul- 
tiple. They  may  be  painful  and  bleed,  but  ulceration  points  to  a  malignant 
process.  In  some  cases  a  large  portion  of  the  tongue  and  floor  of  mouth  may 
be  covered  by  papillomatous  growths  and  from  various  points  multiple  car- 
cinomas may  develop  (diffuse  buccal  papilloma tosis) . 

Lymphatic  varicosity  affecting  the  papillae  may  produce  a  bulky,  papil- 
lomatous growth  of  tongue  or  buccal  mucosa  (Robin-Leredde,  Kaufmann, 
Rehn). 

While  some  papillomas  long  remain  benign  and  enjoy  a  limited  growth 
there  is  a  strong  tendency  toward  malignant  change  which  is  indicated  by 
increasing  growth,  induration,  and  fixation  of  the  base,  and  ulceration.  A 
large  proportion  of  lingual  carcinomas  exhibits  a  brief  preliminary  papillo- 
matous stage,  and  the  more  pronounced  this  character  as  a  rule,  the  slower 
the  progress  of  the  disease. 

The  chief  interest  in  lingual  and  buccal  papilloma  lies  in  the  differential 
diagnosis  from  carcinoma.  The  former  readily  responds  to  radium  or  to 
simple  excision  of  the  lesion,  and  many  successful  operations  for  lingual  car- 
cinoma refer  to  simple  papilloma  or  papilloma  with  precancerous  or  minia- 
ture carcinomatous  changes.  A  careful  microscopical  study  is  therefore 
indicated  before  operation. 

ADENOMA 

Adenoma  is  an  organoid  tumor  which  reproduces  the  structure  of  a  gland. 

The  attempt  to  further  define  this  neoplasm  meets  at  once  with  limita- 
tions. A  complete  and  typical  adenoma  reproduces  epithelial  alveoli,  gland 
ducts,  membrana  propria,  stroma  and  vessels,  in  a  somewhat  orderly  and 
functionating  organ,  as  in  mamma  and  thyroid.  More  atypical  adenomas  are 
devoid  of  definite  function,  of  differentiated  ducts,  of  specific  stroma,  and 
of  membrana  propria,  these  features  being  lost  in  the  order  named. 

Langhans  and  Lubarsch  find  a  definite  membrana  propria  in  most  ade- 
nomas, but  not  in  all.  Dreyfuss  could  find  it  only  in  traces  in  mammary 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS 


453 


adenoma,  but  he  describes  a  proliferation  of  the  cells  of  the  membrana  in 
certain  cases,  in  which  it  is  difficult  to  distinguish  between  sustentacular 
epithelium  and  stroma-cells.  Hyaline  thickening  of  the  membrana  is  also 
observed. 

In  adenoma  malignum  the  hyperplastic  and  hypertrophic  cells  maintain 
their  polarity  so  that  orderly  but  giant  alveoli  and  glands  constitute  the 
tumor  unit.  Such  a  tumor  is  still  an  adenoma,  preserving  the  gland  type,  and 
the  common  suggestion  to  abandon  the  term  "malignant  adenoma"  seems 
ill-advised. 

In  gross  appearance  the  adenomas  are  usually  well  circumscribed  or 
encapsulated  tumors  which  do  not  infiltrate  the  surrounding  tissue  as  do 
carcinomas.  They  are  well  nourished  by  blood-vessels  running  in  a  sufficient 
stroma  and  are  therefore  not  prone  to  necrosis.  On  superficial  surfaces  they 
often  produce  polypoid  tumors,  and  in  the  organs  they  frequently  assume  a 


FIG.  198. — Adenoma  of  axillary  sweat  glands. 

cystic  or  papillary  character.  While  some  are  of  miliary  size  and  multiple, 
others  are  single  and  large,  while  a  few  by  virtue  of  good  nutrition  or  cyst  for- 
mation reach  voluminous  dimensions. 

Clinically  true  adenomas  are  usually  slow  of  development  and  of  limited 
growth  capacity.  Their  disturbance  of  the  organism  is  chiefly  mechanical. 
The  occurrence  of  metastases  would  lead  many  to  separate  the  tumor  from 
the  group  of  adenomas,  while  others  would  classify  such  growths  as  a  form 
of  malignant  adenoma.  Most  metastasizing  simple  adenomas  exhibit  areas 
of  adenocarcinoma  in  some  portions  of  the  tumor. 

Even  in  the  benign  metastasizing  thyroid  struma,  which  is  the  best  ex- 
ample of  simple  adenoma  yielding  secondary  tumors,  many  have  claimed  that 
the  morphology  is  that  of  adenocarcinoma.  The  peculiar  relations  of  thy- 
roid and  adrenal  alveoli  to  the  blood-vessels  are  exceptionally  favorable 
for  cell  emboli  from  these  growths.  Encapsulation  is  a  strong  barrier  against 


454 


NEOPLASTIC  DISEASES 


malignant  change  so  that  adenomas  of  embryonal  origin  long  retain  their 
type,  while  those  arising  on  a  basis  of  diffuse  chronic  inflammation  or  on 
mucous  or  serous  surfaces  more  readily  become  malignant. 

In  judging  of  the  probable  course  of  an  adenoma  it  is  important  to  consider 
which  organ  is  affected.  Simple  adenomas  of  the  thyroid  and  stomach  are 
frequently  malignant,  those  of  the  rectum  rarely. 

While  the  study  of  single  sections  of  an  adenoma  may  fail  to  yield  a  cor- 
rect estimate  of  malignancy,  the  finer  histological  details  are  usually  of  dis- 
tinct prognostic  significance.  Uniformly  atypical  cell  forms,  nuclear  hyper- 
chromatism,  abundance  of  mitoses,  and  reduplication  of  cell  layers  are  com- 
monly associated  with  dangerous  types  of  adenomas,  but  the  significance 
of  these  signs  must  be  learned  for  each  organ. 

Functional  capacity  is  retained  by  many  adenomas;  occasionally  it  is  much 
increased,  and  probably  in  all  cases  the  product  is  abnormal.  Fatty  material 


FIG.   199. — Structure  of  a  thyroid  tumor  of  frontal  bone.     Subject,  male,  65  years. 
Thyroid  gland  apparently  normal. 

appears  in  adenoma  sebaceum  (Barlow)  and  in  tumors  of  the  breast.  I  have 
found  rudimentary  hairs  in  adenoma  of  the  hair  follicles.  Overproduction 
of  mucus  is  excessive  in  some  ovarian  tumors,  but  Schmidt  regards  this  as  a 
pathological  activity  not  shared  by  the  cells  of  origin,  which  do  not  secrete 
mucus.  In  gelatinous  adenoma  malignum  of  the  colon  the  production  of 
mucus  may  be  enormous,  even  destroying  portions  of  the  tumor.  Bile  is 
often  seen  in  adenoma  of  the  liver  (Schmidt,  Lit.),  and  Marckwald  found  the 
secretion  excessive.  Thyroid  adenomas  occasionally  contain  colloid  both  in 
the  main  tumor  and  in  heterotopic  and  metastatic  growths  (Wolfler).  Schmidt 
points  out  that  the  structure  of  adenoma  or  adenocarcinoma  is  regularly 
assumed  in  functionating  malignant  tumors  of  thyroid  and  liver.  Early 
adrenal  adenomas  contain  much  lipoid  material,  but  the  formation  of  adrenalin 
in  such  growths  has  not,  I  believe,  been  demonstrated.  Yet  some  adrenal 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  455 

adenomas  are  extensively  pigmented,  and  in  a  well-known  group  remarkable 
hirsuties  and  sexual  precocity  point  to  disturbed  or  excessive  functional 
activity. 

Contrasted  with  this  group  of  functionating  adenomas  stands  another, 
chiefly  of  embryonal  origin,  in  which  there  is  a  sharp  suppression  of  function. 
Hence  it  appears  that  function  in  adenomas  represents  an  acquired  character 
of  the  cells  of  origin  and  that  it  is  not  an  essential  feature  of  this  tumor  group. 

Mode  of  Growth. — In  adenoma  the  neoplastic  process  resides  either  in 
the  gland-cells  alone  or  in  both  cells  and  stroma.  In  the  former  case  highly 
cellular  tumors  develop,  in  the  latter  nbro-adenomas.  The  original  impulse 
is  probably  always  located  in  the  epithelium  which  exerts  a  formative  in- 
fluence over  the  connective-tissue  structures.  Yet  in  some  adenomas  the 
growth  appears  to  begin  in  both  elements  simultaneously,  and  occasionally 
the  stroma  overgrows  the  glands.  The  vessels  may  also  become  extremely 
prominent.  The  key  to  the  morphology  of  most  adenomas  is  to  be  sought  in 
the  course  of  the  normal  embryonal  development  of  the  gland,  which  is  re- 
peated in  the  tumor  (Ribbert).  Yet  many  secondary  factors,  as  mechanical 
pressure,  retention  of  secretion,  and  overgrowth  of  stroma,  modify  or  dominate 
the  structure. 

Tubular  adenoma  results  chiefly  from  elongation  of  the  affected  gland, 
as  in  the  colon,  but  the  same  process  may  give  rise  to  an  alveolar  appearance 
in  cross-sections  of  folded  and  twisted  glands.  White  cut  serial  sections  of  a 
lobule  of  mammary  adenoma,  finding  that  all  the  alveoli  represented  a  single 
tubule  entering  the  lobule  from  the  main  tumor.  Saccular  or  follicular  ade- 
noma results  from  the  formation  of  lateral  sacculi  from  original  glands.  This 
process  occurs  in  many  organs,  but  is  best  seen  in  some  adenomas  of  the  breast 
and  thyroid.  In  serial  sections  of  a  rectal  polypoid  adenoma  White  found 
lateral  sacculi,  communications  between  adjoining  acini,  and  multiplication 
of  surface  openings. 

Papillary  cystic  adenoma  is  a  form  assumed  by  many  adenomas  in  which 
with  or  without  retained  secretion  the  original  alveoli  are  distended  by  fluid 
or  by  papillary  outgrowths  of  epithelium  and  connective  tissue.  There  has 
been  much  discussion  of  the  mechanism  which  causes  the  distention  in  cystic 
adenoma  (Dreyfuss,  Lit.).  Both  retention  of  secretion  and  primary  over- 
growth of  epithelium  and  connective  tissue  with  secondary  enlargement  of 
the  alveolus  are  concerned  in  the  result.  Fusion  of  neighboring  alveoli  is 
also  a  factor,  while  serous  and  bloody  exudates  and  extravasations  may  cause 
rapid  enlargements  of  cystic  tumors.  Paget  divided  cystic  tumors  accord- 
ing to  the  prominence  of  these  processes.  Rokitansky  regarded  the  true 
cystic  adenoma  as  a  structure  tending  essentially  to  grow  in  cystic  form, 
and  Dreyfuss  emphasizes  the  importance  of  proliferation  of  the  membrana 
cells  as  leading  to  a  widened  lumen.  He  found  the  ducts  patent  in  some  cystic 
adenomas  of  the  breast  and  the  smaller  alveoli  empty.  It  has  often  been 
urged  that  pressure  alone  causes  atrophy  rather  than  overgrowth  of  lining 
cells. 

Structure. — Adenoma  malignum  maintains  the  alveolar  structure  and 
the  polarity  of  the  lining  cells,  but  early  loses  ducts  and  specific  membrana 
propria,  while  the  stroma  is  deficient  or  absent.  The  alveolar  structure  may 
be  rigidly  maintained  even  in  metastases,  but  the  cells  are  usually  hypei- 
trophic  and  atypical,  and  the  nuclei  hyperchromatic.  In  this  form  the  tumor 
has  infiltrative  capacity  and  produces  metastases.  Adenoma  malignum 
often  passes  into  adenocarcinoma. 

Morphological  distinctions  between  benign  adenoma  and  adenoma  malig- 
num vary  in  different  organs.  Adenoma  of  the  thyroid  may  yield  metastases 


456  NEOPLASTIC  DISEASES 

oj  quite  typical  form.  In  an  interscapular  metastasis  of  gastric  adenoma 
I  found  regular  alveoli  lined  by  a  single  row  of  normal-sized  cuboidal  cells 
with  slight  nuclear  hyperchromatism.  In  a  splenic  metastasis  from  adenoma 
of  the  corpus  uteri  the  alveoli  were  more  typical  than  in  the  uterus,  but  the 
cells  were  twice  as  large  as  the  columnar  cervical  epithelium.  Hence  the 
statement  is  correct,  that  the  alveoli  of  adenoma  malignum  may  not  differ 
from  those  of  ordinary  adenoma  or  of  glandular  hyperplasia.  As  a  rule, 
however,  the  alveoli  of  adenoma  malignum  are  atypical,  the  cells  larger, 
the  nuclei  more  hyperchromatic,  the  cell  layers  are  multiplied,  secondary 
alveoli  form,  quite  atypical  cells  begin  to  appear,  and  there  is  an  entire  ab- 
sence of  membrana  propria.  For  each  organ  a  special  standard  is  needed 
in  estimating  the  grade  of  anaplasia  and  malignancy.  The  relation  of  glands 
and  stroma  is  also  of  much  importance.  Borst  emphasizes  the  promiscuous 
distribution  of  glands  and  stroma  in  malignant  adenoma. 

Adenocarcinoma  is  a  tumor  of  gland-cells  resembling  adenoma,  but  failing 
to  completely  preserve  any  of  the  normal  features  of  the  gland.  The  orderly 
alveolus  is  the  essential  element  of  an  adenoma,  but  in  adenocarcinoma  even 
the  alveolus  is  imperfectly  formed  and  the  epithelial  cells  begin  to  lose  their 
polarity.  Markedly  atypical  cell  morphology  and  extensive  overgrowth 
are  also  characters  of  adenocarcinoma,  and  this  tumor  may  lose  all  adenoma- 
tous  characters  and  pass  into  carcinoma.  Yet  many  infiltrating  and  highly 
malignant  tumors  exhibit  numerous  traces  of  alveolar  formation. 

The  attempt  to  classify  adenomas  on  purely  morphological  features  is 
quite  unsatisfactory.  In  many  cases  tumors  which  show  simple  adenoma- 
tous  structures  in  one  portion  exhibit  adenocarcinomatous  areas  in  another, 
and  pure  carcinomatous  infiltration  in  still  other  areas.  This  instability  of 
the  adenomatous  structure  is  more  notable  in  some  organs  than  in  others,  but 
is  a  rather  general  characteristic  of  many  adenomas. 

While  the  tendency  is  usually  toward  greater  anaplasia  with  continued 
growth,  occasionally  the  metastases  of  an  adenocarcinoma  are  more  dis- 
tinctly adenomatous  than  the  original  tumor.  Apolant  was  able  to  trans- 
form an  adenocarcinoma  of  the  mouse  into  an  adenoma  by  transplantation 
in  partially  immune  animals.  The  study  of  many  adenocarcinomas  indi- 
cates that  the  pure  adenomatous  structure  may  represent  an  intermediate 
or  transitory  stage  in  the  evolution  of  the  tumor  process  which  is  rapidly 
traversed  and  soon  passes  into  a  more  atypical  carcinomatous  phase. 

There  may  be  considerable  or  pronounced  variation  in  the  structural 
type  of  the  adenoma  in  the  same  tumor.  Thus  in  an  adenocarcinoma  of  the 
prostate  I  have  found  hypertrophied  alveoli  recalling  adenoma  malignum; 
many  small  alveoli  resembling  simple  tubular  adenoma;  distended  tubules 
rilled  with  neoplastic  papillary  ingrowths;  as  well  as  fibrocarcinoma.  Clin- 
ically this  tumor  pursued  the  course  of  carcinoma. 

Accordingly,  if  the  term  "adenoma"  is  to  enjoy  any  great  pathological  sig- 
nificance, its  application  must  be  made  with  due  reference  to  the  gross  ana- 
tomical and  the  clinical  features  of  the  disease.  From  this  standpoint  there 
are  still  many  tumors  which  tend  to  maintain  the  morphology  of  adenoma, 
with  some  persistence  of  the  function  of  the  originating  gland,  and  pursue 
a  clinical  course  which  is  less  malignant  and  destructive  than  that  of  carcinomas 
of  the  same  organ. 

Examples  of  this  true  adenoma  in  the  general  biological  sense  are  those 
of  the  cutaneous  glands,  fibre-adenoma  of  the  breast,  follicular  adenoma  of 
thyroid,  adrenal  adenoma,  the  adenoma  of  the  islands  of  Langerhans,  Kauf- 
mann's  adenoma  of  the  testis,  and  some  adenomas,  chiefly  papillary,  of  dif- 
ferent organs.  All  of  these  tumors  arise  under  somewhat  peculiar  conditions, 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  457 

exhibit  little  morphological  variation,  and  run  a  uniform  and  commonly 
benign  clinical  course. 

Physiological  Conception. — When  one  considers  the  great  variety  of  con- 
ditions in  which  an  adenomatous  morphology  is  presented  and  analyzes 
their  physiological  and  clinical  significance,  the  conclusion  must  be  reached 
that  adenoma  is  rarely  a  distinct  morphological  entity,  but  is  rather  to  be 
regarded  as  a  series  of  structures  which  tissues  assume  in  response  to  various 
forms  of  irritation,  functional  activity,  and  overgrowth.  It  is  chiefly,  if  not 
exclusively,  the  adenomas  of  embryonal  origin  which  fail  to  show  this  com- 
plex significance.  It  were  better,  therefore,  in  most  instances  to  avoid  the 
rigid  morphological  conception  of  adenoma  and  to  regard  the  diseases  marked 
by  adenomatous  hyperplasia  as  specific  clinical  and  pathological  entities. 
The  justification  of  this  view  will  appear  in  dealing  with  some  of  the  many 
forms  of  adenomatoid  and  adenomatous  hyperplasia. 

Most  authors  distinguish  sharply  between  true  adenoma  and  adenomatous 
hyperplasia  of  organs  and  tissues.  It  is  highly  desirable  that  the  distinction 
should  be  made  wherever  possible,  but  it  cannot  always  be  accomplished  on 
morphological  data  alone.  It  is  usually  necessary  to  consider  the  conditions 
under  which  the  abnormal  process  develops  and  its  clinical  course.  In  the 
extensive  group  of  adenomatoid  hyperplasias  it  is  often  impossible  to  dis- 
tinguish the  morphology  from  that  of  adenoma  of  other  types,  but  reference 
to  the  clinical  data  reveals  that  the  process  is  dependent  on  chronic  inflamma- 
tion and  tends  to  run  a  self-limiting  course.  In  the  thyroid  and  hypophysis 
adenomatoid  changes  result  from  functional  hyperplasia.  In  many  situa- 
tions adenomatoid  hyperplasia  becomes  progressive  and  passes  into  a  neo- 
plastic  process  and  when  this  stage  is  reached  the  conditions  exhibit  the  same 
potentialities  as  other  adenomas.  In  intestinal  polyposis  different  portions 
of  the  intestine  exhibit  peculiar  inflammatory  overgrowth,  adenomatoid  hy- 
perplasia, adenoma,  and  even  carcinoma. 

The  adenoma  arising  under  such  conditions  may  differ  in  some  respects 
from  other  adenomas,  but  still  deserves  recognition  as  a  neoplasm.  All  of  these 
considerations,  which  apply  equally  to  adenoma  and  carcinoma,  urge  the 
necessity  of  regarding  these  tumors  from  the  biological  or  clinical  standpoint 
rather  than  from  the  morphological  side  alone. 

On  physiological  analysis  adenomas  are  found  to  represent  several  dif- 
ferent processes,  and  from  this  standpoint  the  interpretation  of  the  mode  of 
origin,  structure,  and  significance  is  most  satisfactory.  • 

Thus  some  adenomas  are  traceable  to  a  localized  inflammatory  over- 
growth. Others  represent  chiefly  an  excessive  response  to  functional  stimulus. 
Some  appear  to  owe  their  existence  to  minor  anatomical  disturbances  hi 
the  blood-supply  or  configuration  of  the  organ.  Many  true  adenomas  repre- 
sent pronounced  neoplastic  growth  of  definitely  misplaced  and  embryonal 
portions  of  gland  tissue.  Probably  more  than  one  of  these  factors  may  be 
combined  in  origin  of  the  same  adenoma. 

Inflammatory  adenomatoid  hyperplasia  is  of  wide-spread  occurrence. 

In  the  mucous  membranes  of  the  gastro-intestinal  tract,  uterus,  and  nares 
it  produces  diffuse  overgrowth  or  single  or  multiple  polypoid  excrescences 
which  constitute  definite  clinical  entities,  and  it  is  a  feature  of  the  late  stages 
of  chronic  catarrhal  inflammation  of  these  tissues.  The  process  affects  both 
glands  and  stroma.  The  glands  become  hypertrophic  or  cystic  and  the  lining 
cells  are  increased  in  size  and  number.  There  is  usually  increased  and  abnormal 
secretion.  The  stroma  shows  new  and  tortuous  blood-  and  lymph-vessels, 
multiplication  of  stroma-cells,  atrophy  of  lymph-follicles,  and  perivascular 
infiltration  by  lymphocytes.  The  process  tends  first  to  produce  a  diffuse 


458  NEOPLASTIC  DISEASES 

thickening,  but  focal  overgrowth  of  the  tissue,  edema,  venous  stasis,  and 
mechanical  traction  lead  to  papillary  and  polypoid  outgrowths  which  may 
become  numerous  and  bulky.  In  this  condition  there  is  a  tendency  to  further 
overgrowth  of  the  predominating  element,  glands,  stroma,  or  vessels.  In 
the  nares  the  mucous  polyps  show  wide  variations  in  structure,  some  being 
glandular,  others  myxomatoid,  other  angiomatous,  but  the  tendency  to  true 
tumor  growth  is  slight. 

In  gastritis  polyposa  the  development  of  polypoid  outgrowths  may  reach 
an  astonishing  grade,  covering  most  of  the  mucosa  and  leading  to  dilatation 
of  the  organ. 

In  colitis  polyposa  the  entire  colon  from  cecum  to  anus  may  be  the  seat 
of  myriads  of  small  or  pedunculated  outgrowths,  the  pedicle  may  be  elongated 
and  ruptured  and  the  polyp  discharged  through  the  anus.  The  ileum  or 
jejunum  is  rarely  affected,  but  Kaufmann  and  Hauser  saw  involvement  of 
the  entire  mucosa  from  cardia  and  pylorus  to  anus,  and  lesions  in  duodenum, 
jejunum,  and  ileum  are  reported  by  Lubarsch,  Niemarck,  and  Petrow.  Pecu- 
liar catarrhal  symptoms  mark  the  onset  of  the  disease,  and  hemorrhage, 
anemia,  and  emaciation,  intussusception,  and  prolapse  occur  in  advanced 
cases  (Virchow,  Luschka,  Hauser,  Schwab,  Smoler).  The  condition  affects 
both  old  and  young  subjects  and  exhibits  an  hereditary,  individual,  and  local 
predisposition  (Cripps,  Smith,  Bickerstedt,  Port,  Verse).  In  the  early  stages 
I  find  one  of  the  earliest  changes  is  a  pronounced  hypertrophy  of  the  epi- 
thelial cells,  a  tendency  which  Verse  regarded  as  the  sole  element  in  the  local 
predisposition.  Although  many  cases  maintain  their  inflammatory  char- 
acter throughout  there  is  a  striking  tendency  toward  the  development  of 
malignant  adenoma  and  carcinoma.  According  to  Quenu  and  Landel  about 
half  the  cases  are  associated  with  carcinoma,  while  Hauser  found  this  com- 
bination as  the  rule,  and  Doering,  who  analyzed  50  cases,  found  37  fatalities, 
31  from  carcinoma.  There  is  probably  no  other  tissue  which  illustrates  so 
clearly  the  transition  of  an  inflammatory  overgrowth  into  a  malignant  tumor. 

Hypertrophic  Endometritis. — Fungous  or  glandular  endometritis. 

In  a  somewhat  limited  group  of  cases  associated  with  myoma,  carcinoma, 
misplacement  of  the  uterus,  or  disease  of  the  adnexa,  the  uterine  mucosa 
becomes  much  thickened  (0.5  to  i  cm.),  very  vascular,  prone  to  hemorrhage, 
cystic,  and  covered  with  papillary  or  polypoid  projections.  There  is  exten- 
sive overgrowth  of  large,  irregular,  compact,  or  dilated  glands.  Infoldings 
of  the  cell,  lining  may  yield  one  or  two  epithelial  rings  within  the  lumma  on 
section.  The  cells  are  considerably  enlarged,  nuclei  hypertrophic  and  often 
in  mitosis,  and  the  layers  may  be  multiple.  In  a  series  of  cases  every  grada- 
tion may  be  observed  from  normal  glands  to  those  of  adenoma  malignum,  and 
one  often  finds  single  glands  outstripping  the  others  in  this  transition.  New 
growth  of  interstitial  tissue,  with  large  flat  decidua-like  cells,  lymphocytes, 
and  plasma-cells  may  appear,  especially  in  the  polypoid  projections  (endo- 
metritis interstitialis).  Hitschman  and  Adler  have  shown  that  many  cases  of 
so-called  glandular  endometritis  represent  merely  the  cyclic  changes  of  men- 
struation and  they  deny  the  existence  of  any  but  an  interstitial  endometritis. 
Yet  the  occasional  occurrence  of  definite  conditions  of  the  type  described 
is  fully  attested  and  the  origin  must  be  attributed  to  the  usual  factors  con- 
nected with  chronic  productive  inflammation  of  mucous  membranes,  to  which 
is  here  added  the  influence  of  tumors  and  inflammations  in  the  uterus  and 
adjoining  tissues  (Weishaupt-Schickele). 

That  chronic  glandular  endometritis  may  pass  into  adenoma  is  strongly 
indicated  by  its  frequent  occurrence  with  myoma  which  nearly  always  shows 
glandular  hypertrophy  and  often  adenoma,  and  by  the  histological  evidence 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  459 

of  the  transition.  The  malignant  change  seems  to  occur  suddenly  and  affects 
first  single  glands,  or  larger  areas.  It  is  marked  by  striking  increase  in  the 
size  of  the  epithelial  cells,  pronounced  hyperchromatism,  atypical  mitoses, 
multiplication  of  cell  layers,  and  reduction  of  stroma.  These  changes  are 
pronounced  and  unequivocal  when  the  diagnosis  of  adenoma  is  justified, 
and  it  is  only  in  rare  instances  that  the  decision  remains  doubtful.  When 
the  adenoma  is  sufficiently  established  to  reach  the  surgeon  all  traces  of  the 
original  hyperplasia  may,  as  Heurlin  found,  be  obliterated. 

Pr astatic  Hypertrophy. — In  the  prostate  inflammatory  overgrowth  is 
responsible  for  the  great  majority  of  cases  of  chronic  prostatic  enlargement 
(q.  v.).  Here  the  results  are  peculiar,  depending  on  the  structure  and  func- 
tions of  the  organ  and  the  changes  must  be  referred  not  exclusively  to  the 
inflammatory  factors  but  also  to  secondary  disturbances  of  nutrition  and 
function.  In  fact,  a  primary  disturbance  in  the  function  of  the  prostate 
may  possibly  prove  to  be  an  essential  factor  in  the  causation  of  hypertrophy, 
since  most  cases  of  active  prostatitis  tend  toward  atrophy  of  the  organ. 
The  inflammatory  process  begins  about  the  ducts,  retains  a  periductal  char- 
acter throughout,  and  causes  more  or  less  new  growth  of  fibromuscular  stroma 
about  the  systems  of  alveoli.  The  nearest  parallel  to  this  condition  is  seen 
in  chronic  mastitis.  The  overgrowth  of  epithelium  is  complicated  by  stasis 
of  secretion  which  may  produce  small  cysts  with  relatively  atrophic  epithelium. 
Or  the  epithelium  is  more  active  and  lateral  sacculations  and  papillary  pro- 
jections form.  Ciechanowski  emphasizes  the  absence  of  any  new  glands 
in  prostatic  hypertrophy,  but  in  many  cases  focal  adenomatous  areas  appear 
and  the  process  passes  into  adenoma  or  carcinoma.  In  other  cases  the  natural 
tendency  is  toward  fibrosis  and  atrophy. 

Many  examples  of  functional  or  congenital  overgrowth  of  gland  tissue 
should  be  separated  from  true  adenoma,  although  no  sharp  line  divides  these 
conditions  from  true  tumors,  and  in  many  instances  the  one  passes  into  the  other. 

(1)  Functional  Adenomatoid  Hyperplasia. — In  the  breast,  hypertrophy, 
which  is  chiefly  of  functional  significance,  produces  extensive  enlargement 
of  both  organs,  at  first  of  slight  degree,  but  later,  often  at  puberty,  increasing 
rapidly  until  both  organs  become  very  bulky  (30  kg.,  Kaufman).    The  condi- 
tion may  remain  stationary  in  this  stage  or  may  increase  during  gestation 
and  enormous  amounts  of  very  fatty  milk  are  secreted.    The  structure  shows 
uniform  increase  of  cellular  connective  tissue  and  of  hypertrophied  gland 
lobules,  but  there  are  many  variations  in  the  proportions  of  these  elements. 
In  some  cases  the  structure  strongly  resembles  a  true  fibro-adenoma.    The 
series  of  cases  analyzed  by  Voges  and  by  Kirchheim  illustrate  many  peculiarities 
of  the  process,  including  an  hereditary  element,  involvement  of  one  breast 
or  both,  or  of  one  or  two  supernumerary  organs,  its  appearance  before  puberty 
or  in  the  eighth  gestation,  after  amenorrhea  and  with  other  ovarian  disturb- 
ances, regression  partial  or  complete  after  pregnancy,  marked  variations  in 
structure,  and  frequent  occurrence  of  pain  and  emaciation.    The  condition 
is  best  interpreted  as  an  excessive  response  to  physiological,  functional,  and 
formative  stimulus  in  congenitally  predisposed  organs. 

(2)  Congenital  hypertrophy  of  thyroid  is  a  rare  condition  observed  in  infants. 
The  organ  is  uniformly  enlarged  to  twice  or  three  times  its  normal  dimen- 
sions.   The  structure  shows  increase  in  number  of  acini  and  hypertrophy  of 
lining  cells,  with  absence  of  colloid.    It  may  cause  early  death  by  pressure 
on  the  trachea  and  larynx  (Kamann,  Fabre-Therenot). 

The  adult  thyroid  in  Graves1  disease  presents  the  most  striking  example 
of  adenoma toid  functional  hyperplasia.  The  gland  becomes  diffusely  en- 
larged, many  new  alveoli  form,  colloid  disappears,  cysts  with  papillary  pro- 


460 


NEOPLASTIC  DISEASES 


jections  develop,  and  atypical  alveoli  and  giant-cells  may  form.  Yet  in  man 
this  condition  rarely  leads  to  a  true  neoplasm.  At  the  acme  of  the  process 
the  cellular  overgrowth  reaches  a  limit  and  becomes  stationary,  or  is  over- 
taken by  atrophy  and  by  fibrosis  of  stroma  or  interstitial  thyroiditis  (Ewing, 
Lit.)-  In  the  fish  this  form  of  hyperplasia  sometimes  results  in  infiltrative 
growth  and  a  true  benign  or  malignant  tumor  (Gaylord). 

Simple  goiter  presents  less  pronounced  features  of  adenomatoid  hyper- 
plasia. In  the  so-called  parenchymatous  struma  the  cellular  overgrowth 
is  extensive,  but  orderly  and  typical.  New  follicles  form  by  budding  from 
the  old,  following  the  normal  course  of  growth  of  the  thyroid  (Wolfler).  A 
somewhat  similar  picture  may  be  produced  experimentally  in  dogs  by  ad- 
ministration of  iodin,  while  a  restoration  to  the  normal  structure  may  be 
secured  by  adjusting  the  diet.  This  instability  of  structure  and  the  ready 


FIG.  200. — Adenomatoid  hyperplasia  of  thyroid  gland  in  Graves'  disease. 

response  to  diet  and  drugs  assures  that  the  hyperplasia  is  in  no  sense  neo- 
plastic  (Kocher,  Marine). 

In  colloid  struma  there  is  abundance  or  excess  of  colloid  in  and  about 
alveoli  and  the  thyroid  may  become  very  large  from  its  accumulation.  Col- 
loid cysts  form  from  the  fusion  of  distended  alveoli  and  hemorrhage  may 
occur  in  these  cysts.  Overdevelopment  of  blood-vessels  is  frequently  seen. 
In  the  late  stages  there  is  fibrosis,  softening  of  cyst  contents,  atrophy  of 
alveoli,  arteriosclerosis,  and  calcification.  All  of  these  changes  may  occur 
in  an  isolated  portion  of  the  thyroid  producing  a  tumor-like  enlargement. 
These  cases  suggest  an  imperfect  alignment  of  a  portion  of  tissue  in  the  gland 
with  abnormality  of  blood-supply  and  possibly  retention  of  embryonal  char- 
acters. 

Nodular  hyperplasias  of  more  definite  neoplastic  character  occur  in  both 
simple  and  Graves'  goiter,  and  it  is  probable  that  both  conditions  favor  the 
development  of  true  adenoma  and  carcinoma. 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  461 

Struma  Hypophysis. — Nodular  or  diffuse  hyperplasia  of  the  hypophysis 
is  frequently  observed  in  subjects  over  35  years  of  age  (Lowenstein,  Lit.). 
Whether  these  conditions,  commonly  called  adenoma,  as  well  as  some  of  the 
more  pronounced  overgrowths  associated  with  acromegaly,  etc.,  are  true 
tumors  or  functional  hyperplasias  still  remains  to  be  determined.  It  is  prob- 
able that  many  definite  adenomas  and  carcinomas  arise  from  such  hyper- 
trophies. 

Struma  Adrenalis. — Nodular  and  diffuse  hyperplasia  of  the  adrenal  is 
frequently  observed.  Either  cortex  or  medulla  or  both  may  be  affected. 
Between  the  nodular  hypertrophies  and  true  adenomas  there  appears  to  be 
every  transition. 

Adenoma  Sebaceum. — In  the  sebaceous  glands  there  is  a  form  of  over- 
growth attended  by  oversecretion  and  marked  hypertrophy  and  multiplica- 
tion of  glands  which  may  approach  a  neoplastic  grade  (Balzer,  Menetrier). 
The  disease  occurs  chiefly  in  epileptics  and  the  mentally  defective  (Crocker) 
and  is  usually  limited  to  the  skin  of  the  face.  In  some  cases  the  long  dura- 
tion, diffuse  distribution,  the  orderly  character  of  the  cell  growth,  and  the 
self-limitation  indicate  a  form  of  functional  overgrowth  (Caspary's  case). 
Here  there  is  extensive  multiplication  of  large  sebaceous  glands  and  pro- 
liferation of  the  cells  of  the  hair-follicles.  The  epidermis  may  be  thickened 
and  the  small  vessels  dilated.  In  other  cases  there  is  extensive  hyperplasia 
of  gland-cells  and  the  lesion  resembles  a  reticulated  epithelioma,  or  adenoma 
of  sebaceous  and  hair-follicles  (Barlow).  While  usually  self -limiting,  these 
lesions  are  doubtless  the  source  of  some  multiple  epitheliomas  of  the  skin. 

The  liver  and  kidney  are  especially  susceptible  to  focal  adenomatoid  hyper- 
plasia as  a  result  of  regenerative  overgrowth.  The  process  may  be  localized 
or  general.  It  occurs  at  all  ages,  in  organs  which  apparently  were  normal, 
in  those  which  were  recently  the  seat  of  acute  degenerative  processes,  and 
in  many  which  are  the  seat  of  advanced  cirrhosis.  The  hyperplastic  nodules 
are  multiple  and  miliary  or  solitary  and  bulky.  In  young  "subjects  nearly 
the  whole  liver  may  be  replaced  by  adenomatoid  nodules.  While  in  many 
instances  the  conditions  never  pass  beyond  a  physiological  stage  and  are 
found  at  death  from  other  causes,  a  variety  of  somewhat  specific  tumors 
take  origin  in  the  hyperplastic  foci.  Their  relation  to  tumors  will  be  con- 
sidered in  detail  in  connection  with  the  tumors  of  these  organs. 

CARCINOMA 

Carcinoma  is  a  tumor  process  characterized  by  atypical  and  destructive 
proliferation  of  epithelium. 

By  emphasizing  the  atypical  morphology  this  definition  separates  carcin- 
oma from  some  destructive  adenomatous  processes,  while  recognition  of  the 
destructive  element  sufficiently  denotes  important  physiological  and  clinical 
features.  From  the  structural  standpoint  emphasis  may  also  be  laid  on  the 
equilibrium  between  epithelium  and  connective  tissue  which  in  papilloma 
and  adenoma  remains  more  or  less  intact,  while  in  carcinoma  it  is  lost.  Better 
than  any  rigid  definition  is  the  conception  that  carcinoma  represents  more 
lawless  overgrowth  than  adenoma  and  leads  to  a  great  variety  of  neoplastic 
structures  which  show  variable  but  pronounced  grades  of  anaplasia. 

Carcinoma  shares  with  sarcoma  the  full  contrast  over  against  inflamma- 
tion. This  contrast  justifies  Virchow's  general  division  of  tissue  changes  into 
three  groups,  normal  growth  and  physiological  changes,  inflammation,  and 
neoplasia.  Malignant  tumors  reveal  this  contrast  in  the  fullest  light,  but 
since  carcinoma  may  result  from  excess  of  growth  energy  or  from  inflam- 


462  NEOPLASTIC  DISEASES 

matory  hyperplasia  there  is  no  wide  gap  between  these  processes.  This 
admission  does  not  allow  that  the  processes  are  essentially  the  same.  With 
every  addition  in  quantity  there  is  a  change  in  quality.  The  rate,  vigor, 
and  extent  of  epithelial  overgrowth  may  steadily  increase  over  the  normal 
or  over  inflammatory  hyperplasia,  until  finally  the  process  expresses  itself 
as  carcinoma.  There  is  no  necessary  change  in  the  nature  of  the  epithelial 
cell.  Hence  Ribbert  states  that  there  is  no  such  thing  as  a  malignant  cell 
endowed  with  new  biological  properties.  It  is  only  the  process  as  a  whole 
and  its  intensity  which  are  new. 

It  is  necessary  to  recognize  two  great  groups  of  carcinomas:  (i)  those 
arising  from  misplaced  portions  of  embryonal  tissue  and  (2)  those  arising 
from  previously  normal  and  adult  cells  through  the  influence  of  chronic  irri- 
tation. 

The  latter  tumors  exhibit  many  points  of  similarity  with  chronic  inflam- 
mation, in  that  the  etiological  factors  are  very  diverse,  the  structural  types 


FIG.  201. — Mammary  cancer.     Carcinoma  simplex.    Fully  developed  carcinoma.     Infil- 
trative  growth  of  atypical  cells,  with  desmoplastic  properties. 

very  numerous  and  the  clinical  courses  very  different,  so  that  they  constitute 
so  many  different  diseases  which  have  in  common  only  the  fact  that  the  under- 
lying tissue  change  is  a  malignant  neoplasm. 

For  very  few  general  characters  of  great  significance  may  be  stated  of 
the  cancer  process.  Chief  among  these  is  its  progressive  and  fatal  course, 
to  which  there  are  exceptions.  It  is  much  more  significant  to  know  the  pecu- 
liar conditions  under  which  a  carcinoma  arises,  the  particular  features  in 
its  gross  and  microscopical  anatomy,  its  distinguishing  clinical  signs,  and 
natural  duration.  Only  in  this  way  can  the  knowledge  of  carcinomas  be- 
come theoretically  sound  and  practically  efficient.  Hence  one  may  conceive 
of  carcinoma  as  a  vast  group  of  clinical  and  pathological  entities  connected 
only  as  malignant  epithelial  neoplasms  of  extremely  varied  morphology. 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  463 

Gross  Anatomy. — The  gross  appearance  of  carcinoma  is  largely  dependent 
on  the  tissue  of  origin  and  to  a  considerable  extent  on  its  structure,  while 
wide  variations  are  observed  in  the  same  and  in  different  organs. 

The  classical  appearance  of  advanced  mammary  carcinoma  with  its  central 
firm  mass  and  many  lateral  extensions  suggested  to  Galen  the  resemblance 
to  a  crab  and  led  to  the  designation  as  cancer. 

Induration  of  the  affected  tissue  is  probably  the  most  constant  and  signifi- 
cant single  feature  of  large  and  even  of  miniature  carcinomas,  and  is  referable 
to  the  desmoplastic  property  of  carcinoma.  It  is  often  of  very  great  diagnostic 
significance,  surpassing  at  times  the  indications  drawn  from  microscopic 
structure.  The  induration  of  carcinoma  is  a  peculiar  physical  quality  owing 
to  its  extreme  density,  and  its  presence  in  suspicious  lesions  must  stand  as  a 
strong  indication  of  carcinoma.  It  is  especially  to  be  distinguished  from  the 
less  resistant  and  more  diffuse  induration  of  chronic  productive  inflammation. 

Associated  with  certain  degenerative  changes  in  the  carcinoma  cells,  as 
exposed  by  section  through  the  tumor,  induration  and  fatty  degeneration 
become  quite  specific  of  carcinoma.  In  carcinomatous  nodules  of  the  breast, 
in  early  carcinoma  of  lip,  tongue,  and  other  mucous  membranes,  in  stenosing 
carcinomas  of  stomach  and  rectum,  a  translucent  matrix  of  new  connective 
tissue  streaked  with  silvery  points  and  lines  of  fatty  epithelium  are  absolutely 
specific  of  carcinoma.  The  silvery  points  lack  the  deep  yellow  color  of  included 
fat. 

Cross-section  also  reveals  the  cicatricial  character  of  many  carcinomas. 
The  surrounding  tissue  appears  to  be  drawn  toward  the  carcinomatous  center, 
which  may  be  sharply  demarcated  from  the  surrounding  tissue,  but  not  en- 
capsulated. 

The  nodule  or  mass  is  often  fringed  with  fine  extensions,  or  from  it  pass 
many  coarse  cicatricial  bands  through  which  the  tumor-cells  are  advancing. 
Induration  also  marks  the  beginning  of  malignant  change  in  the  bases  of 
polypoid  tumors  which  thus  become  fixed  to  the  supporting  tissues.  It  marks 
the  beginning  of  deep  infiltration  from  superficial  and  ulcerating  carcinomas 
of  mucous  membranes. 

Induration  is  a  common  but  alone  is  not  a  safe  criterion  in  judging  of  the 
nature  of  enlargements  of  lymph-nodes.  The  encapsulation  of  these  small 
organs  permits  very  marked  density  to  be  displayed  by  inflammatory  changes 
within  the  nodes.  Here  fixation  is  a  most  important  sign  of  carcinoma.  In 
scirrhous  carcinoma  induration  begins  early  and  continues  prominent  through- 
out the  process,  producing  tumor  masses  of  uniform  and  extreme  density. 
The  lesion  is  usually  cicatricial  in  character,  deforming  the  affected  organs, 
as  in  the  breast,  or  causing  extreme  stenosis,  as  in  pylorus  or  intestine.  Yet 
in  some  cases  a  tendency  to  hyaline  swelling  of  the  fibrous  tissue  limits  the 
contraction  or  even  increases  the  bulk  of  the  tumor.  In  cancer  en  cuirasse 
a  progressive  fibrosis  accompanies  the  wide  extension  of  mammary  carcinoma 
over  chest,  back,  neck,  and  even  abdomen,  and  surrounds  the  body  in  a  rigid 
encasement  which  occludes  lymph-  and  blood-vessels  and  greatly  hampers 
respiration. 

Marked  induration  usually  indicates  a  slow  progress  of  the  local  lesion, 
but  very  often  such  quiescent  nbrocarcinomas  become  the  source  of  actively 
growing  and  cellular  tumors  in  the  neighborhood  or  at  a  distance. 

Very  cellular  carcinomas  fail  to  exhibit  marked  induration,  but  appear 
as  opaque,  whitish  nodules  or  masses  presenting  a  rounded  or  convoluted 
border,  a  peripheral  ring  of  congestion  or  hemorrhage  marking  the  growing 
edge,  a  broad  intermediate  zone  of  tumor  tissue,  and  often  a  central  depressed 
cicatricial  area.  Secondary  cellular  carcinoma  of  this  type  may  be  difficult 


464  NEOPLASTIC  DISEASES 

to  distinguish  from  massive  tuberculosis  or  syphilis,  but  the  latter  lesions 
usually  exhibit  more  necrosis  and  less  fibrosis  than  carcinoma.  The  terms 
"encephaloid"  or  "medullary  cancer"  are  often  applied  to  the  soft  cellular 
tumors,  from  a  fancied  resemblance  to  brain  tissue. 

Papillary  and  adenoid  carcinomas  usually  appear  as  bulky  circumscribed 
masses  which  are  fragile,  crumbly,  and  of  wholly  different  appearance  and 
consistence  as  compared  with  the  involved  organ.  Minute  inspection  fre- 
quently reveals  specific  markings  which  give  a  clue  to  the  microscopical 
structure.  The  entire  group  of  papillary  carcinomas  may  usually  be  recog- 
nized by  the  circumscribed  character  of  the  conglomerate  nodules  and  the 
branching  opaque  cords  of  cells.  Papillary  and  adenoid  carcinomas  are 
usually  vascular  and  subject  to  interstitial  hemorrhages  and  necrosis  which 
often  lend  characteristic  gross  features. 

Many  cystic  tumors  are  of  carcinomatous  structure.  The  tumor  may 
originate  by  papillary  growth  into  an  enlarging  gland-duct  or  alveolus,  and 
while  the  tumor  remains  encapsulated  the  carcinomatous  process  remains 
confined  and  comparatively  harmless.  Or  the  cysts  form  in  previously  solid 
tumors  by  accumulation  of  secretion,  edema,  hemorrhage,  or  liquefaction 
necrosis. 

Specific  degenerative  changes  are  sometimes  highly  characteristic  of  cer- 
tain glandular  carcinomas.  Chief  among  these  is  the  excessive  mucus  pro- 
duction of  gelatinous  carcinoma  of  the  gastro-intestinal  tract,  peritoneum, 
ovary,  breast,  and  other  organs,  which  tends  to  cause  rapid  increase  in  the 
bulk  of  the  tumor  while  actually  retarding  the  proliferation  of  tumor-cells. 
Yet  such  tumors  may  prove  highly  malignant,  since  the  distention  of  tissue 
spaces  by  the  mucus  facilitates  the  dissemination  of  the  surviving  cells.  The 
entire  abdominal  cavity  may  be  distended  with  mucinous  material  in  col- 
loid cancer  of  the  intestine,  or  the  entire  stomach  wall  may  be  thickened  and 
honeycombed  by  such  growth.  Pseudomyxoma  peritonei  is  a  form  of  diffuse 
implantation  tumor  arising  from  mucinous  ovarian  cancer,  in  which  an 
originally  carcinomatous  process  becomes  greatly  altered  by  a  peculiar  in- 
flammatory process  about  masses  of  mucus. 

Calcific  changes  are  relatively  uncommon  and  belong  chiefly  to  the  re- 
gressive processes.  There  may  be  extensive  calcification  of  the  pearls  of 
epidermoid  carcinoma,  and  of  atrophic  portions  of  rodent  ulcer,  or  in  old 
necrosed  areas  of  glandular  carcinoma.  In  psammocarcinoma  of  the  ovary, 
parotid,  or  kidney,  actively  growing  portions  of  the  tumor  may  present  an 
enormous  number  of  dense  sand  grains  derived  from  epithelial  concretions 
which  seem  not  to  inhibit  the  progress  of  the  growth.  In  a  form  of  cylin- 
droma  of  the  skin,  growth  terminates  in  diffuse  calcification.  In  many  cases 
the  walls  of  blood-vessels  and  areas  of  stroma  undergo  hyaline  transforma- 
tion followed  by  calcification,  and  leading  to  extensive  atrophy  of  the  tumor 
parenchyma. 

Extensive  calcific  deposits  in  the  organs  form  a  remarkable  feature  of  the 
metabolic  disturbance  in  rare  cases  of  carcinoma.  Thus  in  a  case  of  mam- 
mary cancer  Elser  found  the  walls  of  the  pulmonary  air-vesicles  calcified  over 
wide  areas. 

Miliary  carcinosis  is  a  gross  anatomical  form  of  the  disease  presented  by 
highly  malignant  and  widely  disseminated  processes.  Here  the  miliary  tumor 
nodules  appear  widely  scattered  over  serous  membranes,  peritoneum,  pleura 
or  meninges,  or  extremely  numerous  foci  appear  in  skin,  muscles,  or  organs, 
having  traveled  through  the  lymphatics  or  blood-vessels. 

Ulcerative  lesions  commonly  result  when  carcinoma  affects  cutaneous 
or  mucous  surfaces.  The  characters  of  the  carcinomatous  ulcer  vary  with 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  465 

the  location  and  form  of  the  disease.  When  primary  they  are  usually  single. 
The  position  is  determined  by  the  mucocutaneous  junctions  or  by  exposure  to 
irritation.  The  base  is  indurated  and  eventually  fixed  to  the  tissues.  The 
secretion  is  scanty,  purulent,  bloody,  subject  to  increase  from  infection, 
and  complicated  by  hemorrhages  from  eroded  vessels.  The  edges  are  raised, 
hard,  usually  not  undermined,  but  rigid  and  opaque.  The  vicinity  shows 
no  essential  change,  but  may  be  secondarily  invaded.  The  regional  lymph- 
nodes  are  enlarged  first  by  inflammatory  changes,  later  by  carcinomatous 
invasion. 

Rodent  ulcer  rarely  invades  the  lymph-nodes.  Carcinomatous  ulcers 
of  the  buccal  or  uterine  mucosa  early  reach  the  first  barrier  of  lymph-nodes, 
but  rarely  pass  the  second  chain,  while  the  ulcer  will  eventually  extend  to  the 
invaded  nodes  and  thence  laterally  until  the  death  of  the  patient  from  infec- 


FIG.  202. — Calcification  of  walls  of  pulmonary  alveoli  in  a  case  of  advanced  mammary 

carcinoma. 

tion  and  hemorrhage.    Ulcerating  glandular  carcinoma,  as  of  the  stomach  or 
uterus,  may  produce  wide-spread  metastases. 

Microscopic  Structure. — No  single  microscopic  feature  and  no  combi- 
nation of  occasional  criteria  can  be  claimed  as  invariably  pathognomonic  of 
the  cancer  process.  The  history  of  the  microscopic  study  of  cancer  presents 
numerous  instances  of  failure  to  establish  this  essential  characteristic.  The 
microscopical  structure  varies  so  extensively  in  different  organs  and  at  suc- 
cessive stages  as  to  eliminate  the  possibility  of  such  rigid  criteria.  It  is  some- 
times impossible  to  determine  whether  a  given  process  should  be  classed 
as  precancerous,  as  miniature  carcinoma,  as  adenoma  or  adenocarcinoma, 
or  as  carcinoma.  Often  several  of  these  phases  of  the  evolution  of  the  process 
are  present  in  the  same  lesion,  and  more  frequently  several  structural  types 
of  true  carcinoma  are  combined  in  the  same  tumor.  Hence  carcinoma  must 
30 


466  NEOPLASTIC  DISEASES 

be  regarded  not  as  a  uniform  structural  alteration,  but  as  a  progressive  process 
which  has  a  diverse  origin,  a  variable  course,  and  an  uncertain  termination, 
each  phase  presenting  its  own  morphology. 

Moreover,  carcinomas  of  the  various  organs  and  different  carcinomas 
of  the  same  organs  may  present  their  own  structural  peculiarities.  It  is 
therefore  necessary  to  learn  the  specific  characters  of  this  disease  as  it  occurs 
under  a  great  number  of  conditions.  This  extremely  varied  morphology 
of  carcinoma  is  the  source  of  much  confusion  of  nomenclature,  of  much  con- 
flict of  opinion  as  to  what  constitutes  carcinoma,  of  great  uncertainty  re- 
garding histogenesis,  and  it  has  especially  obscured  the  distinctions  between 
carcinoma  and  sarcoma. 

Primary  Versus  Secondary  Structure  of  Carcinoma. — It  is  highly  impor- 
tant to  distinguish  between  the  primary  structure  of  a  tumor,  which  usually 
reflects  its  original  tendencies,  and  secondary  changes  in  structure  which 
result  from  inflammation,  hemorrhage,  adaptation  to  mechanical  environ- 
ment, and  interference  by  surgical  procedures.  The  primary  structure  often 
gives  a  definite  clue  to  or  clearly  reveals  the  origin  of  the  tumor,  as  in  the 
various  forms  of  epidermoid  carcinoma,  adenocarcinoma  of  uterus,  embry- 
onal carcinoma  of  testis,  etc.  When  altered  by  any  of  the  above  influences 
all  carcinomas  tend  to  assume  an  indifferent,  diffuse  or  perivascular  structure 
in  which  most  of  the  original  features  are  lost,  and  from  which  it  is  usually 
hazardous  to  attempt  to  reach  any  conclusions  regarding  histogenesis.  Thus 
epidermoid  carcinoma  may  appear  as  a  round-  or  spindle-cell  growth,  adeno- 
carcinoma of  uterus  may  recur  after  curetage  as  perithelioma,  and  melanoma 
may  recur  as  a  round-cell,  diffuse  or  perivascular,  pigment-free  tumor. 

Structure. — A  detailed  analysis  of  the  structure  of  carcinomas  reveals  at 
least  the  following  features,  any  one  or  all  of  which  may  be  present : 

(1)  Cellular  overgrowth  passing  beyond  that  observed  in  other  processes 
affecting  the  same  tissue. 

Excessive  overgrowth  indicating  abnormal  powers  of  proliferation  is  a 
very  notable  feature  of  many  carcinomas.  Its  degree  may  at  once  reveal 
that  the  process  differs  in  kind  from  functional  or  inflammatory  hyperplasia. 
It  is  usually  associated  with  atypical  qualities  in  the  cells,  but  in  the  thyroid 
gland,  pancreas,  and  adrenal  the  cell  type  may  not  differ  markedly  from  that 
observed  in  other  forms  of  hyperplasia.  On  the  other  hand,  excessive  over- 
growth is  not  an  impressive  characteristic  of  some  epidermoid  carcinomas; 
the  bulk  of  cells  in  some  scirrhous  mammary  cancers  is  probably  less  than  that 
of  the  normal  breast;  while  many  relatively  benign  tumors  of  the  gastro- 
intestinal tract  are  more  massive  than  the  highly  malignant  growths  in  these 
tissues. 

(2)  Atypical  Qualities  of  the  Cells. — Although  there  is  no  characteristic 
morphology  of  the  cancer-cell,  yet  a  change  in  appearance  from  that  of  the 
originating  cell  is  a  nearly  constant  element  in  the  cancer  process.     This 
change  consists  chiefly  in  an  increase  in  the  chromatin  content  of  the  nucleus, 
and  signifies  increased  nutrition  and,  as  the  behavior  of  the  cell  ordinarily 
shows,  increased  powers  of  growth.     The  nuclear  change  may  be  the  only 
discernible  alteration,  for  such  cells  may  be  either  larger  or  smaller  than  nor- 
mal and  otherwise  unaltered. 

In  some  early  multiple  carcinomas  of  the  skin  described  by  Janeway, 
the  lesions  consisted  exclusively  of  a  slightly  increased  number  of  epithelial 
cells  throughout  the  Malpighian  layer,  with  very  marked  hyperchromatism. 
Usually  such  cells  show  some  hypertrophy. 

In  early  flat  carcinomas  of  the  larynx  the  lesion  may  consist  of  a  thick- 
ening of  the  epithelial  layer  due  to  hypertrophy  of  cells  with  hyperchromatic 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  467 

nuclei.  Distinct  hyperplasia  and  heterotopia  are  for  a  time  absent.  More 
frequently  still  the  altered  cells  exhibit  hyperplasia  and  heterotopia. 

In  a  large  group  of  carcinomas  the  altered  cells  are  smaller  than  normal, 
as  in  some  very  malignant  tumors  of  prostate,  pancreas,  liver,  adrenal,  and 
other  organs.  Indeed,  the  small  cell  carcinomas  as  a  class  may  be  regarded 
as  particularly  malignant. 

The  whole  series  of  nuclear  changes  in  cancer-cells  forms  an  extensive 
chapter  in  the  morphology  of  cancer  which  is  discussed  elsewhere.  An  abun- 
dance of  mitoses  is  observed  in  many  rapidly  growing  tumors,  but  is  notably 
absent  in  others.  The  atypical  quality  of  the  mitoses  may  or  may  not  be 
prominent  and  is  not  essential.  An  extensive  list  of  degenerative  nuclear 
and  cytoplasmic  changes  also  belongs  to  the  occasional  regressive  processes 
in  cancer  tissue. 

The  changes  in  the  type  of  the  cancer-cell  are  often  designated  as  meta- 
plasia, but  since  this  term  is  more  clearly  applicable  to  inflammatory  and  func- 
tional alterations  of  cells  which  lack  malignant  attributes  its  use  in  connec- 
tion with  the  cancer  process  is  not  wholly  desirable.  Since  these  changes  go 
with  destructive  proliferation,  and  signify  loss  of  organization  and  restraints 
to  growth,  Hansemann's  term  "anaplasia"  appears  the  more  acceptable. 

(3)  Heterotopia. — The    advance    of    proliferating    epithelium    beyond    its 
normal  limits  is  nearly  identical,  as  a  feature  of  carcinoma,  with  distinct 
invasive  properties,  but  there  are  instances  in  which  heterotopia  is  not  in- 
vasive or  destructive.     Within  gland  ducts  and  alveoli  malignant  prolifera- 
tion of  epithelium  may  force  the  cells  into  abnormal  positions  within  the 
confined  space.     There  is  heterotopia  without  invasion  of  tissues.     In  many 
papillary  epidermoid  carcinomas  islands  of  epithelium  may  become  displaced 
by  inflammatory  processes  or  by  elongation  and  twisting  of  rete  pegs  before 
there  is  definite  invasion  of  the  connective  tissue.    More  pronounced  down- 
ward growth  of  surface  epithelium  is  usually  preceded  by  round-cell  infiltra- 
tion and  weakening  of  the  connective  tissue.    The  equilibrium  between  epi- 
thelium and  connective  tissue  being  thus  disturbed,  the  epithelium  begins 
to  pass  beyond  its  normal  limits  and  true  cancerous  heterotopia  is  soon  estab- 
lished. 

(4)  Local    Invasive    and    Destructive    Properties.  —  Infiltration    of    tissue 
spaces,  lymphatics,  and  blood-vessels  is  the  criterion  of  fully  developed  car- 
cinoma.    The  invasion  may  be  by  single  cells  or  cell  groups,  or  by  alveoli 
of  adenocarcinoma.     Analysis  of  the  process  furnishes  ground  for  the  belief 
that  several  factors  are  concerned.    Chief  among  these  is  probably  the  mechan- 
ical pressure  of  proliferating  epithelium.     In  certain  comedocarcinomas  of 
the  breast  the  appearances  point  most  directly  to  the  mechanical  forcing 
of  cells  through  hernias  and  tears  in  the  distended  basement  membranes 
out  into  the  connective  tissue,  and  in  many  other  cases  the  shape  and  posi- 
tion of  the  cells  is  best  explained  as  the  result  of  pressure.     The  ameboid 
properties  demonstrated  in  certain  cancer-cells  may  facilitate  their  progress 
through  the  invaded  tissues,  but  the  evidence  in  favor  of  this  view  is  scanty. 

Chemotaxis  exerted  by  agents  toward  which  proliferating  cells  travel 
appears  to  have  been  demonstrated  in  Fischer's  experiments  with  sudan  III, 
but  in  a  process  which  proves  not  to  be  carcinoma. 

There  appears  to  be  no  support  for  the  suggestion  that  tumor-cells  secrete 
heterolytic  ferments  which  loosen  or  dissolve  the  invaded  tissues,  but  an 
incompetent  barrier  of  round  cells,  congested  and  proliferating  vessels,  and 
edema  often  render  the  tissues  less  resistant.  In  some  mucous  carcinomas 
the  wide  diffusion  of  fluid  mucus  evidently  determines  the  peculiar  manner 
in  which  such  tumors  advance. 


468  NEOPLASTIC  DISEASES 

Highly  malignant  carcinomas  penetrate  the  preformed  lymphatics  and 
blood-vessels  often  like  an  infection,  but  when  there  is  much  local  inflamma- 
tion and  fibrosis  the  invasion  is  more  localized,  slower,  and  largely  through 
new  formed  spaces  created  by  the  tumor-cells.  There  is  abundant  support 
of  the  general  rule  that  carcinoma  travels  by  preference  through  the  lymphatics. 

The  extent  of  the  lymphatic  invasion  may  be  extremely  wide.  In  mam- 
mary carcinoma  the  skin  of  nearly  the  whole  trunk  may  be  invaded,  and 
Handley  traced  continuous  permeation  through  lymphatics  from  breast  to 
humerus  and  femur.  Depending  apparently  on  the  activity  of  the  process 
and  the  resistance  of  the  organism,  lymphatic  invasion  is  attended  by  peri- 
lymphangitis  with  fibrosis  and  atrophy  of  tumor-cells,  or  by  no  reaction 
whatever. 

The  invasion  of  blood-vessels  occurs  chiefly  in  organs  in  which  the  vas- 
cular supply  is  unusually  favorable  to  this  event,  as  in  thyroid,  liver,  adrenal, 
and  kidney.  It  is  also  relatively  frequent  in  young  adults  suffering  from 
highly  malignant  tumors. 

Serous  cavities  are  traversed  by  permeation  through  the  abundant  sub- 
serous  lymphatics  or  by  mechanical  dissemination  of  cells  discharged  into 
the  cavity.  In  the  peritoneum  and  especially  in  the  meninges  the  invasion 
may  be  extremely  rapid,  simulating  an  inflammatory  process. 

The  destruction  of  tissues  invaded  by  carcinoma  is  a  common  event. 
Pressure  atrophy  of  supporting  structures,  especially  the  blood-vessels,  is  the 
chief  factor  at  work,  and  its  influence  is  most  evident  in  metastatic  carci- 
nomas of  internal  organs.  There  is  much  variation  in  the  resistance  of  differ- 
ent tissues  to  advancing  carcinoma.  Arteries  and  tendons  are  least  affected, 
but  bone  and  cartilage  are  readily  absorbed  and  destroyed. 

On  exposed  surfaces  mechanical  trauma  is  added  to  the  pressure  atrophy, 
so  that  on  mucous  and  cutaneous  surfaces  carcinoma  early  tends  toward 
necrosis  and  ulceration.  In  the  stomach  the  gastric  juice  promptly  attacks 
the  feebly  nourished  tissues  of  many  early  carcinomas,  converting  them  into 
ulcerating  lesions.  In  Verse's  series  several  early  gastric  carcinomas  were 
found  with  superficial  erosion  of  epithelium  which  permitted  access  of  infec- 
tion with  purulent  inflammation.  In  most  epidermoid  carcinomas  infection 
becomes  established  sooner  or  later,  contributes  to  the  destructive  process,  and 
may  even  dominate  the  clinical  course  and  anatomical  picture  of  the  disease. 

The  mechanical  pressure  of  contracting  muscle-fibers  seems  to  account  for 
the  form  and  mode  of  dissemination  of  many  malignant  tumors.  The  con- 
stant contractions  of  the  pylorus  probably  explain  the  wide  dissemination  of 
gastric  cancer  along  the  coats  of  this  organ.  The  contractions  of  the  bladder 
serve  to  maintain  the  polypoid  form  of  most  carcinomas  of  the  urinary  bladder. 
Likewise  the  activity  of  the  smooth  muscle-fibers  of  the  prostate  may  facilitate 
the  extensions  of  prostatic  cancer.  Embolic  cells  travel  long  distances  down 
the  lymphatics  of  the  esophagus.  The  movements  of  the  tongue  may  hasten 
the  dislodgment  of  cells  from  invading  lingual  tumors. 

(5)  Desmoplastic  Properties. — Among  the  most  significant  features  of  the 
cancer  process  is  its  power  of  exciting  the  growth  of  new  cellular  connective 
tissue.  This  tissue  reaction  may  be  a  very  prominent  and  very  early  element 
in  carcinoma,  so  that  it  deserves  important  consideration  as  a  diagnostic  sign 
of  malignant  disease.  In  some  carcinomas  of  the  prostate  it  may  antedate 
characteristic  changes  in  the  epithelium,  and  in  carcinoma  of  the  breast  it  is 
often  prominent  in  very  early  and  minute  lesions.  In  true  fibrocarcinoma 
of  breast,  or  stomach,  in  linitis  plastica,  and  in  peritoneal  metastatic  nodules, 
the  bulk  of  new  connective  tissue  may  far  exceed  that  of  the  tumor-cells, 
which  may  eventually  disappear. 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  469 

That  this  product  has  the  same  significance  as  the  connective  tissue  of 
productive  inflammation  is  shown  by  the  fact  that  it  is  often  replaced  or 
preceded  by  or  associated  with  lymphoid  infiltration  and  commonly  termi- 
nates in  sclerosis.  For  the  same  reasons  it  must  be  interpreted  as  a  reaction 
of  immunity  on  the  part  of  the  tissue.  In  this  respect  carcinoma  exhibits  a 
parallel  with  chronic  inflammatory  processes.  According  to  the  activity 
and  age  of  the  reactive  process  the  new  tissue  is  composed  of  lymphocytes 
and  plasma-cells,  capillary  blood-vessels  and  endothelium,  proliferating 
fibroblasts  with  soft  mucinous  stroma,  or  acellular  fibrous  tissue.  Polynu- 
clear  leukocytes  take  no  part  in  the  uncomplicated  reaction  to  invading 
carcinoma.  In  linitis  plastica  there  is  marked  proliferation  of  endothelium 
and  fibroblasts  in  the  gastric  submucosa,  and  these  cells  mingled  with  scanty 
tumor-cells  present  a  highly  peculiar  picture  of  a  process  which  is  essentially 
desmoplastic. 

(6)  Loss  of  Polarity. — Disturbance  in  the  relation  of  epithelial  cells  to 
one  another  belongs  chiefly  to  the  advanced  phases  of  carcinoma.     Gland 
cells  normally  stand  upon  a  basement  membrane  and  adhere  in  orderly 
fashion  to  their  neighbors,  and  this  arrangement  may  be  assumed  as  essential 
to  normal  growth  and  function.    Complete  loss  of  these  relations  is  observed 
in   diffusely   growing   carcinomas   arising   from   such   glands   and   signifies 
advanced  anaplasia.     Traces  of  normal  polarity  may  long  persist  in  small 
alveolar  carcinomas  in  which  a  definite  lumen  appears  in  the  centers  of  cell 
groups.     Persistent  retention  of  polarity  is  a  peculiar  feature  of  adenoma 
malignum  and  adenocarcinoma,  appearing  in  the  secondary  alveoli  forming 
in  distended  gland  spaces,  and  reappearing,  often  in  striking  distinctness, 
in  some  distant  metastases  from  such  tumors.    The  significance  of  loss  of 
polarity  as  a  measure  of  anaplasia  appears  in  the  series  of  comedo  carcinomas 
of  the  breast,  some  of  which  produce  definite  secondary  alveoli  within  the 
ducts,  while  in  others  the  cells  grow  diffusely.     The  former  long  spare  the 
lymph-nodes,  while  the  latter  rupture  the  basement  membrane  and  invade 
the  breast  and  axillary  nodes.     Much  the  same  variations  may  be  traced 
among  the  epidermoid  and  papillary  carcinomas. 

(7)  Metastases. — Apart  from  the  continuous  permeation  of  lymphatics 
and  tissue  spaces  it  is  a  highly  significant  property  of  carcinoma  to  give  rise 
to  cell  emboli  which  pass  through  the  blood-  or  lymph-vessels  and  originate 
distant  secondary  tumors.     While  this  feature  belongs  especially  to  the 
actively  growing  tumors  it  is  also  observed  in  very  early  stages  of  the  evolu- 
tion of  carcinoma.     In  the  benign  metastasizing  thyroid  struma  extremely 
abundant  secondary  tumors  may  appear  in  lungs  or  bone-marrow  in  which 
the  structure  closely  approaches  that  of  the  normal  gland.     Early  adrenal 
adenoma  may  nearly  duplicate  this  phenomenon.    In  the  liver  adenoma  may 
pass  easily  into  the  numerous  venules  of  this  organ,  but  its  cells  do  not  readily 
survive  in  other  organs.     In  vascular  tissues,  as  the  tongue,  upper  lip, 
stomach,  testicle,  very  small  carcinomas  may  be  found  to  have  yielded 
metastases.     On  the  other  hand,  some  true  carcinomas  with  wide  local  ex- 
tensions,   as    rodent    ulcer,    seldom    or   never    invade    lymph-nodes.      The 
property  of  producing  metastases  cannot  therefore  be  demanded  of  all  car- 
cinomas and  cannot  be  regarded  as  a  reliable  measure  of  the  degree  of 
anaplasia.    In  so  far  as  the  embolic  cells  are  able  to  survive  transplantation 
and  show  even  accelerated  powers  of  growth,  metastases  reveal  a  property 
entirely  foreign  to  normal  cells. 

A  survey  of  the  different  forms  of  cancer  occurring  in  various  organs 
demonstrates  that  the  above  microscopical  features  may  be  combined  in 
very  different  degrees.  Many  highly  malignant  and  fully  developed  carci- 


470  NEOPLASTIC  DISEASES 

nomas  exhibit  all  of  them  from  a  very  early  period  in  their  evolution.  In  a 
large  group  of  tumors  the  characteristic  features  are  much  more  pronounced 
in  one  portion  of  the  growth  than  in  another.  It  is  usually  observed  that 
the  recurrence  of  a  carcinoma  is  more  atypical  and  malignant  than  the 
original  tumor.  In  a  series  of  four  recurrences  of  an  epidermoid  carcinoma 
derived  from  the  enamel  organ  the  tumor  exhibited  increasing  grades  of  ana- 
plasia  and  finally  grew  as  a  diffuse  round-cell  carcinoma.  In  the  group  of 
adenocarcinomas  some  of  the  characters  of  fully  developed  carcinoma  are 
regularly  lacking.  Finally,  in  the  beginnings  of  carcinoma  in  many  organs, 
in  lesions  designated  as  precancerous,  it  is  sometimes  possible  to  trace  the 
gradual  addition  of  one  after  another  of  the  microscopical  features  of  the 
fully  developed  disease. 

From  these  observations  several  important  conclusions  follow: 

(1)  Carcinoma  does  not  necessarily  spring  full-fledged  into  being,  but  is 
to  be  regarded  as  a  process  which  often  exhibits  stages  of  evolution  which 
gather  momentum  as  they  progress. 

(2)  It  is  not  possible  nor  advantageous  to  distinguish  sharply  between 
processes  which  show  more  or  less  of  the  microscopic  characters  of  carcinoma. 
It  is  necessary  to  learn  by  clinical  experience  the  natural  history  of  micro- 
scopical structural  changes  and  to  class  with  cancer  all  those  which  tend  to 
progress  to  the  fully  developed  forms  of  the  disease. 

(3)  The  doctrine  of  precancerou?  lesions  finds  abundant  support  in  the 
progressive  evolution  of  processes  which  from  the  first  have  commonly  been 
classified  as  carcinoma. 

Structural  Classification  of  Carcinoma. — While  the  structure  of  carci- 
nomas is  extremely  varied,  it  is  possible  to  recognize  several  well-defined 
anatomical  types. 

Adenocarcinoma. — As  previously  indicated,  adenocarcinoma  is  a  type  in 
which  the  growth  reproduces  more  or  less  completely  the  original  gland 
alveoli  from  which  the  tumor  springs.  It  is  a  partially  developed  form  of 
carcinoma  in  which  the  arrangement  of  cells  in  alveoli  with  central  lumina, 
the  polarity  of  the  cells,  and  frequently  some  trace  of  their  function,  are 
partially  preserved.  In  some  cases  the  relation  of  cells  to  stroma  is  main- 
tained. The  alveoli  usually  differ,  sometimes  very  notably,  from  the  original 
type,  but  occasionally  it  may  be  difficult  to  distinguish  the  neoplastic  from 
the  normal  alveolus.  The  reproduction  of  alveoli  does  not  identify  the  tumor 
with  adenoma  of  the  particular  organ,  for  adenocarcinoma  lacks  the  restrained 
growth,  the  orderly  proliferation,  and  more  typical  reproduction  of  alveoli, 
of  adenoma.  Adenocarcinoma  commonly  exhibits  a  strong  tendency  to 
assume  the  structure  of  typical  carcinoma  in  certain  portions  of  the  tumor, 
so  that  it  is  ordinarily  invasive  and  destructive  and  clinically  malignant. 
Adenoma  malignum  is  also  invasive,  but  tends  to  maintain  throughout  an 
orderly  glandular  structure.  It  also  may  exhibit  the  transformation  into 
true  carcinoma,  in  which  case  it  is  practically  identical  with  adenocarcinoma. 

The  tendency  to  form  acini  with  central  lumina  is  persistently  retained 
in  many  malignant  tumors  of  the  organs,  and  it  becomes  extremely  difficult 
at  times  to  determine  whether  the  tumor  is  an  adenocarcinoma  or  a  diffusely 
infiltrating  growth  in  which  the  cells  appear  in  small  groups. 

Papillary  carcinoma  is  a  form  of  adenocarcinoma  arising  from  glands, 
mucous  surfaces,  and  occasionally  from  cutaneous  surfaces.  Its  relation 
to  adenocarcinoma  is  revealed  in  the  partial  preservation  of  cell  polarity  and 
of  the  supporting  stroma.  It  produces  tufts  and  finger-like  branching 
projections  of  exuberant  epithelium  which  may  be  supported  by  vascular 
strands  of  connective  tissue.  The  epithelial  layer  is  multiple  and  the  over- 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  471 

growth,  far  outstripping  the  connective  tissue,  may  form  thick  masses,  or 
convoluted  layers  which  fuse  with  one  another.  In  this  manner  the  original 
polarity  of  the  cells  is  completely  lost  and  the  papillary  structure  becomes 
diffuse.  Papillary  carcinomas  also  exhibit  malignancy  by  epithelial  invasion 
of  the  bases  or  cores  of  the  papillae.  A  large  proportion  of  cystic  tumors  are 
papillary  adenocarcinomas. 

Cystic  Carcinoma. — Many  glandular  carcinomas  develop  cysts,  within 
gland  alveoli  or  ducts  which  become  greatly  distended  by  a  growth  which 
long  remains  confined  by  the  thickened  wall  of  the  resulting  cyst.  The  dis- 
tention  is  favored  by  internal  pressure  from  the  epithelial  mass,  from  retained 
secretion,  and  from  hemorrhage  and  exudate,  while  the  cyst  wall  may  exhibit 
intrinsic  powers  of  growth  and  participate  in  the  process. 

The  epithelial  growth  within  the  cyst  may  be  papillary  or  glandular  and 
is  usually  of  the  order  of  adenocarcinoma.  The  papillary  structures  may  be 
very  numerous  and  low  or  very  long  and  complex,  and  present  all  the  features 
of  other  papillary  carcinomas.  They  are  especially  prone  to  perforate  the 
cyst  wall  and  continue  their  growth  in  papillary  or  diffuse  form  in  the  invaded 
tissues  or  in  adjacent  cavities. 

Glandular  cystadenocarcinoma  presents  extensive  multiplication  of  glandu- 
lar alveoli  of  the  ordinary  type  of  adenocarcinoma. 

Certain  organs',  as  ovary  and  breast,  are  particularly  prone  to  develop 
cystic  carcinomas,  and  the  form  of  the  tumor  seems  dependent  upon  the 
particular  conditions  under  which  it  develops.  In  the  breast  cystic  car- 
cinoma arises  chiefly  from  the  malignant  transformation  of  a  previous  cyst 
or  cystadenoma.  The  tumor  perforates  the  capsule,  which  lacks  muscle 
tissue,  before  reaching  large  dimensions.  In  the  ovary  carcinoma  appears 
in  very  small  cysts  which  by  fusion  form  relatively  large  tumors.  The  capacity 
of  the  fibromuscular  stroma  of  the  organ  to  resist  pressure  as  well  as  invasion 
may  partly  account  for  the  great  bulk  attained  by  some  malignant  ovarian 
tumors.  Yet  perforation  of  the  capsule  frequently  results  at  Tan  early  stage. 

Secondary  cysts  form  in  many  carcinomas  by  liquefaction  necrosis,  edema, 
lymphangiectasis,  and  hemorrhage. 

Fully  developed  carcinoma  appears  in  a  great  variety  of  structural  forms 
for  which  there  is  a  wide  choice  of  terms. 

Small  alveolar  carcinoma  is  a  specific  term  which  may  properly  designate 
a  carcinomatous  structure  in  which  the  cells  appear  in  small  groups  supported 
by  a  moderate  amount  of  connective  tissue.  The  cell  groups  do  not  as  a 
rule  surround  a  central  lumen,  but  lie  compactly.  Yet  in  many  cases  the 
restoration  of  a  small  lumen  very  readily  appears  in  occasional  cell  groups 
and  should  not  release  the  tumor  from  consignment  to  the  anaplastic  class 
of  true  carcinoma.  Large  alveolar  carcinoma  equally  well  designates  a  similar 
structure  in  which  the  cell  groups  are  larger,  but  still  well  defined.  As  these 
structures  are  probably  the  most  frequent  histological  types  of  the  disease, 
they  are  often  described  as  carcinoma  simplex. 

Tubular  carcinoma  refers  to  the  appearance  of  elongated  cords  of  tumor- 
cells,  of  the  type  of  carcinoma  simplex,  which  may  or  may  not  inclose  a  lumen. 
When  small  lateral  cell  groups  branch  off  from  such  central  tumor  cords  the 
term  acinar  carcinoma  is  sometimes  applied. 

In  different  organs  many  special  peculiarities  in  the  structure  of  carcinoma 
appear  and  some  have  received  special  designation  as  indicated  in  the  descrip- 
tions of  these  tumors. 

The  attempt  to  designate  a  given  carcinomatous  tumor  by  a  specific  term 
meets  the  difficulty  that  several  structural  types  may  be  presented  in  different 
portions  of  the  growth.  Not  only  the  most  advanced  form,  but  the  simplest, 


472 


NEOPLASTIC  DISEASES 


and  the  most  prominent  are  of  importance  in  determining  the  nomenclature, 
and  in  this  dilemma  the  structure  is  often  passed  as  carcinoma  varia. 

Diffuse  Carcinoma. — In  the  most  malignant  and  highly  anaplastic  forms 
of  carcinoma  the  cells  lose,  their  specific  features,  all  trace  of  polarity  and 
capacity  to  excite  connective-tissue  reaction,  and  they  grow  diffusely,  pre- 
senting no  trace  of  alveolar  formation.  Such  structures  may  be  designated 
as  diffuse  carcinoma.  They  are  observed  in  very  active  or  fulminant  tumors 
of  many  organs,  especially  in  young  subjects,  in  the  breast  during  gestation,  in 
certain  tumors  arising  from  embryonal  structures,  and  in  the  accelerated 
growth  of  simpler  tumors  recurring  after  operation.  In  the  most  pronounced 
stages  of  such  growth  the  structure  may  be  difficult  to  distinguish  from  lym- 
phosarcoma,  but  the  perfectly  fixed  cells  usually  remain  polyhedral.  Many 
diffuse  carcinomas  have  figured  in  the  literature  as  sarcomas,  especially  of  the 
testis  and  adrenal. 


FIG.  203. — Atypical  diffuse  carcinoma  of  nares. 

Embryonal  Carcinoma. — Certain  tumors  present  a  structure  which  re- 
sembles that  of  the  embryonal  type  of  the  organ  from  which  they  are  derived. 
They  may  be  adenomatous,  adenocarcinomatous,  or  carcinomatous.  Some 
fall  in  the  structural  class  of  diffuse  carcinoma.  A  typical  example  is  the 
epithelial  type  of  Wilms'  tumor  of  the  kidney  which,  even  when  composed 
almost  entirely  of  epithelium,  at  once  declares  its  embryonal  nature.  At 
the  other  extreme  stands  the  hornifying  epidermoid  carcinoma,  which  is 
distinctly  adult  in  type.  In  nearly  all  glandular  organs  are  occasionally  en- 
countered cellular  carcinomas  recalling  the  embryonal  structure  of  the  organ, 
and  many  of  these,  as  in  the  thyroid,  are  composed  of  small  cells  consisting 
chiefly  of  nuclei. 

The  embryonal  nature  of  a  tumor  should  not  be  confused  with  an  ana- 
plastic  character.  While  many  embryonal  carcinomas  are  also  highly  ana- 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS 


473 


plastic,  others  are  relatively  slow  in  growth  and  vary  little  from  the  cells  of 
origin.  The  failure  to  distinguish  between  embryonal  and  anaplastic  char- 
acters gives  rise  to  much  misapprehension  regarding  the  prognosis  of  cellular 
carcinomas,  since  embryonal  carcinomas  are  very  prone  to  sudden  variations 
in  growth,  they  often  respond  to  x-ray  treatment,  and  their  course  is  distinctly 
less  malignant  than  that  of  anaplastic  carcinoma  of  corresponding  structure. 

Embryonal  carcinomas  must  be  conceived  as  arising  from  embryonal 
structures,  often  misplaced,  and  since  the  cells  of  origin  are  imperfectly 
developed  the  tumor  reflects  this  character  throughout.  The  embryonal 
character  does  not  signify  that  there  has  been  any  reversion  of  the  originating 
cells  of  the  tumor  from  an  adult  to  an  embryonal  type.  It  is  possible  to 
grade  the  carcinomas  of  many  organs  according  to  this  principle,  as  adult  or 


FIG.  204. — Mammary  cancer.    Embryonal  adenocarcinoma  producing  a  bulky,  rapidly 

growing  malignant  tumor. 

embryonal,  and  in  the  kidney  especially  it  appears  that  the  classification 
corresponds  with  the  stage  of  development  which  the  originating  cells  have 
reached  at  the  time  the  tumor  develops  from  them. 

Fibrocarcinoma. — While  most  carcinomas  excite  some  connective-tissue 
reaction,  in  some  the  connective  tissue  is  excessive  in  amount,  it  is  subject  to 
hyaline  changes,  and  it  compresses  the  cells  so  that  their  growth  is  impeded. 
Fibrocarcinomas  are  usually  of  slow  growth,  of  dense  consistence,  and  of  cica- 
tricial  appearance.  They  are  most  frequently  seen  in  elderly  and  resistant 
subjects.  The  peculiar  structure  may  appear  from  the  beginning,  as  in  mam- 
mary scirrhus,  or  it  may  develop  later  in  regressing  areas.  Eventually  the 
tumor-cells  may  entirely  disappear.  Typical  examples  are  observed  in 
sclerosing  fibrocarcinoma  of  the  pylorus,  in  metastatic  peritoneal  nodules,  and 
especially  in  cancer  en  cuirasse. 


474 


NEOPLASTIC  DISEASES 


In  most  cases  the  development  of  fibrocarcinoma  appears  to  depend 
chiefly  on  local  conditions,  since  a  localized  fibrocarcinoma  may  develop  very 
cellular  secondary  tumors  at  a  distance  or  even  in  the  same  organ. 

Epidermoid  Carcinoma. — From  surfaces  lined  by  squamous  cells,  and  by 
metaplasia  of  other  epithelial  cells,  develop  tumors  presenting  the  characters 
of  squamous  epithelium.  The  general  term  "epithelioma"  is  commonly 
applied  to  this  entire  group,  but  should  doubtless  be  displaced  in  favor  of 
the  designation  "epidermoid  carcinoma." 

There  are  two  main  groups  of  epidermoid  carcinoma,  those  presenting 
flat  squamous  cells  and  sometimes  called  acanthoma,  and  those  presenting 
smaller  cells  of  the  basal  type,  and  called  basal-cell  carcinoma. 

These  terms  may  give  a  false  inference  that  the  one  tumor  is  derived  from 
the  squamous  cells  of  the  Malpighian  layer,  the  other  from  the  basal  cells. 
Yet  acanthoma  arises  from  downgrowth  of  both  basal  and  overlying  cells, 


.  .  . 

* 


FlG.  205. — Mammary  cancer.     Primary  scirrhus  or  fibrocarcinoma  in  a  young  subject. 

which  immediately  exhibit  some  of  the  normal  changes  into  flat  cells,  often 
with  intercellular  spines.  Basal-cell  carcinoma  arises  perhaps  exclusively 
from  basal  cells,  often  from  misplaced  and  embryonal  groups  of  such  cells, 
but  the  normal  transformation  into  squamous  cells  entirely  fails. 

Many  subvarieties  of  epidermoid  carcinoma  are  observed.  Acanthoma 
presents  adult  flat  epithelium,  with  hornification,  concentric  groups  of  cells 
flattened  by  pressure  (epithelial  pearls),  and  often  intercellular  fibrils. 
Keratohyaline  granules  may  usually  be  demonstrated  by  appropriate  stains. 
The  younger  cells  of  such  tumors  tend  to  lose  their  adult  characters  and 
infiltrate  the  tissues,  producing  cords  of  very  opaque  polyhedral  cells  (tubular 
epidermoid  carcinoma). 

The  squamous  cells  may  become  more  and  more  atypical,  producing  cel- 
lular carcinomas  of  many  types,  eventually  growing  diffusely,  and  even 
appearing  as  round-cell  or  giant-cell  carcinoma.  Many  epidermoid  carcinomas, 
as  in  the  cervix  uteri,  reproduce  the  entire  epithelial  layer  of  the  originating 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  475 

structure  which  becomes  convoluted,  invaginated  into  the  underlying  sub- 
mucosa,  and  appears  as  a  structure  which  may  be  designated  as  plexiform 
epithelioma.  Others  break  up  early  into  small  groups  of  cells  which  rapidly 
infiltrate  the  tissues.  They  are  more  malignant  than  the  plexiform  type. 
An  extensive  group  maintains  a  papillary  structure.  Or  an  original  glandular 
tendency  may  appear  pronounced  in  the  tumor,  as  when  it  arises  from  the 
ducts  of  cutaneous  glands  or  the  enamel  organ,  and  produces  a  glandular 
epidermoid  carcinoma.  So  great  is  the  variety  of  structures  in  epidermoid 
carcinoma  that  they  must  be  dealt  with  separately  in  the  organs  in  which 
they  occur. 

Squamous  metaplasia,  affecting  the  cells  before  the  development  of  the 
tumor,  or  appearing  in  the  course  of  glandular  carcinoma,  or  as  an  element 
in  teratomas,  accounts  for  the  presence  of  epidermoid  carcinoma  in  unusual 
situations. 

Precancerous  Lesions. — The  beginnings  of  carcinoma  have  been  sought 
in  most  organs  without  wholly  satisfactory  results.  As  a  rule  the  cells  of 
the  smallest  established  carcinoma  appear  to  be  entirely  separate  from  the 
normal  tissues  and  to  differ  essentially  from  those  phases  of  atypical  hyper- 
trophy or  inflammatory  overgrowth  which  accompany  many  carcinomas. 
These  well-established  observations  have  led  Ribbert  to  assert  that  the  cells 
of  carcinoma  are  isolated  throughout  their  entire  course  and  hence  the  cells 
of  origin  must  be  isolated.  This  author  has  affirmed  that  no  one  has  ever 
seen  the  beginnings  of  carcinoma  of  the  breast,  all  true  carcinomas  of  this 
organ  being  so  well  differentiated  from  the  normal  gland  that  the  attempt 
to  trace  the  neoplastic  from  the  normal  cells  invariably  fails. 

This  tenet  conveys  an  important  principle  in  the  histogenesis  of  carcinoma, 
namely,  that  the  initial  proliferation  of  cancer-cells  proceeds  rapidly,  usually 
obliterates  any  traces  of  the  transformation  of  normal  into  tumor-cells  and 
renders  extremely  difficult  the  decision  just  what  form  the  progenitors  of 
cancer-cells  presented.  It  is  therefore  necessary  to  regard  with  caution  the 
interpretation  of  many  forms  of  atypical  cell  growth  as  preliminary  to  the 
development  of  true  cancer. 

Moreover,  the  comprehensive  lists  of  tissue  abnormalities  as  catalogued 
by  R.  Williams,  R.  Meyer,  and  many  others,  has  established  on  a  very  broad 
basis  the  theory  of  Cohnheim  that  tumors  develop  from  misplaced  and  em- 
bryonal cell  groups  which  have  never  enjoyed  a  normal  structure.  This 
theory  must  also  include  structural  abnormalities  and  tissue  predispositions 
which  are  not  revealed  by  obvious  microscopical  changes,  but  which  certainly 
contribute  to  the  origin  of  tumors.  In  all  this  group  of  cases  the  origin  of 
cancer  is  from  congenitally  misplaced  or  abnormal  cells  and  not  from  trans- 
formed normal  cells. 

In  another  and  very  extensive  group  the  evidence  points  to  the  origin 
of  carcinoma  from  previously  normal  adult  cells  which  pass  through  a  series 
of  changes  induced  by  chronic  irritation  and  terminating  in  carcinoma.  This 
class  of  tumors  has  been  called  the  "irritation  group,"  and  the  preliminary 
cell  changes  have  been  called  "precancerous  lesions." 

The  evidence  in  support  of  this  view  is  both  clinical  and  morphological. 
Clinical  observation  has  long  indicated  that,  the  majority  of  important 
tumors  are  not  dependent  on  congenital  abnormalities  in  tissue  structure, 
but  arise  from  once  normal  but  previously  altered  tissues,  and  that  various 
forms  of  chronic  inflammation  are  observed  to  precede  the  appearance  of 
most  tumors. 

In  1872  Hutchinson  termed  various  manifestations  of  buccal  syphilis 
precancerous.  Billroth  observed  that  cancer  almost  never  arises  in  a  normal 


476  NEOPLAST1C  DISEASES 

breast  and  later  studies  have  shown  that  chronic  mastitis  frequently  precedes 
mammary  cancer.  V.  Bergmann  stated  that  primary  cancer  of  the  skin 
without  previous  cutaneous  lesions  does  not  exist.  In  the  various  organs 
it  is  universally  recognized  that  certain  pathological  conditions  are  followed 
in  a  variable  but  high  proportion  of  cases  by  carcinoma.  For  these  condi- 
tions the  term  "precancerous  diseases"  has  been  employed  by  Orth,  but  it 
should  be  emphasized  that  these  diseases  possess  in  themselves  no  essential 
element  of  the  cancer  process,  and  are  merely  observed  to  precede  and  favor 
the  development  of  cancer. 

The  so-called  precancerous  conditions  fall  into  several  distinct  classes, 
but  the  majority  of  them  represent  specific  forms  of  chronic  productive  in- 
flammation. 

i.  Chronic  Inflammation. — In  the  skin  well-known  forms  of  cancer  arise 
in  the  cicatrices  of  burns,  tuberculous  and  syphilitic  lesions,  and  amputation 
wounds.  A  long  period  usually  elapses  before  cancer  appears  in  scars  and 
the  tumor  is  often  multicentric  or  diffuse  in  origin.  Lupus  carcinoma  may 
arise  in  the  active  tuberculous  lesions,  but  in  30  per  cent,  of  the  cases  it  occurs 
in  the  scar  tissue  (Steinhauser).  It  develops  usually  toward  the  thirtieth 
year  of  the  disease  and  never  before  the  fifth.  Ashihara  reports  several  car- 
cinomas in  syphilitic  scars.  .X"-ray  dermatitis  is  a  remarkable  instance  of 
a  destructive  and  inflammatory  process  tending  to  develop  cancer.  A  period 
of  3  to  ii  years  precedes  the  malignant  process,  and  is  occupied  by  necrosis 
of  tissue  cells,  occlusion  of  vessels,  fibrosis,  and  epithelial  overgrowth  (Porter, 
Wolbach). 

In  glands  and  mucous  membranes  chronic  inflammation  is  frequently 
followed  by  cancer.  In  the  gall-bladder  cancer  was  preceded  by  gall-stones 
in  100  per  cent,  of  Janowski's  cases  and  the  proportion  of  cases  of  cholelithia- 
sis developing  carcinoma  was  placed  by  Slade  at  18  per  cent.  The  irritation 
of  cholesterin  seems  to  have  a  peculiarly  effective  influence  in  inducing 
atypical  epithelial  proliferation. 

In  the  uterus  chronic  catarrhal  endocervicitis  precedes  cancer  in  the 
majority  of  cases  (34  of  48,  Polese).  Cervical  erosions,  leukoplakia  of  portio 
and  canal  have  frequently  been  traced  into  carcinoma.  For  corpus  carci- 
noma, the  hyperemia  and  endometritis  accompanying  myoma  may  be  held 
responsible  for  the  development  of  carcinoma.  It  usually  develops  opposite 
the  point  of  contact  of  the  myoma  and  the  eroded  endometrium.  Acanthoma 
and  adenoacanthoma  follow  leukoplakia  of  the  endometrium  (Benckizer). 

In  routine  material  I  find  transition  stages  from  hypertrophic  endometritis 
to  carcinoma  rather  frequently,  but  clinical  observations  are  still  inadequate 
to  prove  the  close  dependence  of  the  malignant  upon  the  inflammatory  process. 
In  44  cases  of  corpus  carcinoma  Heurlin  failed  to  find  any  transition  stages, 
but  29  of  his  cases  were  diffuse. 

In  the  urinary  bladder  most  cancers  may  be  traced  to  previous  or  coexist- 
ent cystitis  (Stoerk,  Cohen).  Specific  vesical  irritants,  as  in  anilin  workers, 
produce  many  tumors,  chiefly  at  the  ureteral  orifices,  50  per  cent,  of  which  are 
malignant  (Rehn,  Seyberth).  In  Bilharzia  disease  the  development  of  car- 
cinoma on  venous  and  lymph  stasis,  with  cystitis  from  irritation  by  ova  and 
lithiasis,  has  often  been  traced  in  detail.  Various  forms  of  balanitis  precede 
carcinoma  of  the  penis.  Demarquay  found  phimosis  in  85  per  cent,  of  his 
cases,  and  Kaufmann  observed  warty  vegetations  in  29  of  33  cases. 

Buccal  and  lingual  cancer  is  almost  always  referable  to  one  or  all  of  three 
factors,  syphilis,  tobacco,  or  decayed  teeth.  The  syphilitic  process  usually 
takes  the  form  of  leukoplakia,  of  which  30  per  cent.,  according  to  Fournier, 
develop  carcinoma.  In  these  cases  there  is  hypertrophy  and  hyperplasia  of 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS 


477 


epithelium,  hyperkeratosis,  lymphocytic  infiltration  of  submucosa,  papillo- 
matous  overgrowth,  and  finally  destructive  invasion  of  deep  tissues.  Darier 
finds  that  the  complication  of  an  ulcer  or  fissure  is  usually  necessary  before 
leukoplakia  becomes  cancer.  Syphilitic  warts,  fissures,  gummas,  and  atrophic 
glossitis  also  precede  cancer. 

Excessive  use  of  tobacco  produces  the  well-known  smoker's  tongue  and 
throat,  in  which  there  is  hyperemia,  edema  and  lymphocytic  infiltration  of 
submucosa,  erosion,  and  then  downward  growth  of  epithelium.  Ragged 
teeth  produce  superficial  erosions,  thickening  of  regenerating  epithelial 
layer,  lymphocytic  infiltration,  heterotopia,  and  then  downward  growth  of 
atypical  cells. 


FIG.  206. — Atypical  adenomatous  proliferation  in  ducts  in  chronic  mastitis. 

In  all  this  group  of  cases  it  is  evident  that  the  carcinoma  is  only  an  indirect 
result  of  the  irritation,  and  the  long  period  which  precedes  the  malignant 
process,  as  well  as  the  infrequency  of  the  malignant  change,  give  opportunity 
for  other  local  or  constitutional  factors  to  come  into  play.  Nevertheless  it 
is  clear,  as  in  Kangri-oven  and  betel  nut  cancer  of  Indian  natives,  that  local 
and  general  predisposition  may  be  ignored,  since  the  tumor  develops  wherever 
the  irritation  is  effectively  applied. 

2.  Physiological  involution  of  organs  and  complicating  mechanical,  nutri- 
tional, and  inflammatory  processes  precede  the  development  of  cancer  chiefly 
in  the  breast  and  prostate.  Definite  neoplastic  tendencies  in  the  "maladie 
de  Reclus"  were  pointed  out  by  Brissaud  and  Schimmelbusch.  Reclus, 


478  NEOPLASTIC  DISEASES 

Saar,  and  many  others  have  declared  that  the  step  from  chronic  mastitis 
to  carcinoma  is  short.  It  is  especially  in  that  form  of  chronic  mastitis  in 
which  cysts  and  epithelial  proliferation  are  prominent  from  the  first  that 
cancer  is  observed  to  develop,  but  no  anatomical  form  of  the  disease  is  free 
from  the  danger  of  malignant  change.  Bloodgood  prefers  to  regard  the  under- 
lying condition  as  pure  senile  involution.  The  proportion  of  cases  of  chronic 
mastitis  developing  cancer  has  been  variously  estimated  from  10  to  15  per 
cent.  (Tietze,  Speese). 

In  the  prostate  the  chief  condition  predisposing  to  cancer  is  chronic 
prostatitis  usually  with  hypertrophy.  Whatever  the  nature  of  prostatic 
hypertrophy  may  be,  it  is  clear  that  the  influence  of  physiological  involution 
is  usually  concerned.  The  principal  age  of  incidence  of  cancer  and  hyper- 
trophy is  the  seventh  decade,  in  which  68  per  cent,  of  the  carcinomas  occur. 
Notable  examples  of  the  development  of  carcinoma  on  hypertrophy  have  been 
recorded  by  many  observers,  the  clinical  evidence  being  a  long  history  of 
hypertrophy  terminating  in  cancer.  Probably  10  per  cent,  of  prostatic  car- 
cinomas give  such  a  history.  The  proportion  of  enlarged  prostates  after 
50  years  which  prove  malignant  has  been  estimated  at  13.3  to  16.5  per  cent. 
(Freyer,  Walker). 

Senile  degeneration  of  the  skin  as  observed  in  seaman's  skin  and  other 
disorders  often  leads  to  multiple  carcinoma.  It  affects  regions  exposed  to 
sunlight,  heat,  and  cold,  and  often  shows  an  hereditary  element.  The  changes 
begin  with  hyaline  degeneration  of  the  derma,  sclerosis  of  vessels  and  atrophy 
of  Malpighian  layer,  followed  by  keratosis,  scaling,  papillary  outgrowths, 
and  elongation  of  deep  papillae.  Finally  the  invasive  features  of  carcinpma 
are  added. 

3.  Regenerative  hypertrophy  may  be  regarded  as  the  predominant  under- 
lying influence  in  the  development  of  certain  forms  of  cancer  observed  in 
the  liver  and  in  the  glands  of  internal  secretion. 

In  fish,  functional  overactivity  and  hypertrophy  of  the  thyroid,  observed 
in  crowded  ponds  where  the  animals  are  fed  on  meat,  leads  in  a  small  pro- 
portion of  cases  to  a  peculiar  form  of  cancer.  This  condition  has  been  pro- 
duced experimentally  by  Gay  lord.  Few  cases  of  thyroid  carcinoma  in  man 
develop  in  subjects  with  entirely  normal  thyroid  history,  but  many  follow 
goiter,  interstitial  thyroiditis,  and  Graves'  disease.  Probably  many  tumors 
of  the  adrenal  and  hypophysis  are  of  the  same  nature. 

In  the  liver  an  important  group  of  primary  carcinomas  or  hepatomas 
represents  malignant  overgrowth  of  regenerating  lobules  following  injury 
with  degeneration  or  cirrhosis  (Menetrier). 

4.  The  transformation  of  benign  into  malignant  tumors  is  a  frequent  source 
of  carcinoma  occurring  in  many  organs  and  has  important  bearing  on  the 
origin  of  cancer.     Some  of  these  benign  tumors  appear  to  originate  from 
inflammatory  processes  and  the  organs  may  present  every  gradation  between 
simple  inflammatory  overgrowth,  adenoma,  and  carcinoma.    The  most  strik- 
ing example  is  colitis  polyposa  which  exhibits  a  peculiar  overgrowth  of  epithe- 
lium with  polypoid  adenomas,  leading  in  about  half  the  cases  to  carcinoma. 
In  the  gastric,  intestinal,  uterine,  and  vesical  mucosa  the  transformation  of 
benign  polyps  into  carcinoma  has  repeatedly  been  observed.     Menetrier 
has  shown  that  gastric  ulcer  usually  leads  to  cancer  through  the  preliminary 
development  of  polypoid  adenomas  on  the  edge  of  the  ulcer.     In  the  solid 
glandular  organs  histological  rather  than  clinical  evidence  indicates  that 
the  passage  from  benign  to  malignant  tumors  may  be  readily  accomplished, 
although  as  a  rule  the  type  of  benign  adenoma  usually  remains  constant. 

Thus  clinical  observation  reveals  several  groups  of  pathological  processes 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS 


479 


which  in  a  small  but  notable  proportion  of  cases  tend  to  become  malignant. 
Such  clinical  data  do  not,  however,  show  that  there  is  any  essential  connec- 
tion between  the  preliminary  process  and  the  subsequent  cancer.  It  may  be 
urged  that  when  carcinoma  follows  chronic  mastitis  a  new  disease  has  been 
grafted  upon  an  entirely  different  condition.  Histological  evidence,  however, 
has  fully  demonstrated  that  an  extensive  series  of  structural  changes  takes 
place  in  the  precancerous  diseases  leading  up  to  the  fully  developed  cancer, 
the  one  passing  slowly  or  rapidly,  but  often  by  insensible  gradations  into  the 
other.  The  details  of  these  changes  will  be  presented  under  the  various  forms 
of  carcinoma  of  the  organs.  It  may  here  be  pointed  out  that  precancerous 
changes  differ  in  each  organ  as  do  also  the  true  carcinomas  of  those  organs. 


FIG.  207. — Diffuse  hypertrophy  of  glands  in  colitis  polyposa. 

As  a  rule  considerable  time  is  required  in  the  transformation  as  is  indicated 
by  the  long  duration  of  the  preceding  disease.  Yet  in  many  cases  it  would 
appear  that  the  liberation  of  the  restraints  to  growth  is  experienced  rapidly, 
so  that  the  resulting  cancer  although  small  is  found  fully  developed,  and  soon 
overgrows  and  obliterates  any  successive  stages  which  may  have  occurred. 

It  is  not  to  be  assumed  that  all  carcinomas  develop  after  a  preliminary 
series  of  changes  in  previously  normal  tissue  such  as  is  now  under  discussion. 
In  the  entire  group  of  tumors  arising  from  misplaced  and  embryonal  cells, 
while  certain  phases  of  abnormal  growth  probably  precede  the  appearance 
of  the  true  carcinoma,  these  changes  are  of  a  different  nature  and  morphology 
from  those  occurring  in  the  irritation  group  of  tumors  arising  from  normal 
cells.  Such  changes  may  be  traced  in  the  development  of  melanoma  from 
pigmented  moles,  and  with  carcinoma  from  adrenal  rests.  They  indicate 


480  NEOPLASTIC  DISEASES 

that  even  here  the  carcinoma  does  not  spring  full-fledged  from  the  cells  of 
origin,  but  evolves  gradually  with  increasing  freedom  from  the  restraints 
to  growth.  Of  the  factors  which  incite  the  malignant  growth  of  embryonal 
cells  little  is  known,  but  one  may  reasonably  search  for  them  among  the  causes 
of  local  hyperemia.  Melanoma  often  develops  after  mechanical  trauma. 

Against  the  theory  of  precancerous  lesions  stands  the  common  observa- 
tion that  many  very  small  cancers  cannot  be  shown  to  follow  such  preliminary 
changes.  Verse  describes  very  early  gastric  carcinomas  in  which  a  limited 
segment  of  mucosa  exhibited  all  the  criteria  of  malignant  adenoma.  Very 
small  but  fully  developed  mammary  carcinomas  are  observed  in  chronic 
mastitis  which  cannot  be  traced  to  the  suspicious  forms  of  atypical  cell 
growth  so  common  in  mastitis.  Clinical  studies  show  that  the  majority 
of  cases  of  chronic  mastitis  pursue  a  prolonged  but  benign  course.  These 
considerations  suggest  caution  in  assuming  that  any  given  precancerous 
lesion  will  develop  cancer,  and  show  that  many  cancers  may  be  preceded 
by  little  or  possibly  by  none  of  the  precancerous  stages,  but  they  seem  not 
to  affect  the  general  validity  of  the  theory  that  carcinoma  as  a  rule  develops 
by  definite  stages  both  from  adult  and  from  embryonal  cells. 

Mode  of  Extension  of  Carcinoma. — The  events  which  follow  the  establish- 
ment of  a  carcinomatous  focus  in  an  organ  vary  greatly  with  the  mode  of 
origin  of  the  tumors,  the  rapidity  of  growth,  and  the  character  of  the  affected 
tissue. 

Influence  of  the  Mode  of  Origin. — Carcinomas  arising  from  misplaced  and 
embryonal  cells  are  isolated  from  their  inception,  probably  remain  so  through- 
out their  history,  and  illustrate  in  the  purest  form  the  principle  that  tumors 
grow  from  their  own  resources  and  not  by  the  progressive  transformation 
of  normal  into  tumor-cells.  Equally  important  with  this  principle,  so 
strongly  urged  by  Ribbert,  is  the  fact  that  many  carcinomas,  during  the 
period  of  their  inception  and  for  some  portion  of  their  early  growth,  involve 
increasing  areas  of  glands  or  mucous  surfaces  in  their  points  of  origin  and  thus 
extend  in  part  by  gradual  transformation  of  previously  normal  cells.  Thus 
one  may  observe  epidermoid  carcinoma  of  the  glans  penis  or  prepuce  covering 
a  wide  area,  in  different  pbrtions  of  which  are  presented  every  gradation  from 
fully  developed  infiltrating  carcinoma  in  the  central  areas,  to  markedly 
hypertrophic,  hyperplastic,  and  atypical  epithelium  in  the  peripheral  zones. 
In  very  extensive  papillary  adenocarcinoma  of  the  rectum  involving  several 
inches  of  the  bowel  a  gradual  extension  of  an  originally  small  lesion  must  be 
assumed.  Hauser  and  Beneke  have  traced  this  transformation  in  intestinal 
carcinoma.  In  carcinomas  of  multicentric  origin  the  separate  foci  may 
eventually  fuse,  forming  one  continuous  area  of  origin.  In  carcinoma  follow- 
ing chronic  mastitis  the  malignant  process  may  originate  in  several  foci, 
even  producing  different  types  of  carcinoma,  and  soon  involving  the  entire 
breast.  It  is,  therefore,  not  to  be  assumed  that  the  observed  mass  of  carci- 
noma is  always  the  result  of  local  invasion  from  a  single  minute  focus,  but, 
on  the  contrary,  this  mass  may  depend  chiefly  on  the  mode  of  origin  of  the 
tumor. 

The  rapidity  of  growth  of  a  carcinoma  determines  in  many  cases  its  mode 
of  extension.  Rapidly  growing  tumors  soon  define  their  field  of  origin,  no 
subsequent  additions  are  made  to  the  originating  cells,  and  the  tumor  rapidly 
extends  through  preformed  and  artificial  paths,  growing  from  its  own  re- 
sources. Many  but  not  all  such  carcinomas  arise  from  isolated  or  embryonal 
cells. 

The  character  of  the  affected  tissue  influences  the  mode  of  extension  in  many 
cases.  On  mucous  membranes  ulceration  and  infection  early  convert  many 


GENERAL  PATHOLOGY  OF  EPITHELIAL  TUMORS  481 

carcinomas  into  ulcerating  lesions,  in  which  the  inflammatory  process  seems 
at  times  to  retard  the  lateral  extensions  of  the  disease,  at  other  times  to  facili- 
tate them.  The  wide  extension  of  some  gastric  carcinomas  is  probably  referable 
to  the  contractile  movements  of  the  stomach  and  to  a  comparatively  resistant 
muscular  coat.  Growing  into  ducts  as  in  the  breast  the  extension  may  long 
be  confined  chiefly  to  these  canals  as  in  comedocarcinoma,  while  in  the  ovary 
cystic  carcinomas  may  long  be  confined  by  the  fibromuscular  cyst  wall.  The 
whole  course  of  gelatinous  carcinoma  of  the  peritoneum  may  depend  upon 
the  early  rupture  of  a  small  colloid  tumor  into  the  free  peritoneal  cavity. 

Collateral  Hyperplasia. — About  the  edges  of  many  carcinomas,  especially 
of  the  mucous  membranes,  the  neighboring  glands  commonly  exhibit  hyper- 
trophy, hyperplasia,  and  a  somewhat  atypical  form  of  the  lining  cells,  which 
may  approach  the  appearance  of  carcinoma.  In  adenoma  malignum  of  the 
rectum  the  surrounding  zone  of  mucosa  exhibits  greatly  elongated  glands 
lined  by  very  large  cells  which  strongly  suggest  a  gradual  transformation  of 
hypertrophied  into  neoplastic  glands.  These  changes  are  only  imperfectly 
reproduced  in  pure  inflammatory  lesions,  for  the  collateral  hyperplasia  of 
tumors  is  rather  specific.  In  some  cases  it  is  extremely  difficult  to  determine 
where  the  hyperplastic  glands  cease  and  the  neoplastic  begin.  Yet  the  most 
careful  histological  studies  indicate  that  such  hyperplastic  glands  do  not 
become  transformed  into  neoplastic  unless  it  be  in  the  early  stage  of  the 
definition  of  the  tumor  focus.  Careful  study  usually  discloses  that  tumor 
epithelium  grows  into  the  enlarged  glands  from  many  sides,  gradually  replaces 
the  lining  cells,  and  occupies  the  gland  compartments.  At  the  most  critical 
points  the  transition  between  hyperplastic  and  neoplastic  epithelium  is 
usually  sharp,  but  in  some  cases  it  cannot,  I  think,  be  denied  that  it  is  impos- 
sible to  say  whether  or  not  a  transformation  of  hypertrophied  into  tumor- 
cells  takes  place. 

Collateral  hyperplasia  also  occurs  in  many  glands  invaded  by  carcino- 
matous  foci  and  has  led  to  the  unproved  assumption  that"  the  presence  of 
foreign  tumor-cells  may  excite  a  tumor  process  in  an  invaded  organ.  For 
example,  in  the  adrenal  invaded  by  carcinoma  from  the  kidney  I  have  seen 
adrenal  acini  assuming  a  form  which  strongly  suggested  neoplastic  qualities. 
In  hepatoma  the  remaining  liver  tissue  may  exhibit  extensive  hypertrophy 
of  liver-cells  which  is  not  duplicated  in  simple  inflammatory  or  regenerative 
changes  of  this  organ. 

Collateral  hyperplasia  seems  to  be  referable  chiefly  to  overnutrition  of 
cells  in  the  vicinity  of  the  actively  growing  tumor.  Inflammatory  factors 
may  also  contribute  a  share  in  the  process.  Yet  the  peculiar  morphology 
suggests  that  other  influences  are  at  work,  and  Beneke  assumes  that  the 
proximity  of  tumor-cells  exerts  a  peculiar  trophic  action  of  the  neighboring 
tissues  in  addition  to  ordinary  inflammatory,  nutritive,  and  regenerative 
effects. 

Local  Invasion. — The  advance  of  carcinoma  from  its  focus  of  origin  occurs 
through  the  continuous  extension  of  tumor-cells  into  normal  tissues.  The 
paths  pursued  are  usually  those  of  least  resistance  and  include  the  natural 
channels  in  glandular  organs,  lymph-vessels  and  spaces,  blood-vessels,  and 
nerve-trunks.  The  ducts  of  glands  become  filled  with  tumor-cells  which 
replace  the  original  lining  cells  over  wide  areas.  In  the  breast  duct  carcinoma 
may  thus  invade  the  entire  organ  before  reaching  the  lymph-nodes  or  pene- 
trating the  fascia  of  the  gland.  Carcinoma  of  the  lung  may  pass  along  the 
air  passages,  filling  air  vesicles,  replacing  the  desquamated  alveolar  epithe- 
lium, and  consolidating  one  lobe  or  a  whole  lung.  In  the  liver,  the  bile-ducts, 
and  in  the  kidney  the  glomeruli  and  tubules  often  conduct  the  proliferating 
31 


NEOPLASTIC  DISEASES 


cells.  Along  mucous  surfaces,  as  of  stomach  or  uterine  cervix,  carcinoma  may 
spread  laterally  by  replacing  the  lining  cells  of  the  glands.  In  the  peritoneum 
the  flat  endothelium  may  be  widely  replaced  by  cylindrical  cells  derived  from 
glandular  carcinoma  of  the  intestine. 

The  lymphatics  form  the  main  channel  of  local  extension.  The  cells  may 
very  early  penetrate  lymph  spaces  and  lymph-vessels  and  form  new  spaces 
in  the  connective  tissue.  It  is  especially  the  perivascular  lymph-channels 
which  are  invaded  and  from  these  the  route  to  larger  lymph-vessels  and 
nodes  is  most  direct.  The  lymphatic  endothelium  remains  passive  or  suffers 
atrophy.  Proliferation  of  these  cells  cannot,  however,  be  excluded  in  the 


FIG.  208. — Edge  of  advancing  adenoma  malignum  of  rectum.     Note  sudden  transition 
of  normal  to  neoplastic  epithelium. 

formation  of  the  new  connective  tissue  that  often  accompanies  local  invasion. 
While  the  growth  in  neighboring  lymphatics  is  usually  continuous,  local 
metastases  may  occur  and  surround  the  main  tumor  with  many  small  second- 
ary nodules.  Yet  the  fine  strands  of  tumor-cells  demonstrable  in  the  lymphatics 
connecting  the  nodules  of  rodent  ulcer  suggest  that  a  continuous  permeating 
cord  of  cells  may  be  broken  by  fibrous  perilymphangitis.  The  invasion  of 
lymphatics  is  greatly  retarded  or  suppressed  in  favorable  cases  by  extensive 
collections  of  lymphocytes  which  gather  in  the  vessels  and  may  even  sur- 
round the  tumor-cells  with  a  rich  lymphoid  ring.  Occasionally  the  entire 
tumor  is  infiltrated  with  lymphocytes,  and  in  such  cases  the  occurrence  of 


GENERAL  PATHOLOGY  OF  EPITHELIAL   TUMORS  483 

many  degenerating  tumor-cells  indicates  that  the  lymphoid  infiltration  is 
a  phenomenon  of  immunity. 

The  lymphatics  of  nerve-trunks  are  readily  penetrated  by  many  tumor- 
cells,  especially  in  epidermoid  carcinoma,  and  through  these  minute  channels 
the  process  may  travel  over  wide  areas.  It  is  probable  that  the  spinal  ganglia 
and  meninges  are  occasionally  reached  by  this  method.  The  nerve-fibers 
suffer  atrophy.  Much  of  the  pain  of  carcinoma  as  well  as  pareses,  pares- 
thesias,  and  the  rare  attacks  of  zoster,  must  be  referred  to  invasion  of  nerve- 
trunks  and  ganglia. 

The  paths  of  access  to  the  local  blood-vessels  vary  much  in  the  different 
organs.  In  the  liver,  kidney,  adrenal,  and  thyroid  the  small  vessels  are 
early  penetrated  by  tumor-cells  of  otherwise  moderate  infiltrative  capacity. 
Hence  tumors  of  these  organs  may  early  present  bulky  intravenous  masses 
from  which  vascular  emboli  are  distributed  or  which  completely  fill  the  vena 
cava  up  to  and  into  the  right  auricle.  The  intravascular  position  of  the  fetal 
villi  accounts  for  the  extension  of  chorioma  through  the  uterine  vessels. 

In  many  carcinomas  the  local  veins  are  penetrated  by  the  cells  filling 
perivascular  lymphatics.  Goldmann's  injections  of  the  veins  of  carcinoma 
show  that  these  vessels  are  often  occluded  by  tumor-cells  and  that  the  local 
advance  of  the  growth  may  be  largely  through  these  vessels.  Primary  car- 
cinoma of  the  liver  may  be  rapidly  disseminated  over  the  entire  organ,  ex- 
clusively through  the  blood-vessels.  The  formation  of  granulation  tissue 
about  ulcerating  carcinomas  often  facilitates  the  local  extension,  probably 
by  providing  many  new  capillary  channels  for  invading  cells. 

The  invaded  vessel  is  usually  filled  by  tumor-cells  and  the  lumen  occluded, 
but  in  many  cases  one  may  observe  flat  or  papillary  mural  implantations, 
or  the  endothelium  may  be  replaced  by  a  flat  layer  of  tumor-cells  while  the 
lumen  remains  pervious.  Interference  with  the  circulation  accounts  for 
much  of  the  edema  in  tumors,  for  the  tendency  toward  central  necrosis,  for 
bulky  areas  of  necrosis  from  infarction,  for  hemorrhage,  and  for  the  partial 
suppression  of  growth  in  the  centers  of  carcinomatous  areas. 

Through  these  various  channels  the  cells  of  an  originally  small  carcinoma 
gradually  involve  successive  portions  of  the  organ  or  even  pass  continuously 
from  one  organ  to  neighboring  structures.  The  wider  dissemination  of  the 
tumor-cells,  especially  by  loosened  cell  groups,  constitutes  the  process  of 
metastasis,  the  complex  details  of  which  have  been  separately  considered. 


CHAPTER  XXVI 
EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 

Hypertrophy  of  Breasts. — Mammary  hypertrophy  occurs  as  a  rare  con- 
genital condition  in  infancy  or  childhood;  it  arises  most  frequently  at  puberty, 
and  is  seen  in  adult£  (Deaver,  McFarland,  R.  Williams,  Lit.). 

1.  Infantile  Hypertrophy. — Congenital  enlargement  is  recorded  by  Hor- 
ritt,  Hahn,  and  Wilson.     Infantile  hypertrophy  is  usually  associated  with 
precocious  sexual  development,  and  is  more  common  in  the  tropics.     It  is 
possibly  connected  with  pituitary  disorders,  and  some  of  the  cases  first  ob- 
served in  infancy  seem  to  have  begun  at  birth  (Mallett,  Sagra). 

2.  Diffuse  Hypertrophy  of  Adults. — Most  cases  arise  at  puberty,  others 
occur  late  in  life,  and  a  considerable  number  is  connected  with  pregnancy. 
An  hereditary  element  has  been  noted  in  a  few  cases  (Rousseau,  Kirchheim). 
Delayed  onset  of  menstruation,  or  suppression  of  menses  frequently  precede 
the  overgrowth.     The  disease  may  best  be  interpreted  as  an  excessive  re- 
sponse   to    functional    and    formative    stimuli    in    congenitally    predisposed 
organs. 

Either  one  breast  or  both,  or  one  or  more  supernumerary  organs,  are 
involved.  A  partial  hypertrophy  has  been  described  by  Richet  and  Billroth. 
The  degree  of  enlargement  may  be  moderate  or  very  great,  Kaufmann 
reporting  a  weight  of  30  kg.  for  both  breasts.  The  structure  varies  con- 
siderably. Lipomatosis  and  glandular  hypertrophy  were  the  chief  elements 
in  the  cases  of  Robert  and  Warren.  Connective-  and  fat- tissue  overgrowth, 
with  moderate  glandular  hypertrophy,  retention  of  secretion,  and  marked 
vascularity  are  observed  in  a  considerable  group.  Porter  described  multiple 
intracanalicular  fibromatous  growths  with  fibrosis,  and  in  many  cases  the 
structure  resembles  diffuse  nbro-adenoma.  A  low  grade  of  adenomatoid 
hypertrophy  is  frequently  seen. 

In  a  well-marked  case,  age  24,  I  found  much  excess  of  fat  tissue  surround- 
ing a  greatly  hypertrophied  breast.  The  gland  presented  a  structure  resem- 
bling the  lactating  organ.  The  alveoli  were  greatly  increased  in  number  and 
while  some  were  compact  with  narrow  lumen  others  were  dilated.  Many 
ducts  were  widely  dilated.  There  was  a  uniform  overgrowth  of  fine  cellular 
connective  tissue  between  the  acini. 

Billroth  describes  very  active  overgrowth  of  glands  resembling  in  places 
adenocarcinoma.  Diffuse  carcinoma  appears  to  have  followed  diffuse  hyper- 
trophy (Billroth,  Aitken). 

The  course  is  usually  active  during  the  first  few  months,  and  after  reaching 
certain  dimensions  a  quiescent  period  is  maintained  for  some  years  with 
exacerbations  during  pregnancy.  The  tumors  often  become  so  large  as  to 
interfere  with  general  health.  Inflammation,  suppuration,  and  gangrene 
have  occurred,  or  death  may  result  from  general  exhaustion.  Very  active 
cases  are  recorded  by  Billroth  and  Huston  in  which  the  breasts  reached  a 
large  size  in  a  few  months,  while  Durston's  case  was  fatal  from  gangrene 
in  4  months.  The  tumor  may  regress  after  pregnancy  and  operative  removal 
is  usually  successful. 

Gynecomastism,  hypertrophy  of  the  male  breast,  with  and  without  changes 
in  the  testicles  and  in  the  secondary  sexual  characters,  has  occurred  in  a  series 
of  cases  collected  by  R.  Williams. 

484 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


485 


Chronic  Productive  Mastitis. — From  the  extensive  literature  recording 
the  history  of  the  knowledge  of  chronic  productive  inflammation  of  the  breast 
it  is  becoming  more  and  more  apparent  that  the  various  forms  of  this  condi- 
tion are  essentially  one  and  the  same  disease.  Some  of  the  variations  depend 
chiefly  on  the  state  of  the  breast  at  the  time  the  inflammatory  process  occurs, 
others  represent  exaggerations  of  single  features  of  chronic  inflammation, 
and  still  others  may  be  explained  as  different  stages  of  the  same  process. 
Much  of  the  long  debate  over  the  inflammatory  as  against  the  neoplastic 
nature  of  the  processes  could  have  been  avoided  had  it  been  recognized  that 
chronic  productive  inflammation  may  consist  in  much  overgrowth  of  con- 
nective tissue  and  glandular  epithelium  and  that  inflammatory  passes  insen- 
sibly into  neoplastic  hyperplasia.  The  disease  begins  as  an  inflammation 


*  &&••**•  *$&?*•    ' 

- 


a 

• 


FIG.  209. — Chronic  adenomatoid  mastitis.    A  diffuse  overgrowth  of  well-formed  lobules. 

and  often  ends  as  a  neoplasm.    Nevertheless  extreme  examples  of  the  different 
forms  of  the  disease  are  widely  separated. 

The  importance  of  the  condition  is  found  not  only  in  its  frequency,  but 
especially  in  its  relation  to  the  development  of  tumors  of  the  breast. 

(i)  Astley  Cooper,  1837,  first  gave  a  lucid  description  of  cystic  mastitis  under  the 
term  "hydatid  disease."  He  described  a  slow  painless  increase  in  the  size  of  the  breast 
affecting  the  whole  or  a  portion  of  the  organ,  resulting  in  the  appearance  of  many  cysts 
as  large  as  a  pea  or  bean,  some  of  which  might  open  externally,  giving  rise  to  sinuses. 
The  breast  was  not  as  hard  as  scirrhous  cancer,  the  axillary  nodes  were  not  affected,  and 
the  general  health  remained  good.  In  1846  Brodie  accurately  described  the  same  con- 
dition in  one  or  both  breasts.  In  1883  Reclus  gave  a  full  description  under  the  term 
"maladie  kystique."  He  emphasized  the  bilateral  distribution  and  the  large  number  of 
cysts  throughout  all  portions  of  the  gland,  especially  at  the  periphery. 

Brissaud,  1883,  found  that  the  formation  of  cysts  was  preceded  by  signs  of  abnormal 


486  NEOPLASTIC  DISEASES 

activity  of  the  gland,  the  structure  resembling  the  fetal  breast.  Both  acini  and  ducts 
became  dilated.  Upon  these  appearances,  suggesting  a  neoplastic  tendency,  he  desig- 
nated the  process  as  "epitheliome  kystique  intra-acineux."  Phocas,  1886,  emphasized 
the  occurrence  of  many  shotty  nodules  throughout  the  organ  and  employed  the  term 
"maladie  noueuse."  In  Germany  Konig  (1875)  described  the  condition  in  some  detail, 
and  later  (1893)  he  followed  the  successive  changes  of  prolonged  cases,  pointing  out 
many  distinctions  from  a  tumor  process.  Schimmelbusch,  however,  reached  the  same 
conclusions  as  Brissaud,  that  marked  activity  of  the  gland  preceded  the  growth  of  con- 
nective tissue  and  persisted  with  the  development  of  cysts,  and  that  the  process  was 
essentially  neoplastic.  This  view  has  been  maintained  by  many  other  writers,  Cornil, 
Lecene,  Lenormant.  The  disease  is  often  referred  to  as  Schimmelbusch's  multiple  cyst 
adenoma.  This  interpretation  has  been  actively  contested  by  Konig  in  Germany  and 
Delbet  in  France,  who  maintain  that  the  process  is  essentially  inflammatory.  Theile 
finds  it  impossible  to  distinguish  between  adenofibroma,  a  tumor,  and  "maladie  kystique," 
an  inflammatory  process  in  the  breast,  and  Delbet  admits  that  the  inflammatory  process 
passes  into  the  adenomatous.  La  Roy  places  the  condition  among  the  pathological 
hyperplasias  which  should  be  separated  from  both  inflammatory  and  neoplastic  processes. 

(2)  A  somewhat  different  form  of  mastitis  was  first  described  by  Werner  as  cirrhosis 
mammae,  by  Velpeau  as  "induration  chronique  en  masse,"  and  by  Virchow  as  "elephan- 
tiasis dura."     It  is  much  less  frequent  than  the  common  cystic  disease.     Billroth  was 
long  uncertain  of  its  existence,  but  describes  a  very  advanced  case  with  extensive  cic- 
atricial  contraction  and  deformity.     Labbe  and  Coyne  described  a  case  in  which  there 
was  diffuse  growth  of  very  cellular  connective  tissue  infiltrated  with  round  cells,  while 
a  small  collection  of  pus  was  found  in  the  axillary  border  of  the  gland.    Konig  recognized 
a  rare  form  of  diffuse  chronic  mastitis  with  a  painful  onset  and  a  marked  tendency  to 
atrophy.     R.  Williams  collected  several  cases  in  both  sexes.    Many  cases  of  apparently 
suppurative  mastitis  with  cicatrization  and  even  calcification   (Bryk,   Houdoupe)   he 
classifies  as  circumscribed  chronic  mastitis.     They  should  be  separated  from  the  non- 
suppurative  diffuse  inflammations.     Delbet  recognizes  the  peculiar  features  of  this  form 
of  mastitis,  but  on  account  of  the  transitional  cases  he  merges  it  with  the  common  cystic 
disease. 

(3)  Finally,  it  has  long  been  known  that  senile  involution  or  precocious  atrophy  of 
the  breast  is  often  accompanied  by  irregular  overgrowth  of  stroma  and  glands  with  the 
formation  of  cysts,  and  various  authors  have  assumed  that  chronic  mastitis  is  essentially 
an  exaggeration  or  sequel  of  the  processes  concerned  in  senile  involution.     R.  Williams 
states  that  the  new  tissue  in  senile  involution  is  usually  free  from  any  signs  of  inflam- 
mation, although  it  may  be  abundant,  as  in  cystic  disease.     Altmann  observed  much 
epithelial   proliferation  in   34  cases  of  senile  and   precocious  atrophy.     Tietze   found 
marked  similarity  between  the  epithelial  changes  in  about  25  per  cent,  of  senile  organs 
and  those  of  cystic  disease. 

Bloodgood  finds  a  close  relation  between  cystic  mastitis  and  senile  involution.  He 
designates  the  former  as  senile  parenchymatous  hypertrophy  and  traces  accurately  the 
stages  of  hyperplasia,  ectasia,  and  cystic  dilatation.  He  recognizes  two  types  of  the 
disease,  one  with  small  cysts  and  moderate  epithelial  hyperplasia,  and  another  with 
larger  cysts  and  pronounced  epithelial  overgrowth. 

An  essential  relation  between  cystic  disease  and  senile  involution  must,  however,  be 
questioned.  Involution  is  chiefly  an  atrophic  process  with  slow  replacement  fibrosis  and 
often  fails  to  exhibit  the  cystic  and  productive  changes.  When  these  are  added  they  are 
best  interpreted  as  an  additional  process  which  may  become  established  in  an  involuting 
breast. 

From  the  above  brief  review  of  the  literature  it  is  evident  that  two  well- 
defined  forms  of  chronic  mastitis  have  been  under  discussion  which  may  be 
designated  anatomically  as  interstitial  and  glandular,  while  a  third  less 
prominent  group  of  cases  includes  those  in  which  normal  involution  atrophy 
is  prominent.  While  accepting  the  essential  identity  of  all  forms  of  primary 
productive  inflammation  of  the  breast,  as  maintained  recently  by  Delbet 
and  Baumgartner,  yet  many  clinical  and  anatomical  peculiarities  seem 
to  me  to  warrant  the  subdivision  of  the  disease  into  at  least  three  types — inter- 
stitial, glandular,  and  senile. 

Etiology. — The  various  forms  of  chronic  mastitis  are  comparatively  com- 
mon, but  satisfactory  statistical  data  are  unavailable.  The  increasing  atten- 
tion to  the  early  stages  of  cancer  is  bringing  under  observation  a  much  larger 
number  of  cases  of  chronic  mastitis.  Many  cases  pass  as  fibre-adenoma, 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  487 

cystadenoma,  and  carcinoma.  When  these  conditions  develop  on  chronic 
mastitis  the  condition  of  the  whole  breast  is  commonly  overlooked. 

The  majority  of  cases  are  first  observed  at  the  menopause,  but  many  are 
encountered  much  earlier.  Of  67  cysts  of  the  breast  Bryant  found  4  under 
30  years,  n  between  30  and  40  years,  33  between  40  and  50  years,  16  from 
50  to  60  years,  and  3  after  60  years.  Delbet  believes  that  most  cases  begin 
some  years  before  recognition.  Phocas  observed  a  nodular  mastitis  at  18 
years  and  Baumgartner  at  19  years.  Rodman  finds  the  condition  more  fre- 
quent in  married  women  and  suggests  that  a  rapid  sequence  of  pregnancies 
lead  to  nutritional  and  inflammatory  changes. 

Delbet  considers  the  disease  a  bacterial  infection,  in  which  the  Staphy- 
lococcus  albus  is  the  most  common  but  not  the  sole  agent.  He  compares 
the  infection  to  the  infectious  mastitis  of  cattle  described  by  Nocard  and 
Mollereau  and  assumes  that  the  microorganism  enters  through  the  lacteal 
ducts  and  penetrates  throughout  the  lobules.  The  structure  in  the  active 
diffuse  lesions  strongly  indicates  the  presence  of  an  irritant  passing  out  from 
the  acini,  but  for  the  more  chronic  forms  this  explanation  is  less  satisfactory. 

The  course  of  the  disease  and  the  structure  of  the  gland  vary  considerably 
in  the  different  anatomical  forms. 

Senile  Involution. — The  natural  history  of  the  mamma  includes  a  terminal 
stage  of  atrophy.  This  change  is  regularly  initiated  at  the  menopause,  con- 
tinues at  varying  rates  and  degrees  throughout  life,  and  is  associated  with 
decline  in  the  nutrition  and  function  of  other  sexual  organs. 

Precocious  atrophy  is  observed  with  sterility  and  disuse  (Williams,  Rey- 
nolds, De  Sinety).  An  atrophic  condition  of  the  breasts  of  Bavarian  women 
has  been  attributed  by  Altmann  to  a  local  custom  against  nursing.  Ovarian 
disease  or  extirpation  appears  to  notably  affect  the  breast  only  when  occurring 
before  the  development  of  secondary  sexual  characters  (Battey).  Yet  some 
observers  note  pronounced  diminution  in  the  size  of  the  breasts  following 
ovariotomy  (Keppler),  while  others  report  hypertrophy  and  increased  secre- 
tion (Baumgartner). 

The  scope  of  the  changes  which  may  be  attributed  to  simple  atrophy 
is  defined  with  difficulty,  since  the  process  is  often  complicated  by  other 
disturbances  in  structure.  In  many  cases  the  fat,  connective  and  gland 
tissue  suffer  alike  and  the  organ  is  greatly  reduced  in  size,  the  cellular  con- 
nective tissue  becomes  fibrous  and  hyaline,  and  the  gland  lobules  are  reduced 
to  a  trace,  all  without  reactive  processes  in  any  element.  The  contracted 
ducts  persist,  usually  with  some  desquamation  of  lining  cells  and  a  notable 
increase  or  prominence  of  smooth  muscle-fibers  about  the  walls.  That  ex- 
treme atrophy  may  occur  without  other  notable  alterations  or  inflammatory 
changes  is  shown  in  many  of  the  34  cases  studied  by  Altmann,  and  it  there- 
fore seems  clear  that  many  structural  variations  often  ascribed  to  senile 
involution  are  not  essentially  connected  with  this  condition. 

In  other  cases,  especially  in  obese  subjects,  the  atrophy  takes  the  form  of 
fat  invasion,  scanty  atrophic  lobules  and  ducts  being  widely  scattered  in 
much  adipose  tissue. 

In  many  cases  the  process  is  marked  by  proliferation  and  desquamation 
of  lining  cells  of  ducts,  the  low  epithelium  may  form  short  lateral  outgrowths 
or  papillary  projections,  small  retention  cysts  may  form,  connective  tissue 
invades  the  lobules  and  disturbs  their  outlines,  and  a  low  grade  of  chronic 
productive  inflammation  is  established.  These  changes  do  not  properly 
belong  to  normal  involution,  but  they  are  so  frequently  observed  in  breasts, 
many  of  which  have  suffered  from  the  effects  of  repeated  lactations  or  previous 
disturbances  of  structure,  that  their  presence  in  moderate  degree  must  be 


488 


NEOPLASTIC  DISEASES 


included  in  the  usual  picture  of  involution.  A  pronounced  degree  of  these 
changes  should  be  classed  with  chronic  productive  mastitis. 

The  advanced  atrophy  of  simple  involution  distinctly  favors  forms  of 
atypical  proliferation  of  the  lining  cells  of  persistent  ducts. 

Chronic  Interstitial  Mastitis. — The  characteristic  type  of  this  condition 
is  a  diffuse  interstitial  productive  inflammation,  with  a  new  growth  of  con- 
nective tissue  about  ducts,  lobules,  and  acini. 

Usually  one  breast  only  is  involved,  and  the  lesion  may  be  more  pro- 
nounced about  the  larger  ducts.  When  affecting  a  circumscribed  portion 
of  the  breast,  the  condition  resembles  a  true  adenofibroma,  but  without  en- 


Sm'w  >iwCf  -'*Vfc*  •  '&  -  4i*Sy8$  •  *•• 

^ 


FIG.  210. — Chronic  mastitis.     Atypical  proliferation  of  acinar  cells. 

capsulation.  It  begins  with  diffuse  and  somewhat  painful  enlargement  of 
the  breast,  which  progresses  slowly  until  the  organ  is  moderately  increased 
in  size.  Exacerbations  occur  chiefly  at  menstruation,  when  the  breast  may 
become  painful  and  the  axillary  nodes  enlarge,  after  which  the  process  remits, 
leaving  new  nodules  or  indurated  areas.  After  months  or  years  contraction 
and  sclerosis  begin,  the  skin  becomes  roughened  (Labbe  and  Coyne,  peau 
d' orange),  adherent  and  contracted,  and  the  breast  may  be  reduced  to  a  de- 
formed area  of  hard  cicatricial  tissue  (Billroth).  Usually  the  whole  organ 
remains  permanently  enlarged,  diffusely  fibrosed,  and  with  or  without  small 
cysts.  The  whole  original  area  of  gland  distribution  may  become  converted 
into  a  bulky  solid  mass  of  elastic  connective  tissue.  Cysts,  isolated  fibromas, 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  489 

and  foci  of  carcinoma  frequently  interrupt  the  smooth  texture.  The  gross 
appearance  of  these  organs  is  quite  specific. 

In  the  acute  stage  the  lesion  consists  in  a  diffuse  growth  of  cellular  con- 
nective tissue  which  surrounds  ducts  and  lobules  and  penetrates  between 
the  acini.  This  tissue  may  be  richly  infiltrated  with  lymphocytes.  The 
acini  are  compressed  and  show  only  moderate  hyperplasia,  but  the  ducts 
may  be  filled  with  desquamated  epithelium.  Cyst  formation  is  not  promi- 
nent. In  the  later  stages  the  new  tissue  may  contract  with  atrophy  of  the 
parenchyma.  In  some  cases,  especially  in  circumscribed  areas,  the  process 
resembles  adenofibroma,  but  on  careful  analysis  the  structure  is  found  to 
consist  of  a  limited  growth  of  fibroblasts  chiefly  about  ducts  and  acini,  pro- 
liferation of  capillaries,  and  infiltration  by  lymphocytes  and  plasma-cells. 
The  very  abundant  overgrowth  of  fibroblasts  and  the  encapsulation  observed 
in  true  adenofibroma  are  missing.  That  true  adenofibromas  may  develop 
on  such  lesions  has  been  maintained  by  many  authors  (Cornil,  Theile, 
Lecene  and  Lenormand,  Delbet,  Borst).  My  own  observations  lead  to  the 
same  conclusion.  Yet  the  natural  tendency  of  the  process  is  progressive 
fibrosis.  Epithelial  tumors  develop  in  the  course  of  diffuse  interstitial 
mastitis,  but  rather  less  frequently  than  in  the  glandular  cystic  mastitis  of 
Reclus  and  Schimmelbusch. 

Chronic  Glandular  Mastitis. — Cystic  Mastitis. — The  common  form  of 
productive  mastitis  is  marked  by  the  production  of  many  small  cysts,  by 
considerable  epithelial  proliferation,  and  by  diffuse  growth  of  firm  fibrous 
tissue.  On  account  of  the  prominence  of  epithelial  changes  the  process  may 
be  designated  as  glandular  mastitis,  and  the  presence  of  many  cysts  has  led 
to  the  use  of  the  term  "cystic  mastitis."  It  is  often  called  "maladie  de  Reclus," 
or  "Schimmelbusch's  disease,"  and  when  many  small  nodules  are  present 
it  has  been  called  by  Phoca  "maladie  noueuse."  Typical  cases  differ  notably 
from  the  diffuse  interstitial  mastitis  of  Werner  and  Billroth,  but  there  are 
transitional  cases  which  connect  the  two  forms,  and  it  is  probable  that  some 
cases  of  diffuse  interstitial  mastitis  later  become  cystic.  Senile  atrophic 
breasts  also  develop  cysts  with  epithelial  proliferation. 

The  disease  usually  develops  first  in  one  breast  and  often  later  in  the 
other.  The  onset  is  slow  and  usually  painless  and  the  condition  may  not  be 
recognized  until  a  cyst  of  some  size  attracts  attention.  There  may  be  a  serous 
discharge  from  the  nipple.  A  bloody  discharge  usually  but  not  always  indi- 
cates a  cystadenoma  or  carcinoma  (Sasse,  Shield).  On  palpation  the  whole 
organ  is  firm,  of  normal  or  increased  size,  and  many  hard,  movable  nodules 
as  large  as  a  pea  or  bean  may  be  detected.  No  part  of  the  breast  escapes. 
There  is  no  adherence  to  the  muscle,  nor  as  a  rule  to  the  skin,  but  the  nipple 
may  be  retracted  (Renon). 

The  process  continues  slowly  progressive  with  exacerbations  for  years. 
It  may  subside  spontaneously,  but  cases  lasting  15,  30,  and  33  years  are  re- 
ported by  Monod,  Trelat,  and  Reclus.  In  the  late  stages  the  cysts  may  open 
and  leave  sinuses  through  the  skin.  Many  cases  are  complicated  with  cyst- 
adenoma,  nbro-adenoma,  and  carcinoma. 

On  horizontal  section  of  the  breast  the  organ  is  found  to  consist  of  an 
irregular  mass  of  fibrous  tissue  broken  by  fat  lobules,  cysts  of  various  sizes, 
and  hard  opaque  nodules.  The  cysts  may  be  small  and  extremely  numerous, 
or  larger  and  infrequent.  The  contents  are  serous,  fatty  or  bloody,  and  thin 
or  inspissated  and  yellowish.  Larger  cysts  may  show  all  stages  of  papillary 
ingrowths,  and  some  (butter  cysts)  contain  much  caseous  fatty  material. 

The  structure  presents  a  great  variety  of  abnormalities.  The  cellular 
or  fibrous  connective  tissue  surrounds  ducts,  lobules,  and  acini.  It  is  usually 


490 


NEOPLASTIC  DISEASES 


acellular  and  cicatricial  in  type,  but  at  various  points  it  may  show  local 
overgrowth  of  embryonal  type.  About  small  ducts  there  may  be  very  pro- 
nounced nodular  thickenings.  Between  the  acini  the  tissue  is  more  cellular, 
and  lymphocytes  and  plasma-cells  are  often  present. 

The  epithelial  changes  take  many  forms,  but  proliferation  predominates 
over  atrophy.  Most  acini  show  a  compact  lining  of  two  rows  of  well-nour- 
ished cells.  The  lumen  is  collapsed  or  contains  globules  of  acidophile 
material,  or  various  stages  of  ectasia  are  visible.  More  pronounced  over- 
growth produces  more  abundant  cells  of  larger  size,  with  hyperchromatic 
nuclei.  All  the  acini  and  ducts  of  a  lobule  may  show  much  overgrowth,  while 
adjoining  lobules  are  normal  or  atrophic.  Suspicious  or  definitely  pre- 
cancerous  changes  appear  when  dilated  acini  or  ducts  become  filled  with 


FIG.  211.- 


-Precancerous  changes  in  breast.    Filling  of  small  ducts  and  acini  with  atypical 
cells.     No  infiltration. 


overnourished  cells  in  compact  masses  or  forming  secondary  alveoli.  Such 
foci  may  be  scanty  and  require  many  sections  in  different  portions  of  the 
breast  for  their  detection.  In  the  fresh  tissue  they  appear  in  the  form  of 
shot-like  solid  nodules.  Another  precancerous  change  consists  in  a  multi- 
plication of  small  alveoli  with  increase  in  the  size  and  nuclear  chromatin  of 
the  cells.  According  to  Dreyfuss  and  Sasse  it  is  the  inner  row  of  secreting 
cells  which  multiply  in  precancerous  foci,  while  McCarthy  locates  the  hyper- 
plasia  in  the  sustentacular  cells.  I  have  been  unable  to  recognize  these  dis- 
tinctions. 

Cysts  form  from  dilatation  of  alveoli  or  ducts  and  are  lined  by  clear 
polygonal  epithelium.  Many  stages  of  the  proliferation  of  these  cells  are 
observed,  including  formation  of  low  papillae,  dendritic  outgrowths  accom- 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


491 


panied  by  stroma,  up  to  pronounced  papillary  adenoma.  From  the  simple 
adenomas  arise  malignant  adenoma  and  adenocarcinoma.  Hemorrhage 
and  exudation  in  these  cysts  may  be  associated  with  malignant  changes  in 
the  wall  of  the  cyst.  Degenerating  butter  cysts  often  show  such  changes 
in  their  walls.  Another  type  of  cyst  forms  in  the  interlobular  ducts  which 
may  be  lined  by  excessive  layers  of  large  cells  which  form  papillary  projec- 
tions or  fill  the  lumen  diffusely.  Such  lesions  may  pass  rapidly  into  a  form 
of  large  alveolar  or  adenocarcinoma  of  the  breast  (tubular  or  duct  cancer, 
Labbe  and  Coyne,  R.  Williams).  Sasse  finds  that  fibrosis  about  larger  ducts 
gives  rise  to  one  or  more  large  and  several  smaller  cysts  in  which  there  is  a 
notable  tendency  to  develop  adenoma  and  carcinoma. 

A  third  form  of  cyst  develops  from  the  sweat-glands  incorporated  in  the 
breast  (Moullin,  Dreyfuss,  Krompecher).  These  are  easily  recognized  by 
the  lining  of  columnar,  strongly  acidophile  cells  which  are  often  thrown  into 
papillary  projections.  Beneath  the  epithelium  there  may  be  overgrowth  of 
muscle  spindles.  All  stages  of  the  development  of  papillary  projections, 
papillary  adenoma,  adenocarcinoma,  and  carcinoma  have  been  traced  by 
Creighton,  Borst,  Kuru,  Krompecher,  and  others. 


FIG.  212. — Precancerous  changes  in  the  breast. 

a  duct. 


Atypical  proliferation  in  a  segment  of 


The  frequency  of  the  development  of  benign  or  malignant  tumor  processes 
in  cystic  mastitis  is  a  question  of  prime  importance.  Delbet  represents  a 
large  body  of  surgical  opinion  in  stating  that  the  affection  is  too  benign  to 
justify  extirpation,  and  while  he  admits  that  there  is  no  other  satisfactory 
treatment,  he  recommends  pressure,  iodid  of  potash,  and  injections  of 
carbolized  glycerin  into  the  cysts.  This  conclusion  is  based  on  the  rather 
frequent  observation  that  characteristic  cases  pursue  a  very  chronic  course 
without  any  neoplastic  complication,  benign  or  malignant.  In  support  of 
this  view  may  also  be  cited  the  fact  that  the  epithelial  overgrowth  is  at  first 
inflammatory  and  that  the  suspicious  carcinomatous  areas  cannot  in  any 
one  case  be  traced  into  fully  developed  carcinoma  and  may  never  pass  be- 
yond the  stages  actually  seen  in  the  simple  cystic  breast.  It  is  also  assumed 
that  the  great  majority  of  carcinomas  are  not  associated  with  chronic  mastitis, 
or  if  so,  that  the  carcinoma  is  a  wholly  distinct  process.  Baumgartner  con- 
cludes that  the  essential  sequence  of  inflammation — adenoma,  carcinoma — is 
not  based  on  irrefutable  proof  nor  disproved  by  established  facts.  This 
conclusion  is  not  helpful. 


492 


NEOPLASTIC  DISEASES 


Against  this  view  stand  the  interpretations  of  Brodie,  Brissaud,  Sourice, 
Schimmelbusch,  and  Saar  that  there  are  neoplastic  qualities  in  the  process 
and  the  step  to  carcinoma  is  short.  The  very  chronic  cases  which  remain 
free  from  complications  are  clinically  impressive,  but  when  cancer  develops 
little  attention  is  commonly  paid  to  the  condition  of  the  remaining  portions 
of  the  organ.  I  find  that  a  very  large  proportion  of  mammary  cancers  occur 
in  breasts  which  are  the  seat  of  chronic  mastitis.  Billroth  long  ago  stated 
that  small  cysts  are  very  often  seen  about  carcinoma  of  the  breast.  Tietze 
in  43  cases  of  cystic  disease  found  cancerous  areas  in  3,  and  computes  that 
about  10  per  cent,  of  cases  of  cystic  mastitis  develop  cancer.  He  describes 


FIG.  213. — Diffuse  proliferation  of  atypical  cells  in  ducts  in  chronic  mastitis.     A  precan- 

cerous  lesion. 

5  cases  of  cancer  with  cystic  disease  in  the  outlying  breast  tissue.  In  5  of 
1 8  breasts  classed  as  senile  involution  he  found  suspicious  areas  suggesting 
cancer,  especially  in  the  peripheral  portions.  Of  295  cases  of  various  types 
of  chronic  mastitis  collected  by  Speese,  1 5  per  cent,  were  reported  as  showing 
carcinomatous  changes.  In  28  cases  of  cancer  of  breast  Verga  found  that 
in  5  the  organ  was  the  seat  of  cystic  mastitis  with  pronounced  carcinomatous 
metaplasia.  In  my  own  material  about  50  per  cent,  of  the  breasts  excised 
for  cystic  disease  show  pronounced  precancerous  changes  or  miniature  car- 
cinomas. Very  few  cancerous  breasts  fail  to  show  phases  of  chronic  mastitis 
in  the  outlying  portions  of  the  parenchyma. 

It  is  therefore  clear  that  chronic  mastitis  is  a  very  important  predisposing 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


493 


condition  to  mammary  cancer.  It  appears  also  from  the  histological  evidence 
that  many  cancers  arising  in  chronic  mastitis  do  not  represent  wholly  new 
processes,  but,  on  the  contrary,  are  the  natural  result  of  steadily  increasing 
epithelial  overgrowth  which  is  originally  inflammatory  and  affects  not  embry- 
onal or  misplaced  tissues,  but  the  normal  and  adult  glandular  epithelium. 

When  carcinoma  develops  in  chronic  mastitis  it  usually  arises  early  or 
progresses  actively  so  that  the  malignant  tumor  overshadows  the  inflam- 
matory changes.  When  the  cystic  disease  passes  a  critical  period  without 
the  development  of  a  tumor  it  tends  to  maintain  a  benign  course  over  many 
years.  Hence  the  clinical  impression  of  the  benign  character  of  the  process 
is  strongly  emphasized  by  a  limited  group  of  cases.  Yet  I  find  precancerous 


FIG.  214. — Adenoma  of  axillary  sweat-glands.    An  occasional  source  of  mammary  car- 
cinoma. 

changes  in  the  outlying  atrophic  and  cystic  breast  tissue  in  cases  of  cancer 
developing  after  70  years  of  age. 

The  treatment  of  chronic  mastitis  must  be  determined  after  consideration 
of  all  the  factors  in  the  case.  To  remove  all  such  breasts  would  certainly 
entail  much  useless  surgery.  It  seems  to  be  a  safe  rule  to  remove  the  whole 
breast  or  the  whole  affected  segment  when  an  incision  is  required  for  diagno- 
sis. The  presence  of  carcinoma  can  nearly  always  be  made  by  the  gross 
examination  of  the  amputated  breast,  and  the  correct  surgical  procedure 
can  then  be  determined  with  certainty.  The  decision  to  leave  untouched  a 
definite  grade  of  cystic  mastitis  should  be  made  only  with  the  knowledge 
that  carcinoma  frequently  develops  in  such  organs.  On  the  other  hand, 


494  NEOPLASTIC  DISEASES 

simple  cysts  often  disappear  spontaneously  and  do  not  constitute  a  definite 
indication  for  surgical  interference.  Yet  the  course  of  the  established  disease 
is  generally  progressive  and  most  cases  eventually  terminate  in  carcinoma  or 
surgical  removal.  Physical  agents  are  worthy  of  trial. 

MIXED  TUMORS  OF  BREAST 

Of  mixed  tumors  of  the  breast  in  which  a  tumor  process  affects  more 
than  one  element  there  are  two  main  groups  and  several  varieties. 

In  one  group  the  structure  is  comparatively  simple  and  presents  adult 
connective  tissue  and  glandular  epithelium,  as  in  adenofibroma  and  its  malig- 
nant derivative  adenosarcoma.  In  a  second  group  the  structure  is  more 
complex  and  often  embryonal,  as  illustrated  in  growths  which  contain  con- 
nective-tissue, cartilage,  bone,  or  mucous  tissue,  and  epithelium  of  both 
glandular  and  squamous  types.  Such  tumors  are  usually  malignant. 

There  is  a  tendency  for  one  element,  of  the  tumor  to  predominate.  Thus 
some  pure  fibromas,  of  which  R.  Williams  has  collected  several  cases,  prob- 
able belong  with  the  adenofibromas  in  origin,  and  the  pure  osteomas, 
chondromas,  and  sarcomas  are  probably  often  one-sided  developments  of  the 
complex  tumors.  Yet  the  majority  maintain  a  uniform  growth  of  more  than 
one  tissue  and  must  be  classed  with  mixed  tumors.  Many  writers  have 
interpreted  these  growths  as  simple  tumors,  chiefly  epithelial.  Beneke 
has  shown  that  the  development  of  the  early  gland  acini  exerts  a  strong 
stimulus  on  the  supporting  connective  tissue.  At  puberty  and  in  pregnancy 
there  is  an  active  new  growth  of  acini  which  may  incite  proliferation  of  the 
supporting  stroma.  Hence  a  tumor  process  originating  in  the  epithelium 
may  be  assumed  to  affect  secondarily  the  connective  tissue.  Many  French 
authors  hold  that  the  majority. of  benign  mammary  tumors  are  primarily 
adenomas  (Delbet).  On  the  other  hand,  many  German  authorities  locate 
the  primary  influence  in  the  connective  tissue  (Virchow).  The  attempt  to 
interpret  the  growths  as  simple  thus  meets  with  difficulties.  Since  the 
tumors  are  usually  well  encapsulated  and  both  epithelium  and  connective 
tissue  are  well  represented  it  seems  most  probable  that  they  arise  from  super- 
fluous or  misplaced  portions  of  breast  tissue  containing  both  elements. 
In  the  more  complex  and  embryonal  tumors  the  mixed  composition  is 
unequivocal. 

An  inflammatory  origin  for  many  of  the  simpler  fibre-adenomas  and 
especially  of  the  cystadenomas  has  been  maintained  by  many  authors. 
Theile,  studying  19  tumors,  concludes  that  it  is  impossible  to  establish  a 
sharp  limitation  between  the  cystic  changes  of  chronic  mastitis  and  fibro- 
adenomas.  Cystadenoma  is  often  multiple  and  associated  with  chronic 
mastitis.  Occasionally  one  finds  several  stages  of  the  growth  of  diffuse 
or  intracystic  fibre-adenoma  in  the  same  case  of  chronic  mastitis.  I  find 
as  a  rule  that  the  tumor-like  areas  in  chronic  mastitis  are  not  well  circum- 
scribed and  show  many  inflammatory  changes,  such  as  the  growth  of  fine 
capillaries  and  infiltration  with  round  cells,  while  the  pronounced  tumors 
are  free  from  inflammatory  signs.  It  seems  probable  that  an  inflammatory 
process  is  a  frequent  inciting  factor  especially  with  the  cystadenomas,  but 
that  a  true  tumor  arises  only  when  there  is  a  tissue  predisposition  in  the 
form  of  superfluous  or  misplaced  material.  A  constitutional  element  may 
also  be  assumed. 

The  earliest  stages  of  fibro-adenoma  have  been  observed  by  Borst  in 
the  form  of  small  groups  of  acini  which  are  not  sharply  circumscribed  but 
exhibit  neoplastic  characters  in  the  epithelium.  Ribbert  pictures  a  very 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


495 


small,  sharply  circumscribed,  typical  fibre-adenoma.  Very  early  and 
circumscribed  cystadenomas  are  frequently  observed.  The  isolation  of  the 
blood-supply,  which  is  usually  from  one  set  of  vessels  without  free  lateral 
anastomoses,  points  to  the  origin  from  misplaced  tissue,  as  do  also  the  con- 
genital and  aberrant  adenomas. 

Adenofibroma ;  Fibro-adenoma. — Two  gross  forms  of  fibre-epithelial 
tumors  occur  in  the  breast:  (i)  Massive  and  (2)  papillary  or  intracystic  fibro- 
adenoma. 

(i)  Diffuse  massive  fibro-adenoma  is  best  illustrated  in  some  cases  of 
diffuse  hypertrophy  of  the  whole  breast  which  exhibit  neoplastic  characters. 
More  frequently  the  tumor  forms  a  circumscribed  mass  of  considerable 


BBk 


FIG.  215. — Intracanalicular  fibro-adenoma  of  breast. 

dimensions  which  is  firm  and  fibrous  or  more  often  soft  and  vascular.  A  very 
common  tumor  occurring  especially  in  young  persons  is  the  solid  encapsulated 
fibroma  which  forms  a  firm,  translucent,  lobulated,  and  freely  movable  growth. 
In  cystic  fibro-adenoma  the  acini  are  often  dilated,  forming  cysts  which  are 
single  or  multiple,  large  or  small,  while  the  contents  are  serous,  mucous, 
bloody,  or  semifluid  fatty  material  containing  cholesterin  crystals. 

The  structure  of  these  tumors  presents  varying  proportions  of  stroma 
and  epithelium.  In  diffuse  adenomatous  hypertrophy  both  glands  and 
stroma  are  well  represented  and  active,  but  the  adenomatous  element  usually 
predominates.  In  the  large  soft  circumscribed  adenomas  the  alveoli  are 
abundant,  large,  and  lined  with  several  rows  of  overnourished  cells,  while 
the  stroma  is  abundant,  very  cellular,  and  sometimes  quite  vascular.  The 


496 


NEOPLASTIC  DISEASES 


firm  solid  encapsulated  tumors  are  chiefly  fibromatous.  The  connective 
tissue  is  cellular  and  either  surrounds  the  acini  in  broad  bands  (pericanal- 
icular),  or  grows  diffusely,  or  forms  complex  papillary  projections  into  the 
acini  (intracanalicular  fibroma).  In  these  growths  the  epithelium  is  quite 
subordinate  and  merely  covers  the  enlarging  connective-tissue  papillae.  In 
the  typical  cystic  fibromas  the  cysts  are  lined  by  one  or  several  rows  of  cubical 
epithelium  which  may  be  thrown  into  low  papillary  projections.  In  one 
case  Buday  found  ciliated  epithelium. 

(2)  Papillary  Intracystic  Fibro-adenoma,  Cystadenoma. — Cystadenoma  is 
a  comparatively  common  tumor.  It  appears  usually  after  the  menopause 
(average  50  years),  but  occasionally  in  young  or  very  old  subjects.  The  usual 
features  are  of  a  single  or  multiple  rounded  tumor,  movable  beneath  the 
nipple,  which  may  be  retracted,  of  slow  growth,  and  often  accompanied  by  a 


FIG.  216. — Multiple  cysts  of  breast,  in  some  of  which  are  papillary  adenomas. 

serous  or  bloody  discharge  from  the  nipple.  The  typical  cystadenoma  is 
inclosed  in  a  cyst  wall.  The  tumor  may  appear  as  a  papillary  growth  attached 
to  one  segment  of  the  wall  and  incompletely  filling  the  cyst,  or  it  may  occupy 
the  entire  cavity  distending  the  wall,  or  numerous  points  of  fusion  unite 
the  tumor  with  the  wall.  These  tumors  develop  by  papillary  growths  into 
the  larger  ducts.  They  are  usually  encountered  when  they  have  reached 
the  size  of  a  hen's  egg,  but  may  grow  considerably  larger.  They  are  usually 
single,  but  occasionally  multiple  and  rarely  bilateral.  The  position  in  the 
central  portion  of  the  breast  is  characteristic,  but  not  invariable.  Cornil 
describes  cases  exhibiting  rapid  growth  which  is  usually  due  to  accumula- 
tion of  fluid  or  myxomatous  degeneration.  Rarely  they  distend  or  adhere 
to  the  skin  or  open  externally.  Johada  found  an  adenoma  floating  free  in 
the  pus  of  an  infected  cyst.  Delbet  and  Mintz  consider  a  bloody  discharge 
as  a  sign  of  probable  malignant  degeneration.  During  pregnancy  and  lacta- 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


497 


tion  these  tumors  may  rapidly  enlarge  and  secrete  milk,  so  that  they  suggest 
a  malignant  process  or  galactocele  (Deaver,  McFarland). 

The  structure  shows  a  papillary  or  complex  dendritic  growth  of  connective 
tissue  covered  by  epithelium.  In  some  tumors  the,  connective  tissue  pre- 
dominates and  forms  coarse  branching  masses  which  are  fibrous,  mucoid, 
vascular  or  cellular,  or  infiltrated  with  lymphocytes.  In  "cystosarcoma 


j  • 

t5T\ 


FIG.  217. — Segment  of  benign  fibre-adenoma  growing  into  a  large  cyst  in  chronic  mastitis. 

phyllodes"  the  papillae  are  largely  of  connective  tissue  which  is  very  cellular, 
and  when  this  tumor  perforates  the  skin  a  false  appearance  of  malignancy  is 
presented.  This  term  was  first  employed  by  J.  Muller  to  designate  the 
cauliflower-like  polypoid  masses  of  connective  tissue  which  fill  a  cystic  cavity 
in  the  breast.  The  same  tumor  Virchow  called  intracanalicular  myxoma. 
It  is  evident  that  these  observers  encountered  much  later  stages  of  these 
growths  than  are  now  commonly  seen. 
32 


498 


NEOPLASTIC  DISEASES 


In  most  cystadenomas  the  epithelium  predominates  and  the  growth  may 
resemble  the  ovarian  cystadenomas.  The  lining  cells  are  cubical  or  cylin- 
drical epithelium  in  one  or  several  rows.  Malignant  forms  of  intracystic 
nbro-adenoma  are  relatively  common,  but  whether  they  represent  malignant 
transformations  of  a  benign  tumor  or  are  malignant  from  the  first  is  difficult 
to  determine.  The  malignant  forms  are  described  by  many  writers  as  duct 
or  villous  cancer.  Delbet  holds  that  the  transformation  is  so  common  as 
to  demand  radical  treatment  of  all  intracystic  fibro-adenomas.  Malignant 
changes  have  been  recorded  by  Guinard,  Speese,  and  others.  Hansen  extir- 
pated a  carcinoma  which  appeared  at  the  base  of  a  nbro-adenoma  excised 
1 6  years  previously.  In  20  cases  of  cystadenoma  Greenough  and  Simmons 
found  adenocarcinomatous  areas  in  3.  The  structure  of  the  malignant  tumors 
is  characteristic  and  follows  the  type  of  adenoma  destruens,  malignant 


FlG.  218. — Fetal  fibro-adenoma  of  breast  in  a  girl  of  10  years.     Marked  overgrowth  of 

epithelium. 

adenoma  (Tietze),  or  adenocarcinonia.  This  structure  is  often  preserved 
in  the  metastases  which  appear  late.  Fully  developed  carcinomas  are  not 
infrequently  seen  which  give  every  appearance  of  having  developed  in  a  seg- 
ment of  a  duct.  These  tumors  are  solid  and  sharply  encapsulated.  An 
outlying  cyst  or  cystadenoma  may  accompany  the  solid  tumor.  The  struc- 
ture usually  preserves  traces  of  a  papillary  or  adenocarcinomatous  type. 
Long  immunity  of  the  lymph-nodes  may  also  characterize  this  group  of  mam- 
mary carcinomas.  When  mucous  degeneration  attacks  the  •  stroma  very 
bulky  tumors  may  result.  I  have  examined  such  a  tumor  as  large  as  a  child's 
head  of  10  years'  duration,  without  involvement  of  lymph-nodes. 

The  prognosis  of  cystadenoma  varies  widely,  corresponding  to  the  struc- 
tural type.  The  simple  adenomas  are  benign  and  an  extirpation  of  the 
whole  breast  or  even  of  the  tumor  alone  is  all  that  is  called  for  (Warren). 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  499 

Adenoma  destruens  is  long  confined  by  the  cyst  wall  and  when  well  encap- 
sulated may  safely  be  removed  with  the  breast.  When  the  capsule  is 
traversed  these  tumors  are  fully  malignant  and  the  radical  operation  is 
indicated,  especially  the  dissection  of  the  axilla.  A  definite  tendency  to 
invade  the  muscles  is  not  common. 

(3)  Fetal  Fibro-adenoma. — A  peculiar  form  of  fibre-adenoma  presents 
several  structural  features  of  the  fetal  breast,  including  very  cellular  con- 
nective tissue,  alveoli  without  membrana  propria,  and  imperfect  differentia- 
tion between  ducts  and  acini.  In  a  characteristic  case  the  tumor  was  soft, 
circumscribed,  and  as  large  as  a  goose  egg.  The  structure  showed  a  moderate 
number  of  alveoli  lined  by  several  layers  of  cubical  cells  without  membrana 
propria  or  the  peculiar  sustentacular  "basket"  cells  of  the  adult  organ.  The 
cellular  overgrowth  was  pronounced  and  suggested  malignant  tendencies. 
These  tumors  occur  usually  between  the  ages  of  15  and  25  years.  They  grow 
rapidly,  producing  soft,  vascular,  well  circumscribed,  lobulated  tumors,  which 
reach  much  larger  dimensions  than  the  fibromas,  and  are  often  regarded  as 
sarcoma.  Yet  they  do  not  recur. 

Pure  adenoma  of  the  breast  is  a  very  rare  tumor,  but  has  been  described 
by  several  authors  (Kuru,  Lit.).  Ziegler  describes  tubular  and  acinous 
varieties.  In  most  of  these  tumors  the  growth  of  connective  tissue  is  con- 
siderable and  approaches  that  seen  in  fibro-adenoma  with  which  they  are 
connected  by  transitional  forms.  The  gross  appearance  and  course  are  very 
similar  to  those  of  fibro-adenoma. 

Pure  fibroma  also  is  rarely  observed  and  bears  a  close  relation  to  fibro- 
adenoma.  Williams  has  collected  several  cases  from  the  older  literature. 

Teratoid  Mixed  Tumors.— Mixed  tumors  in  which  mesodermal  or  ecto- 
dermal  tissues  differentiate  toward  the  adult  type  are  not  infrequent  in  the 
human  breast.  In  the  dog  this  type  of  complex  mixed  tumor  is  very  fre- 
quently observed  and  the  tissue  changes  are  presented  far  more  extensively 
and  clearly  than  in  man  (Virchow,  Cornil  and  Petit,  Gushing). 

Two  main  groups  of  teratoid  tumors  of  the  breast  may  be  recognized, 
which  are  chiefly  (i)  mesodermal,  or  (2)  ectodermal  (Baumgartner). 

(i)  Mesodermal  tumors  appear  to  be  closely  related  to  adenosarcoma 
both  in  origin  and  structure.  Thus  Bowlby  described  a  cystic  adenosarcoma 
throughout  which  were  many  nodules  of  hyaline  cartilage.  Pilliet  found 
myeloid  giant-cells  about  the  bony  trabeculae  in  an  adenosarcoma.  In  the 
dog  breast  I  find  that  most  adenosarcomas  yield  islands  of  bone  or  cartilage. 
Diffuse  calcification  of  a  large  sarcoma  of  3  years'  duration  was  observed 
by  B.  Clark,  and  in  an  axillary  tumor  Dubar  found  much  diffuse  osteoid 
tissue. 

Frequently  true  bone  tissue  is  found  replacing  islands  of  cartilage  in 
normal  development,  as  occurred  in  cases  reported  by  Stilling,  Battle,  Cornil, 
and  Souligoux. 

Nearly  pure  chondroma  of  the  breast  is  not  extremely  rare  (Lange, 
Cambria,  Leser,  Davidsohn).  Happel's  tumor  was  large  and  cystic.  Sou- 
lier  observed  extension  to  the  superior  maxilla.  Not  a  few  are  cellular  and 
embryonal  in  type  and  malignant  (Desoil).  Myxomatous  degeneration  is 
often  present  and  tends  to  increase  the  size  of  the  growth.  Chevrier  and 
Debral  found  a  large  tumor  occupying  the  whole  breast  and  containing 
fibroma,  myxoma,  chondroma,  osteoma,  and  gland  alveoli.  Combinations 
of  chondroma  with  carcinoma  are  recorded  by  Wagner,  Coen,  and  others. 
Kaufmann  has  described  a  large  cystic  chondrocarcinosarcoma.  Warren 
saw  3  cases  combined  with  scirrhous  cancer.  S.  W.  Gross  described  a  bony 
stroma  inclosing  islands  of  lymphoid  bone-marrow  with  giant-cells  and  sur- 


500  N EOF LA  STIC  DISEASES 

rounded  by  carcinoma  simplex.  Coen  analyzed  a  slowly  growing  tumor 
with  vascular  well-formed  bone,  which  he  attributed  to  metaplasia.  Hacker's 
case  contained  bone,  cartilage,  carcinoma,  and  fibrocystadenoma,  and  he 
regarded  it  as  a  terminal  product  of  an  original  cystadenoma.  I  have 
examined  a  very  large  solid  and  cystic  tumor  containing  chiefly  masses  of 
poorly  developed  cartilage,  myxomatous  tissue,  and  areas  of  diffuse  em- 
bryonal carcinoma.  Metaplasia  could  not  have  accounted  for  the  extensive 
development  of  cartilage. 

Chondroma  and  osteoma  of  the  breast  are  usually  associated  with  sar- 
coma or  carcinoma,  but  in  the  series  of  reported  cases  there  is  a  gradual  reduc- 
tion in  the  malignant  elements,  leaving  eventually  pure  chondroma  or  osteoma. 
Some  of  these  growths  are  therefore  probably  one-sided  developments  of 
mixed  tumors. 

(2)  Ectodermal  mixed  tumors  take  the  form  of  multiple  cholesteatoma 
or  squamous-cell  carcinoma,  often  combined  with  sarcoma.  The  multiple 
sebaceous  cysts  of  the  breast  were  early  noted  by  Astley  Cooper  and  by 
Virchow  and  have  later  been  studied  by  Grohe,  Wilms,  and  others.  The 
true  tumors  resemble  cystic  fibre-adenomas  with  characteristic  sebaceous 
material  and  epithelial  detritus  in  the  cysts,  which  are  lined  by  squamous 
epithelium.  This  lining  may  show  differentiation  into  strata,  both  horny 
and  Malpighian,  with  eleidin  granules.  Stoerk  and  Erdheim  point  out  that 
13  of  14  reported  cases  showed  the  general  architecture  of  sarcoma  phyllodes. 
The  gland  alveoli  may  show  adenomatous  growth  and  the  stroma  is  often 
sarcomatous.  In  Konjetzney's  case  the  squamous  epithelium  had  suffered 
malignant  transformation. 

In  another  group  of  cases  squamous  epithelium  appears  in  isolated  foci 
associated  with  fibre-adenoma  or  glandular  carcinoma  without  cholesteato- 
matous  features.  Beginning  with  the  case  of  Stoerk  and  Erdheim,  in  which 
scanty  islands  of  squamous-cells  appeared  in  a  fibre-adenoma,  one  finds  a 
series  of  cases  in  which  squamous  epithelium  becomes  more  and  more 
abundant.  I  have  studied  one  case  in  which  glandular  and  squamous  epi- 
thelium were  about  equally  divided,  while  the  transformation  of  one  type 
into  the  other  seemed  obvious.  In  Duval's  tumor  the  cells  were  squamous, 
cuboidal,  or  giant.  Walther  described  a  large  tumor  the  periphery  of  which 
was  pericanalicular  fibroma,  in  the  center  cystic  adenoma,  while  a  single 
cyst  was  lined  by  well-developed  skin.  Nadal  found  many  squamous-cell 
groups  scattered  in  a  sarcomatous  matrix. 

The  course  and  prognosis  of  the  teratoid  mixed  tumors  vary  with  their 
structure,  but  as  a  rule  they  are  slowly  growing  and  comparatively  benign. 
Yet  carcinomatous  and  sarcomatous  metastases  are  observed  reproducing 
the  original  structure.  Nadal  found  in  the  spleen  a  nodule  of  chondro-adenoma 
resembling  the  original  tumor. 

The  origin  of  the  teratoid  tumors  of  the  breast  has  been  attributed  to 
complex  embryonal  inclusions  containing  mesodermal  skeletogenous  material 
and  fetal  ectoderm.  This  view  has  been  maintained  by  Wilms,  Lecene, 
Nadal,  Menetrier,  and  others.  The  encapsulation  of  the  early  growths  and 
the  wide  diversity  and  fully  adult  character  of  the  tissues  produced  favor  this 
view.  Some  rapidly  growing  complex  chondrosarcomas  strongly  suggest  an 
origin  from  cells  of  undiminished  and  embryonal  growth  capacity.  On  the 
other  hand,  it  has  been  clearly  shown  that  this  series  of  tumors  includes 
many  transition  stages  from  fibro-adenoma  up  to  the  most  complex  forms. 
Close  histological  study  appears  to  show  every  stage  of  metaplasia  from  the 
ordinary  gland-  and  stroma-cells  of  the  breast  into  cartilage,  bone,  and  squa- 
mous epithelium.  In  the  dog  tumors  this  histological  evidence  is  unequivocal. 


501 

Hence  it  appears  necessary  to  accept  the  theory  of  autochthonous  or  local 
development  of  mammary  mixed  tumors  as  maintained  by  Grohe,  Cornil, 
and  Herrenschmidt. 

In  the  breast  one  sees  the  most  remarkable  forms  of  metaplastic  tumor 
growth,  and  while  this  view  does  not  exclude  the  origin  of  the  tumors  from 
embryonal  and  misplaced  cell  groups  it  renders  this  assumption  no  more 
urgent  for  the  teratoid  growths  than  for  the  simpler  fibro-adenomas. 

Adenosarcoma. — Adenosarcomas  represent  the  malignant  form  of  adeno- 
fibroma,  but  their  many  striking  clinical  and  anatomical  features  render  them 
a  rather  specific  form  of  mixed^  tumor  of  the  breast.  It  is  quite  probable, 
as  Delbet  suggests,  that  most  pure  sarcomas  are  identical  in  origin  with 
adenosarcoma.  This  view  must  be  accepted  at  least  for  the  true  spindle-cell 
sarcomas.  Not  only  is  their  structure  identical  with  that  of  adenosarcoma, 
but  recurrence  of  adenosarcoma  may  take  the  form  of  spindle-cell  sarcoma 
(Finsterer).  These  tumors  form  from  7  to  10  per  cent,  of  mammary  neo- 
plasms (Gross,  Schmidt,  Schouler).  While  the  chief  age  of  incidence  is 
between  30  and  50  years  (average  40)  the  condition  has  been  observed  by 
Gross  at  9  years  and  at  75  years.  Labbe  and  Coyne  early  pointed  out  that 
nearly  half  the  cases  represent  a  malignant  transformation  of  a  long-standing 
fibre-adenoma,  and  that  gestation,  lactation,  and  trauma  appear  to  be  excit- 
ing causes  of  the  change.  Ropke  and  Gebele  emphasize  the  relation  to 
trauma,  but  identical  histories  are  observed  without  trauma.  Tumors  of 
very  long  duration  eventually  becoming  malignant  are  satisfactorily  recorded 
also  by  Gross  (40  years),  Schouler  (39  years),  Mornard,  Masson  (24  years), 
Borchmeyer  (6  years). 

The  form  of  the  tumor  is  usually  rounded  and  lobulated.  Cornil  describes 
solid  and  papillary  cystic  types,  the  former  developing  from  solid  adeno- 
fibromas,  the  latter  from  cystadenofibromas.  The  same  breast  may  contain 
adenosarcoma  and  benign  fibromas.  The  cystic  forms  produce  the  largest 
tumors  seen  in  the  breast,  Velpeau's  tumor  weighing  20"  kg.  Labbe  and 
Coyne  evacuated  a  liter  of  fluid.  In  the  early  stages  the  tumors  are  circum- 
scribed or  encapsulated,  but  active  growth  leads  to  dissemination  through  the 
organ,  and  fungating  masses  perforate  nipple  and  skin  with  ulceration. 
Edema,  hemorrhage,  necrosis,  and  suppuration  complicate  the  advanced 
stages.  In  some  cases  myxomatous  changes  and  overgrowth  of  blood-vessels 
are  prominent. 

The  structure  presents  considerable  variations.  Most  tumors  are  com- 
posed chiefly  of  spindle-cells,  large  or  small,  surrounding  gland  acini  or  ducts, 
or  growing  within  distended  channels  or  spreading  diffusely.  The  glands 
may  participate  for  a  time  in  the  overgrowth,  but  in  advanced  cases  they 
usually  disappear,  or  are  found  in  isolated  islands.  Round-cell  growths  are 
less  numerous  and  rather  more  malignant.  Such  cells  usually  show  traces  of 
a  spindle  or  polygonal  form,  and  sometimes  an  alveolar  arrangement.  Myxo- 
matous changes  may  appear  in  large  areas  of  bulky  tumors.  Giant-cells  of 
myeloid  type  occur  in  spindle-  and  round-cell  growths. 

It  is  evident  that  some  European  authors  have  included  among  adeno- 
sarcomas  certain  rather  cellular  adenofibromas  which  have  no  distinct  ma- 
lignant qualities,  but  have  reached  a  large  size  by  virtue  chiefly  of  long  dura- 
tion. It  also  seems  highly  probable  that  some  cases  reported  as  adenosarcoma 
are  rapidly  growing  carcinomas  in  which  the  anaplastic  tumor  cells  assume 
a  spindle  or  rounded  form  and  grow  about  hypertrophied  ducts.  The  true 
adenosarcoma  of  the  breast  is  very  rare  and  usually  follows  a  long-standing 
adenofibroma. 

Definite  association  of  sarcoma  with  carcinoma  is  reported  by  Lecene. 


502 


NEOPLASTIC  DISEASES 


Cornil,  and  Kettle.    In  several  such  cases  I  have  not  been  satisfied  that  the 
spindle-cell  areas  were  not  modified  epithelium. 

The  course  of  the  true  adenosarcoma  when  once  established  is  usually 
rapid  and  fatal.  Yet  in  early  stages  remissions  in  the  growth  are  recorded, 
without  satisfactory  explanation.  Gross  emphasized  the  capricious  character 
of  the  growth  of  both  cystic  and  solid  sarcoma,  but  a  rapid  growth  once 
established  was  usually  maintained.  In  the  late  stages  the  progress  is 
continuous  or  fulminating,  the  skin  becomes  adherent  and  ulcerated,  dilated 
veins  appear  over  the  surface,  and  cachexia  develops  from  absorption  of 
degenerating  and  necrotic  material,  and  from  metastases.  The  relative 
immunity  of  the  lymph-nodes  has  frequently  been  noted.  Gross  in  156 
cases  of  various  types  of  sarcoma  found  the  nodes  invaded  in  only  3, 


FIG.  219. — Mammary  cancer. 


Alveolar  and  diffuse  carcinoma,  simulating  carcino- 
sarcoma. 


one  of  which  was  a  melanoma.  A  much  higher  proportion  of  invasion  of 
lymph-nodes  is  recorded  in  Finsterer,  Gebele,  and  Rosenstein.  Generaliz- 
ation by  the  blood-vessels  with  internal  metastases  is  recorded  by  Schouler 
in  12.4  per  cent,  of  the  cases.  Secondary  tumors  have  been  found  in  lungs, 
liver,  pancreas,  bones  and  brain,  and  elsewhere.  Persistent  local  recur- 
rence is  observed  in  a  high  proportion  of  cases.  In  Hoffmann's  remarkable 
case  proliferating  gland  acini  persisted  in  the  twelfth  recurrence,  but  were 
missing  in  metastases  in  the  abdominal  wall.  Recurrence  as  round-cell  sar- 
coma and  as  carcinoma  are  recorded  by  Poulsen.  Pean  reported  local  return 
after  25  years.  Gross  observed  recurrence  in  51  per  cent,  and  metastases  in 
12  per  cent,  of  cystic  sarcomas,  with  12  per  cent,  of  cures  by  operation.  Many 
cases  requiring  multiple  operations  are  recorded,  on  one  of  which  by  S.  D. 
Gross  21  excisions  during  4  years  eventually  eradicated  the  disease. 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  503 

PURE  SARCOMAS  OF  THE  BREAST 

When  one  excludes  from  the  group  of  mammary  sarcomas  the  adeno- 
sarcomas,  the  malignant  forms  of  mixed  tumois  containing  cartilage,  bone, 
mucoid,  or  fat  tissue,  and  certain  malignant  round-,  spindle-,  and  giant-cell 
alveolar  pseudosarcomas  which  are  really  atypical  carcinomas,  there  is  little 
remaining  of  a  once  formidable  group  of  mammary  neoplasms.  There  are 
reasons  for  believing  that  such  a  disintegration  of  the  group  is  justifiable. 
In  fact,  the  situation  today  is  much  as  it  was  in  1894,  when  Williams  found 
it  impossible  to  write  the  history  of  pure  mammary  sarcoma  because  of  the 
absence  of  requisite  data. 

Of  Gross'  collection  of  156  cases,  33  per  cent,  were  adenoid,  50  per  cent, 
cystic,  and  50  per  cent,  solid.  On  clinical  grounds  Billroth  and  Konig  con- 
cluded that  the  cystic  sarcomas  were  closely  related  to  adenofibroma,  and 
Schimmelbusch,  from  thorough  anatomical  study,  reached  the  same  conclu- 
sion. Gross  mentions  that  adenoid  structures  persist  chiefly  in  the  spindle- 
cell  sarcomas,  and  that  myxomatous  changes  are  almost  peculiar  to  spindle-cell 
and  cystic  tumors.  The  great  predominance  of  the  forms  thus  entangled  in 
the  group  of  malignant  fibre-epithelial  growths  is  indicated  in  Finsterer's 
recent  series — cystosarcoma,  18  cases;  spindle-cell,  10;  myxosarcoma,  5; 
round-cell,  6;  lymphosarcoma,  i. 

The  pseudosarcomas  of  epithelial  origin  probably  cover  a  considerable 
subgroup  of  mammary  sarcomas.  A  definitely  alveolar  structure  points 
at  once  to  an  atypical  epithelial  tumor  process.  Not  a  few  such  tumors  are 
included  in  the  lists  of  sarcoma.  They  are  difficult  to  distinguish  in  the  gross 
from  medullary  carcinoma.  Billroth  fully  recognized  the  difficulties  of 
diagnosis  and  seems  to  have  reached  the  conclusion  that  they  belong  in  a 
group  of  carcinosarcoma.  I  have  studied  several  rapidly  growing  cellular 
tumois  of  alveolar  or  diffuse  structure  and  failed  to  find  any  definite  evidence 
of  a  mesoblastic  origin.  On  the  contrary,  as  Billroth  observed,  areas  can 
usually  be  found  which  are  duplicated  by  portions  of  undoubted  medullary 
carcinoma.  Finsterer  saw  a  supposed  alveolar  sarcoma  recur  as  frank 
carcinoma.  G.  B.  Schmidt's  angiosarcomas  consisted  of  cells  of  "distinct 
epithelial  form"  in  alveolar  arrangement.  The  uncertain  significance  of 
perithelial  structures  in  breast  tumors  is  well  elucidated  in  the  discussion  of 
Nadal's  case  of  mixed  osteosarcoma  and  perithelioma. 

Melanoma  also  figures  among  the  alveolar  and  giant-cell  sarcomas. 
Fioriana  describes  a  melanotic  lymphangiosarcoma,  a  form  not  infrequently 
assumed  by  melanoma.  The  lobular  and  encapsulated  form  of  some  reputed 
cases  of  giant-cell  sarcoma  suggest  an  origin  from  cystic  adenocarcinoma 
in  which  diffuse  areas  of  round  and  giant-cells  are  not  uncommon. 

The  round-cell  sarcomas  of  various  authors  form  an  ill-defined  group. 
They  probably  include  very  atypical  tumors  of  the  same  nature  as  the  spindle- 
cell  sarcomas,  malignant  and  atypical  carcinomas,  and  some  pigment-free 
melanomas.  Gross  found  their  chief  occurrence  at  48  years,  the  period  of 
beginning  physiological  decline  of  the  breast,  while  the  spindle-cell  tumors 
appear  earlier,  36  to  38  years.  Six  of  Finsterer's  40  cases,  5  of  Gebele's  34 
cases,  and  27  per  cent,  of  the  series  collected  by  Gross  were  round-cell  tumors. 
That  the  nature  of  these  tumors  is  often  highly  uncertain  is  indicated  by 
the  simultaneous  occurrence  of  small  round-cell  sarcoma  in  one  breast  and 
glandular  carcinoma  in  the  other,  as  in  Finsterer's  case  21;  or  by  his  case  23, 
of  lymphosarcoma  of  alleged  traumatic  origin.  That  the  structure  of  round- 
cell  sarcoma  may  be  duplicated  by  carcinoma  is  demonstrable  in  certain 
atypical  acinar  carcinomas  in  which  considerable  areas  may  fail  to  show  any 


504 


NEOPLASTIC  DISEASES 


alveolar  arrangement.  Billroth's  case  of  acute  lymphosarcoma  of  both  breasts 
arising  in  gestation  and  fatal  in  5  months  is  very  suggestive  of  the  atypical 
carcinomas  of  pregnancy.  Battle  in  reporting  a  large  fungating  round-cell 
sarcoma  states  his  belief  that  the  growth  was  some  form  of  fungating  tumor 
arising  within  a  cyst. 

True  sarcomas  composed  of  rounded  or  short  spindle-cells  probably 
represent  an  atypical  form  of  spindle-cell  sarcoma.  They  are  highly  ma- 
lignant, 60  per  cent,  recurring  and  25  per  cent,  becoming  generalized  (Gross). 
In  one  of  Finsterer's  cases  the  malignant  tumor  followed  excision  of  a  cysto- 
sarcoma,  and  in  most  cases  a  slowly  growing  tumor  has  existed  for  some 
months. 

Pure  spindle-cell  sarcomas  of  the  breast  form  a  rather  well-defined  group 
which  closely  resemble  both  clinically  and  anatomically  their  more  complex 
homologues,  the  adenosarcomas.  The  most  characteristic  form  of  this  tumor 
begins  as  a  well-circumscribed  growth  presenting  the  lobulated  appearance 


. 

FIG.  220. — Mammary  cancer.      Diffuse  growth  of  large  polyhedral  and  spindle-cells. 

of  a  soft  fibroma.  The  rate  of  growth,  however,  is  very  rapid,  and  the  tumors 
reach  very  large  dimensions  in  a  few  months  or  weeks,  fungating  through  the 
skin,  undergoing  central  liquefaction,  and  eventually  becoming  infected  with 
extensive  necrosis,  fever,  and  cachexia.  Radical  removal  in  an  early  stage 
may  be  successful,  but  local  recurrence  is  common,  and  pulmonary  metastases 
frequently  develop.  They  vary  greatly  in  consistence,  cell  content  and  form, 
vascularity,  and  in  the  degree  of  secondary,  especially  myxomatous,  degenera- 
tion. Combinations  with  osteoma,  chondroma,  and  lipoma  are  occasionally 
observed  (Gross).  They  formed  68  per  cent,  of  Gross'  cases  and  the  great 
majority  of  Finsterer's.  The  prominence  of  cysts  emphasizes  their  relation 
to  adenosarcoma.  In  clinical  course  and  gross  appearance  they  are  not  to 
be  distinguished  from  the  adenosarcomas,  but  there  is  a  tendency  toward 
occurrence  at  earlier  ages  and  persistent  local  recurrence. 

Even  the  presence  of  an  apparently  pure  spindle-cell  structure  does  not 
positively  assure  a  mesoblastic  origin.  Diffuse  or  atypical  carcinomas,  espe- 
cially the  malignant  forms,  may  yield  broad  areas  of  small  spindle-cells,  and 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  505 

only  a  thorough  study  of  many  areas  as  well  as  of  the  history  of  the  tumor 
can  establish  a  positive  diagnosis. 

Osteochondromyxosarcoma  is  a  relatively  common  variety  of  complex 
mammary  sarcoma.  Its  relation  to  the  teratoid  growths  is  clearly  brought 
out  in  the  combinations  with  dermoid  cysts,  adenoma,  and  carcinoma.  More 
often  the  tumors  are  purely  mesoblastic  (St.  Arnold,  Lit.).  The  tumors  are 
large,  solid  or  cystic,  actively  growing,  and  tend  to  ulcerate  and  suppurate. 
The  sarcomatous  areas  are  composed  of  spindle-,  round,  or  giant-cells  (Gross, 
Manz,  Durham).  Two  tumors  of  this  type  in  the  same  breast  with  areas 
of  spindle-  and  round-cell  sarcoma  were  observed  by  Borst. 

MISCELLANEOUS  TUM  ORS  OF  THE  BREAST 

The  usual  benign  tumors  of  the  skin  occasionally  develop  in  the  mammary 
region. 

Angioma,  beginning  near  the  nipple,  after  trauma,  and  gradually  extend- 
ing as  a  pulsating  tumor  throughout  the  breast  is  described  by  Image  and 
Hake  and  by  Langenbeck.  Subcutaneous  angiomas,  cavernous  or  cystic,  and 
erectile,  are  reported  by  Williams,  and  Quenu  and  Kiiss.  A  peculiar  diffuse 
erectile  angioma  involving  the  stroma  of  the  gland  and  the  peri-  and  inter- 
acinar  connective  tissue  with  atrophy  of  gland  tissue  has  been  studied  by 
Malapert.  Lymphangiomas  of  large  dimensions  are  described  by  Wegner, 
Miiller,  and  Pinner,  and  some  large  serous  cysts  in  this  region  probably  arise 
from  lymphangiomas.  A  metastasi  zing  angioma  of  breast  is  described  on 
page  228. 

Sebaceous  cysts  and  papillomas  occur  chiefly  about  the  nipple  and  may 
be  the  source  of  carcinomas. 

Leiomyoma  of  the  nipple  or  skin  has  been  recorded  by  Virchow,  Sokolow, 
and  Niklas. 

Melanoma  has  been  reported  by  many  authors,  and  presents  its  usual 
malignant  features.  It  occurs  in  both  sexes,  chiefly  about  the  nipple.  Vier- 
egge  records  a  case  in  an  infant.  Billroth  and  Cornil  and  Ranvier  described 
melanotic  carcinoma  involving  the  breast  tissue,  but  there  is  no  evidence  that 
the  tumor  arose  from  the  gland  tissue.  In  these  and  other  cases  an  origin 
from  moles  of  the  skin  or  included  epidermal  rests,  or  a  secondary  pigmenta- 
tion from  hemorrhage  must  be  assumed. 

Dermoid  cysts  of  the  breast  are  rare,  but  several  cases  have  been  collected 
by  Williams  and  Baumgartner.  They  are  of  interest  in  connection  with  the 
mixed  tumors  and  cholesteatomas.  A  large  dermoid  described  by  Reverdin 
and  Mayor  was  associated  with  fibre-adenomas.  In  the  middle  line,  between 
manubrium  and  gladiolus,  there  is  sometimes  a  congenital  fossa,  and  here 
simple  dermoids  have  been  observed  (Williams,  Lit.). 

Lipoma  of  Breast.- — Diffuse  lipomatosis  is  often  associated  with  diffuse 
hypertrophy.  Intraglandular  lipomas  are  very  rare,  but  are  described  by 
A.  Cooper,  Koehler,  and  Begouin.  They  show  lobulated  overgrowth  of  fat 
tissue  with  scattered  gland  alveoli.  Hofer  found  a  small  mass  of  bone  in  the 
center  of  a  mammary  lipoma. 

Retromammary  lipomas  may  reach  very  large  dimensions.  Billroth's 
case  measured  43  cm.  in  its  long  diameter.  Queirel's  tumor  arose  from  the 
tissues  of  the  pectoralis  and  weighed  800  gm.  Paget  describes  a  case  in  a 
male  subject.  The  subcutaneous  lipomas  may  be  single,  multiple,  or  bilateral 
(Reclus,  Baker,  and  Bowlby).  They  are  subject  to  central  softening  and  in  a 
group  of  cases  some  of  which  are  congenital  myomatous  areas  appear  (Moore, 
Ashby,  and  Wright). 


506 


NEOPLASTIC  DISEASES 


Epithelioma  of  the  skin  of  the  breast  occurs  along  thoracic  and  mam- 
mary fold,  where  it  is  favored  by  intertrigo  (Richet,  Winiwarter),  along  the 
axillary  border,  and  in  the  nipple,  whence  it  may  invade  the  breast  and  simu- 
late carcinoma.  In  this  last  situation  it  requires  differential  diagnosis  from 
Paget's  disease  which  is  more  superficial  and  wide-spread  (Hauser),  and  from 
metaplastic  squamous  changes  in  duct  carcinoma.  Cornil  traced  a  squamous 
epithelioma  of  the  nipple  extending  some  distance  into  the  large  ducts.  Mor- 
estin  observed  epithelioma  of  the  nipple  associated  with  true  carcinoma  of  the 
gland.  Robinson  described  a  rodent  ulcer  at  the  nipple.  The  tumors  may 
be  preceded  by  a  papilloma  or  a  sebaceous  cyst  (Bryant).  They  do  not 
differ  essentially  from  epitheliomas  in  other  regions,  but  in  the  nipple  the 
course  may  be  unusually  active. 


CARCINOMA  OF  BREAST 

General  Etiology. — Incidence. — The  U.  S.  Census  for  1914  reports  5423 
deaths  from  cancer  of  the  breast  among  52,420  total  cancer  deaths.  The 
mortality  rate  rose  enormously  between  1900  and  1912,  the  average  annual 
death  rate  from  1901  to  1905  being  18.45  Per  cent.,  from  1906  to  1910,  30 
per  cent.  There  has  certainly  been  no  such  increase  in  the  incidence  of  the 
disease  and  the  recorded  increase  must  be  due  largely  to  improved  diagnosis 
and  registration.  Since  a  certain  proportion  of  breast  cancers  are  cured  by 
operation  the  morbidity  record  must  be  somewhat  higher.  R.  Williams  from 
4628  cases  of  cancer  in  women  in  London  Hospitals,  1868  to  1888,  calculates 
that  40.3  per  cent,  were  mammary,  34  per  cent,  uterine.  English  mortality 
statistics,  however,  placed  uterine  and  ovarian  cancer,  34.7  per  cent.; 
mammary  cancer,  21.2  per  cent.  In  Ireland  the  ratio  was:  stomach,  22.4  per 
cent.;  breast,  21.5  per  cent.;  uterus,  14.1  per  cent.  In  Frankfurt-am-Main: 
1860  to  1889,  uterus,  27.5  per  cent.;  stomach,  18.3  per  cent.;  breast,  11.3 
per  cent. 

In  1912  the  mortality  from  mammary  cancer  in  England  and  Wales  was 
19.8  per  100,000  of  population.  Hoffmann  points  out  that  there  is  great 
variation  in  the  mortality  in  different  countries.  Thus  from  1906  to  1910 
the  rates  per  100,000  of  population  were:  England  and  Wales,  17.9;  United 
States,  13.3;  Bavaria,  9.1;  Italy,  5.8;  Japan,  1.8. 

Of  all  mammary  tumors  carcinoma  forms  82  to  84  per  cent.  (Delbet). 

Age  Incidence. — 

U.  S.  Census,  1914.     Age  Incidence  of  Mammary  Cancer 


Years 
15-19 

20-4 

25-9 

3»-4 

35-9 

40-4 

45-9 

50-4 

55-9 

60-4 

65-9 

70-4 

75-9 

80-4 

85^> 

90-4 

95-100 

Cases 
4 

6 

44 

IOI 

301 

460 

646 

671 

658 

55i 

529 

435 

3ii 

207 

93 

23 

6 

British  mortality  statistics,  ipoi  to  1903,  place  the  highest  mortality 
between  55  and  65  years.  Mortality  statistics  of  Williams,  Paget,  Nunn,  and 
of  most  surgeons  place  the  mean  age  of  incidence  at  45  to  50,  or  about  the 
48th  year  (Schmidt). 

The  earliest  authentic  cases  recorded  appear  to  be  those  of  Kaufmann,  17 
years;  Henry,  21  years,  and  Williams,  24  years.  Brewer  reports  a  fibro- 
adenoma  with  carcinomatous  areas  in  a  negress  of  16  years. 

Lactation.     Of  628  cases  of  Velpeau,  Gross,  and  Winiwarter,  441  had 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  507 

nursed  children,  187  had  not.  Lehmann  offers  statistical  evidence  that  nurs- 
ing is  a  prophylactic  against  mammary  cancer.  Pregnancy  is  without  definite 
influence. 

Hereditary  influence  has  appeared  to  exist  in  5  to  10  per  cent,  of  various 
series  of  cases  studied  specifically  for  this  purpose  (Delbet).  With  more 
rigid  criteria  Guleke  reduces  the  possible  hereditary  cases  to  2.36  per  cent. 
Williams  found  cancer  in  the  family  in  24.2  per  cent,  and  quotes  Sibley's 
observation  of  a  mother  and  5  daughters  who  died  of  cancer  of  left  breast. 

There  is  a  slight  predominance  of  the  disease  in  the  left  breast.  It  appears 
to  originate  in  both  breasts  in  about  1.5  per  cent.  The  frequency  of  bilateral 
cancer  at  the  time  of  observation  is,  however,  much  greater.  Handley  finds 
5  per  cent,  of  advanced  cases  bilateral  and  Hubbart  9  per  cent.  Benassey 
rightly  distinguishes  between  (i)  cancer  of  the  second  breast  developing  after 
amputation  of  the  first,  which  is  not  uncommon,  and  (2)  cancer  developing 
in  the  second  breast  from  an  original  focus  in  the  first,  and  (3)  primary  bilateral 
cancer,  which  is  rare.  The  upper  axillary  segment  is  the  chief  site  of  origin 
(Delbet).  Traumatism  has  been  asserted  or  suspected  in  5  per  cent,  by 
Schmidt,  12.5  per  cent,  by  Schultheis,  and  12.7  per  cent,  by  Fink.  Its 
essential  relation  to  mammary  cancer  is  still  unproved,  but  injury  not  infre- 
quently accelerates  growth.  In  an  organ  constantly  exposed  to  trauma  as  is 
the  breast  an  apparent  relation  to  cancer  must  be  subjected  to  the  most  rigid 
criteria.  Thus  Williams  who  obtained  a  history  of  antecendent  trauma  in  25 
per  cent,  of  his  cases  found  not  a  single  instance  in  which  the  disease  had 
developed  out  of  induration  or  other  obvious  lesion  thus  induced. 

Previous  exudative  inflammation  often  leaves  tissue  changes  predisposing 
to  cancer.  Winckel  found  such  lesions  in  17.5  per  cent,  of  a  series  of  cases, 
including  abscesses  in  15;  lesions  of  the  nipple,  8;  and  inflammation  without 
suppuration  in  one  of  24  cases. 

Developmental  anomalies  are  traceable  chiefly  in  the  origin  of  cancer 
from  sequestrated  portions  of  the  breast.  Of  132  cancers  -observed  by  Wil- 
liams 13  arose  from  aberrant  tissue,  in  axillary,  sternal,  or  infraclavicular 
regions.  In  not  a  few  of  these  aberrant  tumors  the  structure  is  nearly  pure 
adenoma  with  evidences  of  functional  capacity,  but  the  true  carcinomas  in 
these  regions  are  often  highly  malignant  and  may  be  atypical.  The  milk 
secreting  adenomas  of  Birkett  and  Power  and  the  tumor-like  swellings  of 
aberrant  breast  tissue  described  by  others  are  regarded  by  Williams  as  hyper- 
trophic  rests  rather  than  true  neoplasms.  Williams  calculates  that  14  per 
cent,  of  fibre-adenomas  arise  from  such  rests.  Many  of  the  complex  mixed 
tumors  are  probably  of  identical  origin,  but  it  seems  unnecessary  always  to 
include  skeletogenous  material  to  account  for  the  bone  and  cartilage  found 
in  them.  Epidermal  inclusions  may  be  held  responsible  for  certain  dermoids 
and  melanomas  of  the  breast,  but  metaplasia  is  a  sufficient  explanation  for 
the  majority  of  cholesteatomas  and  the  squamous-cell  islands  of  mixed 
tumors. 

The  alveoli  of  sweat-glands,  which  are  nearly  constantly  found  scattered 
through  the  breast,  especially  in  the  neighborhood  .of  the  larger  ducts,  give 
rise  to  a  specific  form  of  mammary  carcinoma  which  corresponds  to  the  duct 
cancer  of  many  writers. 

According  to  Creighton  the  duct  system  of  the  breast  is  a  derivative  of 
the  cutaneous  sweat-glands.  Superfluous  or  aberrant  portions  of  this  system 
retain  the  characters  of  sweat-glands,  persist  in  the  adult  organ,  and  give 
rise  to  most  of  its  tumors.  The  secreting  gland-cells  he  derives  from  the  meso- 
blastic  fat-cells  about  the  ducts,  which  readily  become  transformed  into  the 
acinar  epithelium  when  the  demands  for  functional  activity  arise.  This 


508  NEOPLASTIC  DISEASES 

interesting  conception  once  had  considerable  authoritative  support,  but  is 
now  almost  entirely  ignored.  There  are  not  a  few  facts  in  the  physiology 
and  pathology  of  the  organ  which  are  consistent  with  this  hypothesis. 

The  effective  causation  of  mammary  cancer  is  to  be  traced  in  the  combi- 
nation of  several  predisposing,  contributing,  and  exciting  factors.  There  is 
ground  for  assuming  that  many  subjects  are  predisposed  to  mammary  neo- 
plasms. Some  of  these  subjects  appear  to  develop  simple  glandular  hyper- 
trophy in  early  life,  and  this  same  instability  of  the  organ  may  under  favor- 
able conditions  be  an  important  factor  in  precipitating  malignant  tumor 
growth  in  later  life.  Developmental  anomalies  leading  to  fibre-adenoma  and 
sequestration  of  breast  tissue  form  a  tissue  predisposition  in  a  certain  group 
of  cases.  By  far  the  most  important  element  in  the  tissue  predisposition  is 
chronic  productive  mastitis.  The  great  majority  of  cancers  develop  in  organs 
altered  by  reactive  inflammatory  processes.  Minute  histological  analysis  of 
the  conditions  surrounding  the  beginnings  of  cancer  in  chronic  mastitis  point 
to  mechanical  isolation  of  cell  groups  in  fibrocarcinoma,  and  irritation  by 
chemically  altered  secretion  and  exudate  in  adenocarcinoma,  as  the  immediate 
precursors  of  atypical  overgrowth.  This  irritation  may  very  well  come  from 
various  microorganisms  and  animal  parasites,  such  as  the  Demodex  follic- 
ulorum  described  by  Borrel,  none  of  which  can  be  regarded  as  specific  excit- 
ing factors.  In  fact,  there  appears  to  be  no  need  of  introducing  the  conception 
of  a  specific  exciting  factor  in  mammary  cancer,  since  the  disease  is  satisfac- 
torily accounted  for  as  the  liberation  of  growth  tendencies  of  overnourished 
and  proliferating  cells,  under  peculiar  anatomical  relations  and  often  but  not 
necessarily  in  predisposed  subjects. 

Pathological  Anatomy. — While  there  are  several  well-defined  anatomical 
forms  of  mammary  cancer  the  specific  features  characterize  chiefly  the  early 
stages  of  the  disease.  Arising  under  markedly  different  conditions  of  a  wide 
variety  the  anatomical  distinctions  are  often  obliterated  when  the  disease  is 
fully  established  and  the  local  lymphatics  are  invaded. 

On  chiefly  anatomical  features  the  disease  may  be  considered  under  the 
following  forms: 

1.  Adenocarcinoma  arising  chiefly  in  cysts  of  ducts  or  sweat-glands. 

2.  Duct  carcinoma  arising  from  the  lining  cells  of  ducts. 

3.  Acinar  carcinoma  arising  from  the  epithelium  of  the  acini. 

Of  these  main  groups  there  are  several  subdivisions,  such  as  gelatinous 
or  mucous  carcinoma,  fibrocarcinoma,  and  carcinosarcoma,  while  striking 
clinical  features  stamp  certain  cases  of  the  disease  as  highly  specific. 

Although  no  other  form  of  carcinoma  absorbs  more  attention  from  sur- 
geons and  pathologists,  the  morphology  of  mammary  tumors  still  requires 
more  searching  analysis  than  it  has  yet  received.  So  variable  and  complex 
are  the  forms  and  structure  of  mammary  cancer  that  the  attempt  to  employ 
a  histogenetic  classification  may  be  premature.  The  present  effort  must  be 
acknowledged  as  only  tentative.  Yet  the  rough  grouping  of  these  tumors 
in  the  current  fashion,  according  to  cell  content,  as  carcinoma  solidum, 
medullare,  and  scirrhus,  while  involving  no  risk,  is  wholly  lacking  in  any 
illumination  of  the  subject.  Not  until  the  anatomical  structure  and  histo- 
genesis  of  these  tumors  is  more  fully  understood  can  any  significant  knowledge 
be  obtained  of  their  etiology,  prognosis,  and  the  value  of  treatment.  The 
separation  of  the  sweat-gland  tumors  of  the  breast  may  be  accomplished 
with  considerable  certainty  on  morphological  grounds,  but  specific  clinical 
features  of  this  group  remain  to  be  defined. 

Ribbert  has  stated  that  no  one  has  ever  seen  a  beginning  carcinoma  of 
the  breast.  While  few  have  accepted  this  dictum,  it  is  not  necessary  to  ob- 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  509 

serve  the  initial  stages  in  order  to  deduce  the  origin  of  many  cystadenocarci- 
nomas,  duct  cancers,  or  even  of  certain  acinar  tumors. 

Clinical  features  seem  to  be  a  less  satisfactory  basis  of  nomenclature 
and  classification  of  cancer  of  the  breast  than  with  many  other  organs. 
When  the  lymph-nodes  or  blood-vessels  are  once  invaded  the  further  course, 
while  extremely  varied,  may  be  much  the  same  with  tumors  of  very  divergent 
antecedent  history.  On  the  other  hand,  the  early  stages  of  most  tumors  are 
closely  correlated  with  their  histogenesis,  structure,  and  the  conditions  under 
which  they  arise. 

The  condition  of  the  breast  at  the  time  of  the  development  of  the  tumor 
has  a  prominent  influence  on  the  anatomical  characters  and  clinical  course  of 
the  disease.  In  elderly  subjects  various  forms  of  carcinoma  develop,  but 
the  disease  is  usually  of  slow  course,  and  fibrosis  and  cicatrization  are  promi- 


FIG.  221. — Single  small  nodule  of  carcinoma  in  the  center  of  an  atrophic  and  fatty  breast. 

nent.  In  small  atrophic  breasts  at  any  age,  glandular  tissue  being  deficient, 
carcinoma  usually  takes  the  form  of  duct  cancer,  of  the  comedo  type,  and 
often  affects  the  sweat-glands. 

In  atrophic  but  very  fat  breasts  there  is  often  a  very  small  fibrous  car- 
cinoma, difficult  to  detect  in  the  organ,  with  bulky,  extensive,  and  cellular 
growths  in  lymph-nodes. 

Very  active,  anaplastic,  and  atypical  forms  of  carcinoma  develop  usually 
in  comparatively  young  women  in  the  child-bearing  period.  During  preg- 
nancy the  disease  is  usually  particularly  active,  anatomically  atypical,  and 
rapidly  fatal. 

Acute  carcinosis  with  fulminant  febrile  course  occurs  usually  in  women 
under  35  years  of  age,  with  well-developed  breasts.  The  anatomical  type 
varies,  but  often  presents  an  adenocarcinomatous  structure  in  primary  areas, 
or  a  diffuse  and  highly  anaplastic  structure. 


510 


N EOF LAST  1C  DISEASES 


An  origin  in  cysts,  in  adenofibromas,  in  the  congenitally  hypertrophic 
breast,  or  after  diffuse  fibromatosis,  or  other  pathological  conditions,  stamps 
the  early  stages  of  the  disease  with  rather  definite  clinical  features. 

The  more  chronic  forms  of  mammary  carcinoma,  especially  those  recur- 
ring after  operation,  take  a  great  variety  of  anatomical  types,  which  compose 
an  extensive  chapter  in  the  history  of  the  disease. 

Adenocarcinoma  is  characterized  by  its  origin  chiefly  in  cysts,  by  the 
markedly  circumscribed  character  of  the  growth,  the  bulky  local  tumor  often 
produced,  the  long  immunity  of  the  lymph-nodes,  the  relatively  favorable 
prognosis,  and  the  specific  structure.  Various  terms  have  been  employed 
to  designate  types  of  adenocarcinoma,  as  carcinome  mlleux  (Cornil),  epithe- 
liome  intracanaliculaire  (Labbe,  Coyne),  villous  duct  cancer  (Williams).  A 
sharp  distinction  between  the  benign  adenomas  and  adenocarcinomas  has 


FIG.  222. — An  adenocarcinoma  of  breast.     The  upper  half  is  slightly  pedunculated  and 
the  vascular  system  telangiectatic. 

not  always  been  attempted,  and  the  more  malignant  forms  have  not  been 
separated  from  other  mammary  cancers  as  clearly  as  they  should  be. 

The  majority  of  these  tumors  arise  in  the  cysts  of  chronic  mastitis.  They 
are  frequently  multiple,  and  simple  cysts,  or  cysts  with  papillary  adenomas, 
may  accompany  the  main  tumor.  In  the  early  stages  and  often  to  a  late 
period  they  form  sharply  circumscribed  masses  near  the  nipple  or  in  out- 
lying regions.  They  are  large,  solid,  opaque,  usually  soft,  and  free  from 
fibrosis.  Later  they  may  break  through  the  skin,  producing  fungating  super- 
ficial masses  which  bleed  and  ulcerate,  and  they  perforate  the  capsule,  in- 
vading the  breast  and  the  lymphatics.  There  is  much  variation  in  the  rapidity 
of  growth  and  malignancy.  Some  take  the  form  of  papillary  or  villous  adenoma 
with  carcinomatous  areas;  others  are  uniformly  solid  and  carcinomatous 
from  the  first,  but  encapsulated.  A  few  are  highly  atypical  and  malignant 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


511 


and  early  perforate  the  capsule  and  invade  the  breast  and  lymph-nodes. 
In  this  form  they  yield  some  of  the  tumors  commonly  called  "encephaloid." 

Secondary  changes  are  relatively  frequent  in  the  advanced  tumors.  Fatty 
degeneration  is  often  observed  and  considerable  areas  of  necrosis  may  appear 
in  gross  section.  Overdevelopment  of  blood-vessels  produces  a  vascular 
tumor  prone  to  hemorrhage,  infarction,  and  necrosis.  I  have  found  the 
entire  tumor  infarcted  and  black,  or  necrotic  without  infarction.  Repeated 
hemorrhages  may  leave  much  pigment  and  give  the  appearance  of  secondary 
melanoma. 

The  structure  shows  marked  variations  from  a  typical  benign  papillary 
adenoma  to  nearly  diffuse  growth  in  which  only  traces  of  papillary  or  ade- 


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FIG.  223. — Mammary  cancer.     Adenocarcinoma  of  ducts. 

nomatous  structure  are  retained.     Portions  of  the  growth  may  be  quite 
diffuse.     Typical  adenoma  malignum  or  destruens  is  occasionally  observed. 

1.  The  simplest  structure  is  a  papillary  adenoma  with  carcinomatous  foci. 
This  type  covers  the  majority  of  the  cases  described  by  Cornil,  Williams,  and 
many  of  the  older  authors,  who  have  clearly  presented  its  relatively  benign 
clinical  features.     The  papillae  are  low,  and  freely  anastomosing  bands  of 
stroma  tend  to  yield  an  alveolar  structure  with  many  secondary  sacculations ; 
or  the  outgrowths  are  long  and  villous.    The  cells  are  cuboidal  or  low  and 
cylindrical,  granular,  opaque,  but  usually  overnourished  and  atypical.    This 
tumor  is  of  slow  growth,  long  remains  encapsulated,  is  slow  to  involve  lymph- 
nodes,  and  in  this  stage  a  radical  operation  is  not  required. 

2.  A  more  malignant  form  shows  little  evidence  of  papillary  structure  in 
the  gross,  but  is  solid  and  opaque.    The  structure  presents  the  complex  features 


512 


NEOPLASTIC  DISEASES 


of  papillary  carcinoma  or  adenoma  malignum.  The  few  strands  of  connective 
tissue  or  the  large  alveoli  are  covered  or  lined  by  large  cuboidal  or  cylindrical 
cells  with  hyperchromatic  nuclei.  Everywhere  epithelium  predominates 
over  stroma.  These  tumors  frequently  perforate  the  cyst  capsule  and  grow 
diffusely  in  the  form  of  small  alveolar  carcinoma.  In  the  lymph-nodes,  lungs, 
and  especially  in  the  blood-vessels  their  growth  tends  to  revert  to  the  type 
of  adenoma  malignum  or  papillary  carcinoma. 

3.  The  most  malignant  forms  of  adenocarcinoma  developing  in  cystade- 
noma  produce  bulky  tumors  invading  most  of  the  breast,  perforating  the  skin 
as  fungating  masses,  and  early  involving  the  lymphatics  in  various  directions. 
The  adenomatous  structure  is  visible  only  in  the  central  portions  or  in  metas- 
tases,  while  the  infiltrating  portions  resemble  other  forms  of  mammary  can- 


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FIG.  224. — Mammary  cancer.     Adenocarcinoma  of  ducts,  beginning  to  infiltrate. 

cer.  These  tumors  occur  at  all  ages  and  are  among  the  most  malignant  in 
clinical  course.  A  characteristic  form  presents  one  or  more  circumscribed 
nodules  of  moderate  size  with  more  bulky  tumors  in  the  axilla.  Or  the  main 
tumor  is  found  of  large  size  having  long  remained  localized  until  a  rather 
sudden  access  of  growth  leads  to  rapid  infiltration  of  vessels  and  wide  dis- 
semination. 

Hislo genesis. — The  gross  appearance,  transitional  types,  and  minute 
structure  point  clearly  to  the  origin  of  these  tumors  from  the  papillary  in- 
growths of  mammary  cysts.  The  remaining  portions  of  the  breast  when 
available  often  show  the  changes  of  cystic  mastitis,  but  adenocarcinoma 
develops  in  breasts  in  which  any  preceding  inflammatory  changes  are  local- 
ized and  soon  obliterated.  Two  types  of  cysts  are  included  in  the  sites  of 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  513 

origin:  (i)  dilated  interlobular  ducts,  and  (2)  the  sweat-glands  of  Moullin, 
Creighton,  Dreyfuss,  and  Krompecher.  From  the  study  of  this  group  of 
tumors  I  have  been  led  to  conclude  that  the  lacteal  ducts  produce  most  of 
the  low  papillary  and  glandular  adenocarcinomas  with  cuboidal  clear  cells, 
while  the  sweat-glands  give  rise  chiefly  to  papillary  and  villous  adenocar- 
cinomas with  cylindrical  cells  of  acidophile  character.  This  latter  group 
constitutes  a  well-defined  structural  group  of  mammary  carcinomas  charac- 
terized by  large,  strongly  acidophile  cells.  Many  of  them  take  the  form  of 
comedo  carcinoma  in  shrunken  breasts. 

Mucoid  carcinoma  is  usually  an  adenocarcinoma  with  mucous  degenera- 
tion of  stroma  or  cells  and  owes  its  slow  course  both  to  its  comparatively 
adenomatous  structure  and  to  the  mucoid  changes  in  its  stroma  which  greatly 
interfere  with  nutrition.  Gelatinous  changes  may  also  occur  in  the  stroma 
of  ordinary  duct  cancers.  The  mucoid  tumors  reach  the  largest  dimensions 
of  any  mammary  carcinomas  and  their  encapsulation  or  local  confinement 


FIG.  225. — Mammary  cancer.     Bulky  fungating  adenoma  malignum. 

may  be  maintained  for  several  years.  They  are  easily  recognized  by  their 
gelatinous  texture  and  large  bulk.  Doutrelepont's  case  was  bilateral.  These 
tumors  are  comparatively  rare.  Gaabe  collected  49  (1.66  per  cent.)  among 
2944  mammary  cancers  and  analyzed  in  detail  their  clinical  peculiarities. 

The  average  duration  before  operation  was  31.43  months,  as  compared 
with  13.28  months  with  ordinary  carcinoma.  Involvement  of  the  lymph- 
nodes  occurred  at  20  to  36  months,  of  skin,  36  to  54  months,  and  of  muscle, 
28  to  60  months,  all  about  three  times  as  long  as  the  periods  fixed  by  Guleke 
for  ordinary  carcinoma.  Late  metastases  constitute  a  striking  feature,  the 
average  period  being  40  months  (ordinary  cancer  13  months).  A  limitation 
of  metastases  to  the  thoracic  organs  is  often  observed.  In  3  cases  the  un- 
disturbed course  of  the  disease  was  n,  12,  and  14  years  (ordinary  cancer 
20  to  27  months).  The  duration  of  life  after  operation  was  5  years,  and  the 
recoveries  after  3  years  53.85  per  cent.,  as  compared  with  30.68  months  and 
28.79  Per  cent-  respectively  with  ordinary  breast  cancer. 

The  structure  shows  a  small  alveolar  carcinoma  or  adenocarcinoma  with 
33 


514 


NEOPLASTIC  DISEASES 


extensive  mutinous  degeneration.  The  mucinous  material  is  usually  found 
in  the  stroma,  while  the  epithelium  is  compressed  into,  small  islands  of  inactive 
cells.  Much  discussion  has  occurred  regarding  the  source  of  the  mucus. 
Its  usual  position  outside  of  and  surrounding  compact  groups  of  well-pre- 
served cells  is  not  in  accordance  with  an  epithelial  origin  and  has  not  been 
satisfactorily  explained  by  those  who  maintain  this  origin.  Lange  found  the 
source  of  the  material  exclusively  in  the  stroma.  Most  authors  trace  its 
origin  to  the  epithelium  with  subsequent  discharge  into  the  stroma  and  solu- 
tion of  epithelial  cells  (Cornil,  Ziegler,  Ribbert,  Zimmerman).  Kaufmann 
finds  that  both  elements  in  different  tumors  give  origin  to  the  mucus.  In 
4  cases  I  have  not  seen  mucous  degeneration  of  epithelium,  but  the  compact 
alveoli  lay  in  broad  areas  of  mucinous  stroma.  There  was  strong  evidence 
that  the  mucinous  change  had  involved  and  partly  originated  in  the  fat  tissue 


FIG.  226. — Mucoid  carcinoma  of  breast.    Mucoid  degeneration  of  stroma  and  fat  tissue. 

in  the  stroma.  In  another  case  of  adenomatous  structure  the  alveoli  were 
filled  with  mucus  as  described  by  Cornil.  There  are  thus  evidently  two  forms 
of  gelatinous  carcinoma  of  the  breast. 

The  causes  of  mucous  degeneration  are  obscure  and  the  origin  of  some  of 
the  tumors  is  uncertain.  The  long  initial  quiescent  period  observed  in  some 
cases  by  Lange  suggested  that  the  tumor  arose  through  transformation  of 
an  adenoma.  Elsasser  describes  a  mucoid  stroma  in  a  carcinomatous  fibro- 
adenoma.  One  of  my  cases  showed  the  usual  structure  of  duct  carcinoma 
with  large  groups  of  clear  polyhedral  cells  quite  isolated  in  gelatinous  stroma. 
The  metastases  are  not  always  gelatinous.  In  Walther's  case  they  appeared 
in  the  cicatrix  in  a  form  like  sago  grains. 

Duct  Carcinoma. — Carcinoma  arising  from  the  lining  cells  of  ducts 
produces  the  majority  of  mammary  cancers.  The  gross  anatomical  features 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  515 

of  this  group  are  very  variable,  and  the  stages  through  which  any  one  case 
passes  are  numerous,  so  that  these  tumors  are  difficult  to  classify.  Yet  two 
forms  of  duct  carcinoma  present  in  surgical  material  such  striking  gross 
anatomical  peculiarities  as  to  deserve  special  recognition.  These  are: 
(i)  Cicatrizing  comedo  carcinoma,  and  (2)  carcinoma  associated  with  diffuse 
chronic  productive  mastitis. 

(i)  The  typical  cicatrizing  comedo  carcinoma  presents  a  very  character- 
istic gross  appearance.  Usually  the  entire  breast  is  transformed  into  a  dense 
fibrous  tumor  mass,  smaller  than  the  original  organ,  involving  the  nipple  and 
often  the  overlying  skin,  which  are  firmly  fixed  to  the  deep  fascia  over  the 
muscle.  On  section  this  mass  is  marked  by  prominent  yellow  streaks  or 
spherical  points  which  are  ducts  filled  with  necrotic  detritus.  Although  the 
points  are  seldom  black,  this  lesion  recalls  the  pustules  of  acne. 

This  process  appears  to  begin  in  the  larger  ducts  and  extends  over  the 
entire  breast  by  gradual  invasion  through  the  ducts,  while  progressive  fibrosis 
draws  the  outlying  portions  of  the  organ  toward  the  central  area  beneath  the 


FlG.  227. — Mammary  cancer.     Advanced  carcinoma  simplex.     Retraction  of  nipple; 

dimpling  of  skin. 

/ 

nipple.  Earlier  stages  of  this  process  are  encountered  in  which  the  distended 
ducts  appear  over  a  very  wide  area,  and  even  in  the  various  prolongations 
of  the  breast  which  have  not  yet  been  drawn  together  by  any  cicatricial 
process.  Such  early  forms  of  comedo  carcinoma  are  difficult  to  recognize 
by  palpation,  since  the  breast  may  be  diffusely  swollen,  and  no  definite  re- 
sistant mass  can  be  detected.  Segmental  forms  of  comedo  carcinoma  also 
occur  in  which  only  a  portion  of  the  organ  is  involved.  The  final  form  of  the 
disease  depends  much  on  the  original  type  of  breast.  Small  compact  breasts 
yield  single  hard  tumor  masses  beneath  the  nipple,  while  widely  disseminated 
breasts  in  fat  subjects  produce  diffuse  ill-definied  tumors  of  larger  dimensions. 
In  all  forms  cicatrization  is  prominent.  . 

Paget's  disease  of  the  nipple  and  skin  is  sometimes  associated  with  typical 
comedo  carcinoma,  but  more  often  with  ordinary  duct  carcinoma. 

The  structure  of  comedo  carcinoma  presents  widened  ducts  lined  by  large 
flat  or  even  squamous-like  epithelial  cells,  and  filled  with  acidophile  necrotic 
material.  Lateral  sacculations  of  the  ducts  are  frequent  and  through  these 


516 


NEOPLASTIC  DISEASES 


the  tumor  cells  invade  the  lymphatics  of  the  cellular  connective  tissue,  dis- 
seminate throughout  the  breast,  and  early  reach  the  lymph-nodes. 

(2)  Carcinoma  arises  in  the  bulky  forms  of  chronic  productive  mastitis, 
usually  as  a  single  nodule,  but  often  in  multiple  foci.  This  combination 
produces  a  very  characteristic  gross  anatomical  form  of  the  disease  which  is 
not  easily  recognized  by  palpation.  The  breast  presents  a  solid  mass  of  firm 
elastic  connective  tissue,  of  large  or  occasionally  of  reduced  dimensions,  and 
in  it  are  found  one  or  more  areas  of  dense  fibrocarcinoma.  The  malignant 
process  arises  in  ducts  or  sweat-glands  which  are  early  broken  through  by 
groups  of  tumor-cells. 

The  clinical  recognition  of  this  group  of  cases  may  be  based  on  a  long 
history  of  chronic  mastitis  with  its  evident  physical  signs,  and  the  discovery 
of  one  or  more  particularly  resistant  nodules  among  the  more  elastic  areas 
of  the  indurated  breast.  Since  the  tumor  may  arise  in  any  portion  of  the 
breast,  fixation  of  nipple,  skin,  or  deep  fascia  is  accidental. 


FIG.  228. — Mammary  carcinoma. 


Diffuse  fibrocarcinoma  with  contraction  and  fixation 
of  breast. 


A  single  very  hard  nodule  in  an  otherwise  normal  breast  is  nearly  always 
carcinoma,  but  in  the  present  group  of  cases  the  hard  nodule  lies  in  rather 
dense  new  connective  tissue,  is  often  overlooked,  and  many  of  these  cases 
are  detected  only  after  amputation  of  the  breast  for  chronic  mastitis. 

(3)  Other  gross  anatomical  forms  of  duct  carcinoma,  including  those  aris- 
ing from  sweat-glands,  while  numerous,  are  less  well  defined  than  the  two 
groups  just  described  Among  them  may  be  mentioned: 

(a)  Single  nodules  of  carcinoma  in  fat  atrophic  breasts. 

(V)  Very  cellular  types  of  carcinojna,  in  which  the  breast  is  little  altered 
by  mastitis,  and  in  which  the  duct  carcinoma  develops  rapidly. 

(c)  Diffuse  anaplastic  carcinoma  developing  in  young  subjects  or  in  gesta- 
tion, enlarging  the  breast,  and  extending  widely  in  skin,  muscle,  and  lymph- 
nodes. 

The  structure  presents  marked  proliferation  of  the  lining  cells,  first  of  the 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  517 

larger,  then  of  smaller  ducts,  or  vice  versa.  The  walls  of  the  ducts  are  thick- 
ened, fibrous,  or  hyaline,  and  the  lumen  moderately  dilated.  Cysts  wider 
than  2  mm.  are  uncommon. 

The  form  and  arrangement  of  the  cells  vary  with  the  degree  of  malignancy, 
of  which  three  grades  may  be  considered  with  advantage : 

i.  Small  Cystic  Adeno carcinoma. — The  cells  are  cylindrical,  only  slightly 
atypical,  and  they  line  the  dilated  ducts  in  the  form  of  fusing  papillae  or  in  a 
solid  multiple  layer  in  which  secondary  alveoli  appear  at  regular  intervals. 
Wide  areas  of  such  cells  with  secondary  alveoli  appearing  at  regular  intervals 
may  form  in  dilated  ducts.  The  process  may  be  traced  from  the  nipple  to 
the  peripheral  lobules.  This  structure  constitutes  a  form  of  tubular  adeno- 
carcinoma. 

Tumors  of  this  type  are  of  slow  growth,  the  tumor-cells  long  remain  con- 
fined to  the  ducts  and  do  not  break  through  the  basement  membrane,  the 
lymph-nodes  are  usually  free  from  involvement,  and  extirpation  of  the  breast 


is  frequently  successful.  Unfortunately,  most  duct  carcinomas  are  more 
atypical  in  the  whole  or  in  portions  of  the  growth  and  the  tumor  falls  in  the 
next  subgroup. 

2.  Small  Cystic  Duct  Carcinoma. — The  alveoli  are  lined  by  stratified 
layers  of  atypical  overnourished,  large,  clear,  polyhedral  cells  resembling 
squamous  epithelium,  without  secondary  alveoli.  The  ducts  are  partly  or 
completely  filled  with  these  cells  and  with  homogeneous  detritus.  Many  of 
them  are  distended  and  ruptured  and  the  cells,  under  evident  signs  of  com- 
pression, are  found  in  all  stages  of  infiltration  of  the  stroma.  Many  lateral 
sacculi  form,  the  process  invades  the  intralobular  ducts  and  even  the  im- 
mature or  atrophic  acini,  and  the  whole  breast  may  become  transformed 
into  a  tubular  or  large  alveolar  carcinoma  in  which  the  prevailing  cell  is 
large,  clear,  and  polyhedral  or  squamous-like.  Very  varied  pictures  are 
produced  in  the  different  phases  of  these  tumors.  Some  are  very  cellular, 
plexiform,  or  show  broad  sheets  or  very  numerous  small  groups  of  clear  cells. 


518 


NEOPLASTIC  DISEASES 


Many  are  strongly  desmoplastic.  Some  present  areas  of  very  large  giant- 
cells.  Nearly  all  the  structures  commonly  designated  as  alveolar,  tubular, 
encephaloid,  simplex,  solid,  scirrhus,  and  small  cystic  carcinoma  may  be 
produced  in  the  established  forms  of  duct  carcinoma.  All  are  locally  aggres- 
sive, highly  invasive  of  lymph-  and  blood-vessels,  and  fully  malignant. 

3.  Fibrocarcinoma  arising  in  chronic  mastitis  presents  a  varying  structure 
chiefly  of  the  type  of  duct  carcinoma.  The  earliest  stages  include  the  lesions 
described  under  Chronic  Mastitis  as  precancerous  changes  or  miniature 
carcinomas  and  consist  in  single  ducts  or  groups  of  ducts  in  and  between 
the  lobules,  which  are  filled  with  atypical  overnourished  cubical  or  flat  cells. 
The  altered  acinar  epithelium  also  frequently  participates  in  these  early 
changes.  Soon  the  distended  ducts  rupture  and  groups  of  large  clear  cells 


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FIG.  230. — Mammary  cancer.     Primary  fibrocarcinoma  in  a  young  woman. 

infiltrate  the  lymphatic  spaces.  Marked  increase  of  connective  tissue  often 
richly  infiltrated  with  round  cells  accompanies  the  process,  and  it  is  this  excess 
of  fibrous  tissue  which  alters  the  gross  and  microscopical  features  of  ordinary 
duct  carcinoma  and  stamps  the  disease  with  peculiar  characters. 

Distinctly  fibrous  carcinomas  are,  as  a  rule,  less  malignant  than  the  cel- 
lular forms,  but  their  clinical  course  varies  greatly.  Some  take  the  course 
of  scirrhous  cancer  and  in  elderly  subjects  may  long  remain  localized.  In 
the  absence  of  a  notable  tumor  surgical  interference  is  often  long  delayed 
so  that  little  advantage  is  gained  from  the  slower  course.  In  a  well-known 
group  of  cases  there  is  a  relatively  small  mammary  tumor,  while  the  lymph- 
nodes  are  found  involved  by  a  very  cellular  growth. 

Duct  carcinoma,  originally  typical,  may  develop  anomalous  forms  which 
are  very  active,  diffuse,  sometimes  pseudosarcomatous,  and  highly  malig- 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


519 


nant.  In  the  case  previously  mentioned  in  pregnancy,  the  main  tumor  was 
composed  of  a  diffuse  growth  of  polyhedral  round  and  spindle-cells  which 
soon  disseminated  through  blood-  and  lymph- vessels.  In  other  cases  of 
diffuse  carcinoma  with  indifferent  rounded  or  spindle-cells  I  have  found  areas 
of  more  typical  plexiform  or  large  alveolar  carcinoma  with  large  clear  cells, 
indicating  an  origin  from  duct  epithelium. 

Histo genesis. — The  origin  of  this  form  of  mammary  carcinoma  has  been 
satisfactorily  traced  to  the  lining  cells  of  the  interlobular  ducts.  In  central 
tumors  lying  beneath  the  nipple  the  larger  ducts  are  especially  involved 


-*',r-    ^ 

*K  '  ^Vv       'i 


FIG.  231. — Mammary  cancer.     Sclerosing  fibrocarcinoma.     Typical  hard  scirrhus. 

and  the  lesion  may  extend  to  the  nipple  or  even  to  the  skin,  as  in  some  cases 
of  Paget's  disease.  The  lesion  also  extends  to  the  intralobular  ducts. 
That  the  acini  themselves  may  become  involved  and  contribute  to  the 
sources  of  these  tumors  is  indicated  by  minute  examination  of  early  cases. 
The  present  group  of  duct  carcinoma,  especially  the  fibrocarcinomas,  does 
not  therefore  arise  exclusively  from  duct  epithelium.  Yet  specific  acinar 
epithelium  is  very  scanty  in  the  lobules  of  many  cases  of  chronic  mastitis 
and  may  be  practically  absent  in  involuting  breasts  in  which  duct  carcinoma 
usually  develops.  The  intralobular  ducts,  on  the  other  hand,  persist  and 


520 


NEOPLASTIC  DISEASES 


widen  and  the  scanty  acinar  epithelium  assumes  the  morphology  of  duct 
tumor-cells. 

It  cannot,  I  think,  be  denied  that  the  minute  analysis  of  these  lesions 
indicates  a  gradual  diffusion  of  the  cancer  process  over  adjoining  lobules 
until  at  least  the  focus  of  origin  reaches  considerable  dimensions,  after  which 
the  tumor  progresses  from  its  own  resources.  Every  portion  of  the  organ 
may  be  completely  invaded  without  demonstrable  increase  in  size.  Nadal 


?* 

FIG.  232. — Mammary  cancer.    Large  and  small  alveolar  carcinoma.    Sweat-gland  type. 

traces  the  origin  of  such  diffuse  forms  of  the  disease  and  concludes  that  the 
neoplastic  process  may  originate  from  all  portions  of  the  breast. 

The  aberrant  sweat-glands  of  the  breast  give  rise  to  tumors  which  may 
be  difficult  to  distinguish  from  true  duct  carcinoma.  The  separation  is 
especially  difficult  between  different  cases  of  comedo  cancer,  many  of  which 
arise  from  the  sweat-glands.  As  a  rule,  the  cells  of  the  duct  carcinoma  are 
clear  and  as  they  become  more  atypical  the  cytoplasm  becomes  less  promi- 
nent. The  cells  of  the  sweat-gland  tumors  are  large  and  the  cytoplasm  is 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  521 

opaque  and  strongly  acidophile,  while  these  features  tend  to  persist  in  exten- 
sions and  metastases. 

The  present  classification  of  duct  carcinomas  somewhat  enlarges  the 
scope  of  this  group  as  recognized  by  some  authors.  It  includes  especially 
the  tubular  and  some  acinar  carcinomas  of  Cornil  and  others.  It  is  impos- 
sible to  claim  that  every  tubular  carcinoma  originates  from  ducts,  yet  many 
such  growths  are  certainly  of  this  origin,  while  their  development  from  true 
acinar  epithelium  is  less  certain.  The  cell  characters  are  of  much  importance 
in  the  diagnosis,  and  wherever  the  cells  are  large  and  clear,  of  polyhedral 
form  and  mosaic  arrangement,  an  origin  from  ducts  is  indicated.  An  exclusive 
origin  from  ducts  or  acini  is  not  always  to  be  assumed.  In  cellular  duct  can- 
cers the  acinar  epithelium  may  be  involved  and  in  many  acinar  tumors  the 
duct  epithelium,  as  Cornil  points  out,  shows  various  phases  of  malignant 
proliferation.  Under  these  conditions  the  tumor  must  be  classified  according 
to  its  predominant  features. 

Acinar  Carcinoma. — Although  the  earlier  observers,  as  Waldeyer  and 
Langhans,  traced  certain  mammary  carcinomas  to  the  acinar  epithelium, 
minute  distinctions  were  not  at  first  attempted  between  intralobular  ducts 
and  acini.  In  1865  Cornil  described  in  detail  the  cancerous  transformation 
of  acinar  epithelium,  and  his  views  were  elaborated  by  Cornil  and  Ranvier, 
and  lately  by  Cornil  in  his  work  on  tumors  of  the  breast.  Many  of  the  struc- 
tures interpreted  by  Cornil  as  demonstrating  the  acinar  origin  are  of  some- 
what uncertain  significance  and,  as  Lecene  and  Lenormant  conclude,  may 
equally  well  be  regarded  as  the  invasion  of  acini  by  tumor-cells  from  other 
sources.  In  the  previous  discussion  of  the  histogenesis  of  duct  carcinoma 
it  has  been  pointed  out  that  the  acini  often  contribute  to  the  origin  of  tumors 
which  are  chiefly  derived  from  the  ducts.  Such  tumors  are  here  classified 
with  duct  carcinoma. 

There  are,  however,  mammary  carcinomas  which  are  derived  chiefly  or 
exclusively  from  the  acinar  epithelium,  and  such  growths  may  be  separated 
from  the  duct  carcinomas  and  included  in  the  present  group.  They  occur 
under  several  different  conditions,  but  their  total  number  is  distinctly  less 
than  that  of  the  duct  carcinomas.  Acinar  carcinoma  in  this  restricted  sense 
develops  in  the  malignant  transformation  of  fibro-adenoma,  it  occurs  in 
rare  cases  of  small  alveolar  carcinoma,  and  it  produces  a  type  of  fibro- 
carcinoma.  These  tumors  are  characterized  in  general  by  a  diffuse  growth 
and  lack  of  encapsulation,  by  absence  of  the  specific  gross  features  of  many 
duct  cancers,  by  a  structure  in  which  small  alveoli  predominate,  while  the 
cells  are  usually  small,  and  lack  the  pavement  form  and  clear  cytoplasm 
of  the  duct  epithelium.  Rarely  they  suffer  mucoid  degeneration  of  the 
stroma. 

(a)  Acinar  Carcinoma  Following  Fibro-ad.enoma. — While  the  malignant 
transformation  of  intracystic  adenoma  is  frequently  observed  and  forms  a 
well-defined  group  of  mammary  adenocarcinomas,  the  development  of  a 
malignant  epithelial  tumor  from  fibro-adenoma  is  rare.  Diffuse  adeno- 
matous  hypertrophy  of  the  breast  is  said  to  have  terminated  in  adenocarci- 
noma  in  cases  described  by  Billroth  and  by  Aitken. 

The  common  fibro-adenoma  appears  to  have  developed  carcinoma  in  a 
few  authentic  instances.  Birch-Hirschfeld  regarded  the  transformation  as 
not  infiequent,  but  specific,  and  detailed  reports  are  rare.  Langhans  de- 
scribed a  bilobed  tumor,  one  portion  of  which  was  fibro-adenoma  and  the 
other  scirrhous  cancer.  Elsasser  studied  two  large  fibro-adenomas  with  small 
cysts  and  single  well-defined  masses  of  carcinoma.  One  of  the  tumors  had 
the  structure  of  small  alveolar  acinar  carcinoma,  the  other  was  very  vascular, 


522  NEOPLASTIC  DISEASES 

pigmented,  the  stroma  mucinous,  and  both  ducts  and  acini  contributed  to 
the  growth.  J.  Miiller  describes  multiple  areas  of  carcinoma  in  a  fibro- 
adenoma.  Many  new  acini  filled  with  atypical  cells  and  diffuse  invasion 
of  the  connective  tissue  appeared  in  these  foci.  Kuru  described  a  large 
elastic  tumor,  14  X  9  cm.,  in  one  portion  of  which  was  a  hard  area.  Here 
the  alveoli  were  much  increased  in  number  and  filled  with  atypical  cells, 
giving  the  appearance  of  carcinoma  medullare  solidum.  This  observation 
does  not  support  Borst's  view  that  the  carcinoma  develops  not  from  the 
fibro-adenoma,  but  from  another  misplaced  embryonal  tissue  mass.  I  have 
encountered  several  moderately  malignant  mammary  carcinomas  which 
appeared  to  have  been  derived  from  fibre-adenomas.  They  contained 
considerable  cellular  connective  tissue  and  many  small  alveoli,  with  or 
without  lumen,  lined  by  atypical  cuboidal  epithelium.  In  a  recent  case  the 
tumor  had  the  gross  appearance  of  an  encapsulated  fibroma,  but  with  fatty 
points  of  carcinomatous  epithelium.  In  most  of  these  tumors  the  structure 
suggests  an  acinar  origin,  and  this  origin  is  accepted  by  the  authors,  but  in 
some  both  ducts  and  acini  appear  to  have  been  involved.  The  usual  history 
indicates  that  a  slowly  growing  fibro-adenoma  existed  for  some  years  and 
eventually  grew  much  more  rapidly  with  the  onset  of  malignant  changes. 
The  malignancy  has  been  moderate. 

(b)  Primary  Acinar  Carcinoma. — Although  Cornil  and  others  have  traced 
the  development  of  many  common  mammary  cancers  to  the  acinar  epithe- 
lium, reasons  have  been  advanced  to  show  that  the  majority  of  the  tubular 
and  small  alveolar  tumors  are  forms  of  duct  cancer  or  are  derived  chiefly 
from  the  ducts,  while  the  acini  are  subsequently  invaded  by  the  tumor-cells  or 
contribute  only  secondarily  or  to  a  slight  degree  to  the  neoplasm.  The 
present  group  includes  tumors  of  a  peculiar  and  specific  histology  which 
is  rarely  observed. 

In  one  form  this  tumor  is  partly  circumscribed,  rather  soft,  vascular, 
and  solid.  The  structure  presents  a  very  large  number  of  extremely  small 
cell  groups  or  acini  lined  by  small  atypical  epithelium. 

In  another  form  which  Cornil  has  described  there  is  an  extensive  mul- 
tiplication of  the  acini  in  rather  well-defined  lobules.  The  lumen  is  long 
retained,  but  the  cells  are  small  cuboidal  and  atypical  and  a  disordered  growth 
may  extend  beyond  the  lobules.  The  structure  somewhat  resembles  the 
lactating  breast.  No  signs  of  proliferation  of  duct  epithelium  are  observed. 
Rarely  the  cells  are  extremely  small,  the  acini  imperfectly  formed,  and  the 
structure  resembles  an  embryonal  alveolar  sarcoma. 

All  these  tumors  show  limited  malignancy,  especially  in  the  early  stages, 
but  when  fully  established  they  invade  the  lymph-nodes  and  pursue  the 
usual  course  of  advanced  carcinoma. 

C.  Fibrous  Acinar  Carcinoma. — In  some  cases  of  productive  mastitis 
and  possibly  in  otherwise  unaltered  breasts  the  acinar  epithelium  may  give 
rise  to  a  malignant  form  of  scirrhus  or  fibrocarcinoma.  The  structure  is 
highly  characteristic.  About  the  unaltered  larger  and  the  intralobular  ducts 
the  acini  become  increased  in  number  and  break  up  into  many  small  groups 
of  atypical  cells  with  hyperchromatic  nuclei.  The  connective  tissue  is  much 
increased  and  soon  becomes  fibrous,  while  the  tumor  cells  are  compressed 
into  narrow  rows  or  small  groups.  Many  cases  of  primary  scirrhous  cancer 
develop  in  this  manner.  The  process  is  fully  malignant. 

Gross  Anatomical  Diagnosis  of  Mammary  Carcinoma. — In  no  department 
of  surgery  is  familiarity  with  gross  anatomical  diagnosis  of  greater  service 
than  in  dealing  with  mammary  tumors.  Moreover,  the  great  majority  of 
mammary  cancers  are  rather  easily  recognizable  by  inspection  and  palpation, 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  523 

and  microscopic  examination,  especially  by  frozen  section,  may  usually  be 
dispensed  with  or  reserved  for  later  study. 

A  single  very  hard  nodule,  with  restricted  mobility,  in  an  otherwise  un- 
altered breast  is  nearly  always  carcinoma.  Cysts  and  fibromas  may  be 
very  firm,  but  they  are  elastic  and  quite  mobile  in  the  breast.  Trauma  from 
blows  or  from  hypodermic  injections  may  produce  cicatricial  masses  which 
increase  in  size,  restrict  the  skin  and  breast,  and  are  very  difficult  to  distinguish 
on  clinical  examination  from  carcinoma.  On  gross  section  they  fail  to  show 
the  specific  characters  of  carcinoma. 

Marked  induration  and  restricted  mobility  characterize  nearly  all  forms 
of  established  carcinoma  in  which  there  is  a  well-marked  tumor,  but  there 
are  diffuse  forms  of  carcinoma  without  tumor,  and  carcinoma  may  begin  in 
the  walls  of  cysts.  Single  or  multiple  nodules  of  carcinoma  in  cases  of  chronic 
mastitis  cannot  often  be  recognized  positively  by  clinical  examination. 

With  the  excised  breast  or  nodule  presented  for  examination,  the  char- 
acters of  carcinomatous  tissue  are  usually  specific.  Chief  among  these  is  the 
cicatricial  appearance  of  the  nodule,  which  may  present  an  opaque  well- 
defined  central  area  surrounded  by  fine  radiating  strands  of  connective  tissue. 
On  close  inspection,  with  or  without  a  hand  glass,  one  detects  yellowish  chalky 
points  and  streaks  in  the  translucent  connective  tissue,  which  occur  only  in 
carcinoma.  In  many  duct  carcinomas  these  chalky  streaks  are  large  and 
prominent.  They  are  produced  by  fatty  degeneration  or  desquamation  of 
tumor-cells.  Even  in  diffuse  carcinoma  without  tumor  formation  the  chalky 
points  are  visible.  When  dealing  with  a  bulky  mass  of  tissue,  such  as  a  breast 
excised  for  chronic  mastitis,  it  is  obvious  that  the  examiner  must  rely  on 
gross  features  to  pick  out  any  suspicious  areas  for  section,  and  that  unless 
one  is  familiar  with  the  gross  appearance  of  carcinoma  small  foci  may  be 
overlooked  even  although  many  sections  are  made. 

Small  areas  of  carcinoma  located  in  the  walls  of  cysts  require  careful 
sectioning  of  all  thickened  points  in  the  wall,  but  when  present  any  carci- 
nomatous focus  will  again  present  the  opaque  texture  and  chalky  points. 

After  trauma  of  various  sorts  cicatricial  processes  develop  in  the  breast, 
and  these  often  involve  much  fat  tissue  which  becomes  opaque  and  indurated, 
or  in  certain  cases,  described  by  Lee  and  Adair,  extensively  necrotic.  Yet 
such  lesions  fail  to  exhibit  the  chalky  points  and  other  positive  features  of 
carcinoma. 

The  writer  has  encountered  solid  adenocarcinoma  filling  small  cysts  which 
did  not  show  a  cicatricial  character  or  chalky  points,  but  had  to  be  identified 
on  the  opaque  solid  texture  of  a  cellular  tumor. 

In  certain  cases  it  would  appear  that  the  gross  diagnosis  of  carcinoma 
of  the  breast  is  a  safer  guide  to  surgical  procedure  than  the  discovery  by  the 
microscope  of  questionable  minute  points  of  precancerous  changes  concern- 
ing which  doubts  and  differences  of  opinion  are  so  frequently  expressed. 
When  a  suspicious  focus  is  so  small  that  it  cannot  be  detected  by  the  trained 
naked  eye  it  is  doubtful  if  a  diagnosis  of  carcinoma  in  the  clinical  sense  is 
justified. 

Modes  of  Extension. — i.  In  the  Breast. — Extension  in  the  mammary 
parenchyma  must  be  interpreted  in  some  cases  as  a  local  evolution  of  the 
tumor;  in  other  cases  as  a  local  dissemination.  Some  acinar  and  many  duct 
cancers  arising  at  one  focus  gradually  extend  over  adjoining  areas  by  a  gradual 
transformation  of  normal  duct  and  acinar  epithelium  into  neoplastic  cells. 
The  whole  organ  may  thus  be  found  to  be  cancerous  while  only  slightly 
increased  in  size.  Long  segments  of  ducts  may  show  many  grades  of  epithe- 
lial proliferation  without  filling  of  the  lumen  by  growth  from  a  distance. 


524 


NEOPLASTIC  DISEASES 


Extension  through  the  ducts  also  occurs  in  several  forms  of  the  disease,  but 
not  to  the  extent  observed  in  the  first-named  process  (Nadal).  Perforation 
of  ducts  by  cells  traveling  in  lymphatics  has  been  demonstrated  by  Gold- 
mann.  The  chief  mode  of  extension  is  undoubtedly  through  the  lymphatics 
of  the  breast,  by  cells  which  have  broken  into  lymph-spaces  and  artificial 
clefts,  and  this  method  is  almost  exclusively  followed  by  highly  malignant 
tumors,  fibrocarcinoma,  acinar  carcinoma,  and  adenocarcinoma.  The  stage 
of  growth  at  which  extension  begins  as  well  as  the  early  paths  pursued  vary 
widely  with  the  character  of  the  growth,  which  is  therefore  the  chief  index 
of  malignancy.  At  one  extreme  stands  the  encapsulated  adenocarcinoma, 
at  the  other  the  locally  invasive  forms  of  duct  carcinoma. 

Rapid  local  extension  may  be  accompanied  by  signs  of  inflammation, 
as  in  the  mastitis  carcinomatosa  of  pregnancy.  On  the  other  hand,  the  whole 
organ  may  be  invaded  without  attracting  the  patient's  attention. 


FIG.  233. — Mammary  cancer.  Fibrocarcinoma.  Reduction  in  size  of  breast;  re- 
traction and  elevation  of  nipple;  retraction  of  skin  about  nipple;  invasion  of  axillary  and 
supraclavicular  nodes. 


The  effects  of  local  extension  are  usually  cicatricial  changes  in  the  affected 
tissue,  which  is  the  most  reliable  sign  of  the  presence  of  carcinoma,  or  increase 
in  the  size  of  the  part,  which  may  be  local  or  diffuse.  Handley  attributes  the 
effects  largely  to  a  sclerosing  perilymphangitis  which  follows  the  permeation 
through  lymphatics,  and  to  this  condition  he  attributes  the  retraction  of  the 
nipple  and  fixation  of  the  skin.  There  is  also  the  desmoplastic  property  of 
the  cancer  process  which  is  not  connected  with  lymphangitis  and  which  pro- 
duces cicatrizing  effects  beyond  the  zone  of  invasion. 

The  condition  of  the  unaffected  portions  of  the  breast  varies  widely,  but 
is  almost  never  normal.  The  most  distant  portions  usually  show  diffuse 
or  cystic  mastitis  with  periacinar  infiltration,  and  overnutrition  or  prolifera- 
tion of  epithelium  (Waldeyer,  Leopold).  Very  small  tumors  beneath  the 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  525 

nipple  or  in  any  segment  may  involve  all  the  breast  tissue  that  can  be  found, 
suggesting  either  a  congenital  hypoplasia  or  an  extreme  grade  of  involution. 
On  the  other  hand,  outlying  lobes  not  previously  noticeable  may  become 
indurated,  as  the  sternal  prolongation  of  Rieffel,  the  axillary  lobe  of  Kermis- 
son,  and  the  xiphoid  appendix  of  Zocher  and  Hennig.  Each  of  these  lobes 
may  be  the  seat  of  carcinoma.  In  some  cases  I  have  found  tumors  originating 
in  these  lobes  atypical  in  structure  and  relatively  malignant. 

2.  Invasion  of  Skin. — The  chief  mode  of  extension  to  the  skin  is  by  way 
of  the  subpapillary  lymphatic  plexus  from  the  periductal  lymphatics.  Hence 
extensive  cutaneous  cancer  of  the  breast  is  observed  in  central  duct  cancers 
which  early  reach  the  nipple.  In  such  cases  the  derma  is  infiltrated  by 
nodules  and  masses,  discrete  or  diffuse,  encroaching  more  and  more  upon  the 
subcutaneous  fat  tissue.  The  area  of  skin  thus  involved  may  be  much 
wider  than  the  underlying  tumor.  Many  of  the  wide-spread  cancers  "en 
cuirasse"  involving  the  skin  of  the  entire  thorax  originate  in  this  way.  Very 
extensive  pustular  and  ulcerating  lesions  of  the  skin  involving  much  of  the 
trunk  are  described  by  Handley  as  illustrating  an  extreme  grade  of  lymphatic 
permeation,  not  through  the  dermal,  but  by  way  of  the  deep  aponeurotic 
plexus. 

A  second  mode  of  skin  invasion  is  through  the  lymphatics  of  Cooper's 
ligaments  which  join  the  subcutaneous  lymphatics  from  the  outer  surface  of 
the  breast.  These  ligaments  connect  outlying  tooth-like  projections  of  gland 
tissue  with  the  derma  and  are  markedly  developed  in  many  subjects  (Stiles). 
Invasion  of  this  type  causes  dimpling,  retraction,  corrugation,  and  fixation 
of  the  skin,  without  marked  thickening. 

A  third  mode  of  invasion  of  the  skin  consists  in  the  destruction  of  the 
epidermis  by  carcinoma.  This  process  may  begin  at  the  nipple  by  a  con- 
tinuation of  the  lesion  in  the  ducts  as  in  Paget's  disease.  Or  extensions  from 
below  may  traverse  the  derma  and  lead  to  erosion  and  ulceration  of  the  epi- 
dermis. Early  perforation  and  extensive  ulceration  of  a  fungating  type  belong 
to  the  adenocarcinomas. 

Active  superficial  extension  through  dermal  lymphatics  may  be  accom- 
panied by  hyperemia  and  reddening  of  the  skin.  Rarely  a  vesicular  erup- 
tion accompanies  the  erythema.  It  has  been  attributed  to  dilatation  of  the 
subpapillary  lymphatics. 

Cancer  en  cuirasse  is  a  term  applied  by  Velpeau  to  a  remarkably  extensive 
cancerous  invasion  and  thickening  of  the  skin  and  subcutaneous  tissues. 
He  described  the  condition  as  involving  the  thorax,  neck,  arms,  and  trunk 
down  to  the  umbilicus,  the  skin  being  greatly  thickened,  very  hard,  and  over 
the  chest  thickly  sown  with  scirrhous  ulcers  and  nodules.  The  rigidity  of  the 
tissue  greatly  interfered  with  movement  of  the  limbs  and  with  respiration. 
Erichsen  describes  also  a  brownish  discoloration,  formation  of  desquamating 
crusts  resembling  the  bark  of  a  tree,  but  without  ulceration.  Handley  ap- 
plies the  term  to  a  condition  of  elephantiasis  best  seen  in  cases  of  extensive 
edema  of  the  arm  in  which  there  is  no  definite  carcinomatous  invasion,  and  he 
interprets  the  process  as  the  result  of  perilymphatic  fibrosis  in  the  deep  fascial 
plexus.  In  many  cases,  however,  there  is  diffuse  cancerous  infiltration  from 
the  epidermis  to  and  even  through  the  chest  wall.  Simple  edema  or  elephan- 
tiasis may  precede  or  accompany  the  cancerous  process. 

Dissemination. — Lymphatics  of  the  Breast. — The  knowledge  of  the  impor- 
tant lymphatics  of  the  breast  in  relation  to  cancer  is  based  on  anatomical 
studies  of  Sappey,  Gerota,  Grossman,  Bartels,  and  others,  and  the  clinical 
and  pathological  observations  -of  Heidenhain,  Oelsner,  Stiles,  Handley,  and 
others. 


526 


NEOPLASTIC  DISEASES 


The  subpapillary  plexus  is  a  rich  network  encircling  the  dermal  papillae  and  is  par- 
ticularly well  developed  at  the  areola.  It  is  limited  at  the  level  of  junction  of  the  super- 
ficial and  middle  thirds  of  the  derma.  From  this  plexus  vessels  run  vertically  communi- 
cating with  those  of  the  breast,  over  the  organ,  and  with  the  deep  fascial  plexus  elsewhere. 

The  fascial  plexus  lies  just  below  the  subcutaneous  fat  and  is  the  main  channel  of 
dissemination  of  cancer.  This  entire  plexus  is  divisible  into  three  thoracic  regions,  by 
the  median  line,  the  clavicles,  and  a  line  running  through  the  umbilicus,  along  which 
the  main  trunks  are  interrupted  by  five  branches  capable  of  arresting  cell  emboli 
(Handley). 

Yet  Oelsner  found  in  2  of  9  cases  large  trunks  in  the  fascial  plexus  connecting 
the  mammary  region  with  the  opposite  axillary  nodes.  Tumors  of  the  internal  segment 


FIG.  234. — General  plan  of  cervical  and  axillary  lymphatic  system. 

and  Beau.} 


(After  Bonamy 


of  the  breast  are  in  the  most  favorable  location  for  extension  to  the  opposite  axillary 
nodes,  as  in  Volkmann's  case  (Billroth).  Riefel  found  that  mercury  injected  into  the 
skin  of  this  quadrant  passed  into  the  opposite  axillary  nodes.  Such  crossed  metastases 
are  rare  in  early  cases  (i  per  cent.),  but  more  frequent  in  advanced  cases  (7  per  cent.) 
(Handley),  while  at  autopsy  Williams  observed  them  in  10  of  44  cases. 

The  lymphatics  draining  the  breast  belong  in  this  system.  Fine  lymph-spaces  are 
found  in  the  intralobular  connective  tissue,  but  the  first  definite  vessels  or  sinuses  demon- 
strable by  injection  encircle  the  lobules  (Waldeyer).  They  unite  to  form  the  main 
efferent  trunks  which  pass  in  several  directions. 

(a)  Axillary  trunks,  usually  two,  pass  from  the  outer  upper  and  under  segments, 
along  the  border  of  the  pectoralis  major  to  the  axillary  nodes.  One  or  two  nodes, 
Sorgius'  group,  may  be  interposed  at  the  third  digitation  of  the  serratus  muscle.  A 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


527 


paramammary  trunk  and  node  may  also  exist  at  the  edge  of  the  pectoral  in  the  anterior 
axillary  line,  at  the  fourth  intercostal  space. 

The  axillary  trunks  are  the  chief  channel  of  dissemination.  They  are  especially  in- 
volved from  tumors  in  the  upper  outer  quadrant  of  the  breast,  which  is  the  most  fre- 
quent location  of  carcinoma,  and  they  are  commonly  invaded  by  all  tumors  which  have 
extended  through  the  breast  tissue. 

They  are  reached  not  only  by  the  main  axillary  trunks,  but  through  anastomoses 
with  the  subpectoral  and  infraclavicular  groups  which  drain  the  intermuscular  trunks 
passing  from  the  under  surface  of  the  breast  through  the  pectoral  muscle  (Hyrtl,  Gross- 
mann).  By  the  latter  route  the  nodes  at  the  extreme  apex  of  the  axilla  may  be  involved 
while  the  lower  superficial  axillary  nodes  escape  (Stiles).  Deep  axillary  nodes  lie  along 
the  external  mammary  artery  and  the  nerve  of  the  serratus  magnus,  and  these  connect 
freely  with  the  humeral  chain  accompanying  the  axillary  vein  and  with  the  subscapular 
nodes.  These  three  groups  are  frequently  the  seat  of  recurrences. 


FIG.  235.— Multiple  recent  tumor-cell  emboli  in  the  sinuses  of  an  axillary  lymph-node. 
From  a  case  of  mammary  cancer  which  had  been  roughly  manipulated  before  operation. 

The  number  and  position  of  the  axillary  nodes  are  subject  to  variations.  All  stages 
of  the  development  of  new  nodes  in  cases  of  mammary  cancer  are  described  by  Fage. 
The  number  varies  also  with  the  physiological  state  of  the  breast.  On  the  other  hand, 
fat  invasion  and  atrophy  of  the  nodes  is  frequently  observed  and  influences  the  spread 
of  the  disease.  Those  usually  present  may  be  grouped  as  follows:  (i)  Pectoral  group, 
on  inner  wall  of  thorax,  in  angle  between  pectoral  muscles  and  serratus  magnus,  drain- 
ing breast  and  front  of  chest;  (2)  humeral  group,  lying  on  axillary  vessels  and  draining 
the  arm.  The  highest  of  these  (subclavian)  lie  in  Mohrenheim's  space  behind  the  costo- 
coracoid  membrane;  (3)  subscapular  group  along  subscapular  vessels  on  the  posterior 
wall  of  the  axilla. 

The  close  apposition  of  many  of  these  nodes  to  veins  and  nerves  favors  early  invasion 
of  the  lumen  of  veins  and  the  sheaths  of  nerves.  It  is  chiefly  from  such  secondary  foci 
that  the  lumen  of  veins  is  reached  in  mammary  carcinoma.  The  significance  of  this 
event  in  the  generalization  of  the  disease  is  not  clear,  but  it  does  not  always  lead  to 
immediate  wide-spread  metastases.  The  sheaths  of  nerve-trunks  are  readily  invaded, 
with  pain  and  degeneration  of  fibers,  and  within  the  lamellar  sheaths  tumor-cells  may 
permeate  long  distances  (Mousseau). 


528  NEOPLASTIC  DISEASES 

(b)  Intermuscular  trunks  pass  from  the  under  surface  of  the  breast  in  the  pectoral 
fascia  and  over  and  through  the  pectoral  muscle  leading  to  nodes  lying  between  the 
pectoralis  major  and  minor  or  to  infraclavicular  nodes.    Between  the  axillary  and  infra- 
clavicular  nodes  there  are  limited  communications,  but  between  the  infra-  and  supra- 
clavicular  nodes  the  connections  are  free  so  that  both  groups  are  usually  involved  to- 
gether.    Exceptions  in  which  the  nodes  above  the  clavicle  are  involved,  while  those 
below  are  free,  Grossmann  refers  to  extension  from  the  axillary  nodes  by  way  of  the 
brachial  lymph-plexus.    Since  the  brachial  plexus  often  communicates  with  the  cervical 
vessels,  the  cervical  and  supraclavicular  nodes  are  often  involved  together.     In  these 
cases  a  cancerous  node  of  the  supraclavicular  group  is  often  found  at  the  inner  end  of 
the  clavicle  in  close  contact  with  the  thoracic  duct  which  is  easily  ruptured  on  removal 
of  the  node. 

(c)  Intercostal  lymphatics  pass  from  the  inner  and  under  segments  of  the  breast 
through  the  pectoralis  and  intercostal  muscles  to  the  sternal  nodes  lying  behind  the 
sternum  in  the  parasternal  line.     Stiles  found  these  vessels  invaded  by  carcinoma,  and 
Oelsner  was  able  to  inject  them  in  the  first  and  fourth  intercostal  spaces.     Extensions 
also  pass  into  the  thorax  along  the  intercostal  nerves. 

The  importance  of  the  intermuscular  trunks  in  the  dissemination  of  carcinoma  was 
pointed  out  by  Heidenhain  and  confirmed  by  Rotter,  Grossmann,  and  others,  and  forms 
the  ground  for  excision  of  the  pectoral  muscle.  Rotter  in  15  of  33  operable  cases,  sev- 
eral of  which  were  early,  and  only  5  adherent  to  the  muscle,  found  invaded  lymph- 
nodes  beneath  the  pectoralis  major.  The  remarkably  close  apposition  of  the  breast  to 
the  pectoral  muscle,  especially  in  cases  of  chronic  mastitis,  facilitates  early  invasion  of 
these  deep  trunks.  Moreover,  Heidenhain  found  islands  of  gland  tissue  within  the 
muscle.  Yet  actual  invasion  of  the  muscle  is  not  frequent.  Heidenhain,  who  found  the 
pectoral  fascia  involved  in  12  of  18  cases,  observed  growth  I  mm.  within  the  muscle 
only  once.  Hence  many  operators  deem  it  sufficient  to  remove  the  pectoral  fascia 
without  sacrificing  the  muscle  (Van verts).  Invasion  of  the  pectoral  fascia  occurs  with- 
out fixation  of  the  breast,  but  when  the  organ  is  adherent  to  the  muscle  the  latter  is 
usually  invaded  by  fine  nodules  or  diffuse  cicatrizing  carcinoma.  In  advanced  cases 
such  invasion  of  the  muscle  is  often  observed.  Yet  Hardouin  found  recurrence  within 
the  pectoral  after  operation  on  an  early  case,  and  Cabot  reports  recurrence  in  the 
pectoral  alone  after  removal  of  a  small  central  carcinoma.  Such  experience  must  be 
rare.  Nadal  describes  miliary  carcinosis  of  the  pectoral. 

It  is  obvious  that  no  uniform  rule  can  apply  to  the  treatment  of  the  muscle  and  that 
an  effort  should  be  made  to  determine  its  condition  from  all  the  data  in  the  case.  Since 
the  subpectoral  nodes  are  involved  in  some  comparatively  early  cases  and  the  muscle 
tissue  usually  escapes  even  in  advanced  conditions,  the  attack  should  be  on  the  nodes 
and  fascia  rather  than  on  the  muscle.  The  question  of  continuous  permeation  through 
the  muscle  must  also  be  considered,  but  is  rarely  demonstrated. 

In  a  recent  study  of  the  breasts  of  100  infants  up  to  2\  years  Mornard  finds  several 
types  of  lymphatic  distribution : 

1.  In  25  per  cent,  of  cases  the  lymphatics  carrying  off  methylene-blue  injected  into 
the  breast  pass  along  the  lower  border  of  pectoralis  major,  under  that  muscle  to  central 
axillary  trunks,  meeting  nodes  on  axillary  vein  which  communicate  readily  with  sub- 
clavicular  nodes. 

2.  In  12  per  cent,  of  cases  a  trunk  passes  from  the  above  to  humeral  nodes  at  the 
insertion  of  the  tendon  of  the  pectoralis. 

3.  In  54  per  cent,  of  cases  there  is  a  double  set  of  axillary  trunks:  (a)  Same  as  above. 
(b)  Superior  external  trunk  passes  beneath  pectoralis  minor  near  its  costal  insertion, 
to  subclavicular  nodes.    They  do  not  penetrate  the  muscle. 

4.  The  above  main  trunks  may  pass  between  the  pectoralis  major  and  minor. 

5.  Three  cases  showed  a  deep  trunk  passing  beneath  muscles  directly  to  supra- 
clavicular  nodes. 

6.  In  10  per  cent,  of  cases  the  injection  passed  from  the  inner  quadrant  along  the 
internal  mammary  artery  reaching  nodes  in  second  or  third  interspace. 

In  no  case  were  any  lymphatics  found  perforating  muscle. 

Generalization. — After  reaching  the  axillary  nodes  and  the  muscular 
aponeuroses,  mammary  cancer  usually  becomes  generalized  and  nearly  any 
tissue  in  the  body  may  become  involved.  The  location  and  course  of  the 
metastases  present  some  of  the  most  remarkable  features  of  the  disease,  which 
have  called  for  very  searching  analysis. 

Gross,  from  423  autopsies,  placed  the  organs  in  the  frequency  of  involve- 
ment in  the  order:  pleura,  50.9  per  cent.;  lungs,  49.9;  liver,  48.6;  bones,  20.5; 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  529 

brain,  9.4;  ovary,  8;  opposite  breast,  7.8;  dura  mater,  5.9;  kidneys,  retro- 
peritoneal  nodes,  and  uterus,  5.7  to  5.2,  other  organs,  less  than  5  per  cent. 
Pearce  Gould  in  128  autopsies  found  the  nodes  involved  in  115,  the  liver  in 
55,  the  lungs,  excluding  pleura,  in  28.  Williams,  also  excluding  pleural  ex- 
tensions, finds  the  liver  more  frequently  invaded  than  the  lungs,  but  the 
grounds  for  such  exclusion  may  be  questioned.  In  2534  mammary  cases 
collected  from  Gross,  Colwell,  Paget,  Handley,  Gould,  and  Torok  the  liver 
was  invaded  in  928,  or  36.6  per  cent.  Torok  and  Wittelshofer,  finding  in 
366  autopsies  191  free  from  enlarged  nodes,  among  which  62  per  cent,  had 
metastases,  concluded  that  failure  of  axillary  invasion  is  no  guarantee  against 
internal  metastases.  Yet  they  did  not  examine  all  the  nodes  microscopically. 
Handley  reports  2  cases  of  abdominal  metastases  without  axillary  invasion. 

The  pleura  is  invaded  by  (i)  fine  lymphatics  which  pass  from  the  pectoral 
fascia  straight  through  to  the  subpleural  lymphatics  and  (2)  from  the  sternal 
and  anterior  or  deep  mediastinal  nodes.  The  latter  route  is  uncommon,  as 
Torok  and  Wittelshofer  in  366  autopsies  found  these  nodes  invaded  in  only 
6.5  per  cent.  Occasionally  cancerous,  subclavian,  supraclavicular,  or  bronchial 
nodes  invade  the  pleura  at  adjacent  points.  The  first  effect  is  a  permeation 
through  the  parietal  and  later  the  visceral  lymphatics  which  may  be  out- 
lined with  remarkable  delicacy.  A  serous  or  bloody  pleurisy  usually  follows. 
Breaking  into  the  pleural  cavity  the  cells  gravitate  below,  cause  thick  adhe- 
sions, and  rarely  perforate  the  thickened  diaphragm.  Handley  observed 
polypoid  pleural  tumors.  He  estimates  the  frequency  of  pleural  invasion 
at  38  per  cent.,  and  reports  3  cases  in  which  an  adherent  pleura  of  the  side 
of  the  growth  escaped  while  the  other  pleura  was  non-adherent  but  cancerous. 

The  lungs  are  reached  superficially  from  the  pleural  lymphatics,  while 
from  the  bronchial  nodes  extensions  pass  along  the  lymphatics  of  the  blood- 
vessels. Extension  to  lungs  through  the  blood-vessels  is  rare. 

The  importance  of  extensions  along  the  muscular  aponeuroses  has  been 
strongly  emphasized  by  Handley. 

By  means  of  vertical  gross  sections  of  the  skin  and  muscles  hardened  in  Orth's  fluid, 
dehydrated,  and  cleared  in  cedar  oil  he  was  able  to  trace  lymphatic  invasion  with 
unusual  success.  He  finds  that  mammary  cancer  travels  by  continuous  permeation 
chiefly  in  the  vessels  of  the  muscular  aponeuroses,  and  extends  not  only  over  the  pec- 
toralis  but  over  the  serratus  magnus,  obliquus,  rectus,  below  the  xiphoid,  and  across 
the  median  line,  covering  an  oval  area  25  cm.  in  diameter.  Approaching  the  center  of 
this  area  and  the  main  tumor  the  underlying  muscles  and  overlying  skin  become  more 
and  more  involved.  By  the  same  methods  he  has  concluded  that  invasion  of  the  per- 
itoneum from  the  epigastric  aponeuroses  by  way  of  the  parietes  or  the  falciform  liga- 
ment of  the  liver  is  of  frequent  occurrence  (44  per  cent.).  Thus  in  422  autopsies  the 
abdominal  organs  were  involved  and  the  lungs  were  free  in  53,  indicating  that  the 
abdominal  extensions  did  not  pass  through  the  thorax.  In  3  cases  by  microscopical 
sections  he  traced  peritoneal  invasion  through  the  rectus  muscle  and  into  the  falciform 
ligament  and  liver. 

Metastases  in  humerus  and  femur  he  also  brings  in  relation  to  the  growth  in  the 
aponeuroses  since  both  humerus  and  femur  appear  to  be  invaded  at  the  insertions  of 
tendons  and  aponeuroses.  All  the  very  wide  extensions  in  the  subcutaneous  tissue  of 
the  trunk,  which  rarely  pass  beyond  elbow  and  knee,  are  most  readily  traced  to  the  same 
route. 

The  conclusions  of  Handley  favor  wide  excision  of  the  aponeuroses  rather 
than  of  the  skin,  and  have  greatly  influenced  surgical  procedure.  Gerota 
(1897),  in  a  subject  of  recurrent  mammary  carcinoma  with  invasion  of  epigas- 
tric and  inguinal  nodes,  was  able  to  inject  the  lymphatics  from  the  breast 
along  the  superior  and  inferior  epigastric  arteries  to  the  inguinal  nodes.  He 
assumed  that  the  recurrent  tumor  had  widened  these  vessels  by  disturbing 
the  normal  lymph  flow.  Stiles  (1899)  points  out  that  the  xiphoid  is  only  2\ 
34 


530  NEOPLASTIC  DISEASES 

cm.  from  the  inferior  border  of  the  breast,  less  than  the  distance  to  the  medias- 
tinal  nodes,  and  that  here  only  a  thin  fibrous  layer  rich  in  lymphatics  sepa- 
rates the  mammary  fat  tissue  from  the  subperitoneal  fat  tissue  and  the  sus- 
pensory ligament  of  the  liver. 

Retroperitoneal,  adrenal,  renal,  lumbar,  and  spinal  extensions  Handley 
traces  from  a  preexisting  pleural  invasion  with  growth  downward  along  the 
diaphragmatic  crura.  Yet  in  6  cases  there  was  retroperitoneal  invasion  with 
the  thorax  free. 

The  bones  most  frequently  involved  are  the  sternum  and  ribs,  femur, 
vertebral  column,  cranium,  humerus,  and  clavicle.  The  humerus  is  invaded 
usually  at  the  junction  of  the  upper  and  middle  thirds,  the  femur  in  its  su- 
perior third,  where  spontaneous  fractures  occur.  Williams  collected  533 
cases,  of  which  the  cranium  was  invaded  in  36,  the  vertebrae  in  12,  the  femur 
and  humerus  each  8.  #-Ray  examinations  are  considerably  increasing  these 
proportions.  Kaufmann  in  63  autopsies  found  33  (53.3  per  cent.)  with  bone 
metastases.  The  osseous  invasion  is  sometimes  very  wide-spread  and  about 
14  per  cent.  (Kaufmann)  show  osteoplastic  changes. 

Peritoneal  invasion  occurs  chiefly  through  the  epigastric  region,  through 
the  crura  of  the  diaphragm  and  rarely  by  the  blood-stream.  Epigastric 
infection  alone  was  demonstrated  in  at  least  12  per  cent,  of  Handley's  cases, 
combined  with  thoracic  infection  in  37  per  cent,  of  early  and  46  per  cent,  of 
late  cases.  If  it  does  not  occur  early  it  seldom  develops  at  all.  The  event  is 
often  indicated  by  epigastric  pain  and  tenderness.  The  first  effect  is  usually 
extension  to  the  liver,  which  yields  superficial  implantations  beginning 
at  the  falciform  ligament,  or  involvement  of  the  portal  nodes,  with  subsequent 
central  invasion  of  the  liver  by  retrograde  growth.  Handley  describes 
efferent  lymphatics  leading  from  portal  nodes  through  falciform  ligament  and 
diaphragm,  thence  between  pericardium  and  chest  wall,  connecting  with 
internal  mammary  lymphatics. 

The  hepatic  lesions  vary  greatly,  from  a  single  nodule  to  complete  trans- 
formation of  the  organ  into  cellular  or  fibrous  carcinoma.  During  the  prog- 
ress of  this  lesion  primary  or  superficial  tumors  often  regress.  The  liver  may 
be  the  only  abdominal  organ  involved,  as  in  36  cases  of  Handley's  series,  but 
frequently  the  peritoneum  itself,  the  omentum,  intestines,  and  pelvic  organs 
are  invaded.  The  subserous  lymphatics  may  be  injected  over  a  large  area, 
but  soon  there  is  rupture  into  the  cavity  and  transportation  of  cells  to  the 
surfaces  of  viscera.  A  low  grade  of  peritonitis  may  be  established,  with 
opacity,  thickening  and  adhesions,  and  serous  or  chylous  exudates.  The 
omentum  may  be  contracted  to  a  small  epigastric  mass.  Gravitation  of 
cells  to  the  pelvis  leads  to  adhesions  of  all  pelvic  organs  and  invasion  of 
ovary,  tubes,  uterus,  and  vaginal  vault.  The  ovaries  are  a  favorable  nidus, 
especially  before  the  menopause,  and  the  lesion  here  presents  the  structure 
of  Krunkenberg's  tumor,  or  of  fibrocarcinoma. 

Diaphrenic  invasion  of  the  abdomen  occurs  only  in  the  late  stages  of 
thoracic  disease.  It  passes  through  the  substance  of  the  diaphragm  with 
invasion  of  the  liver,  or  through  the  crura,  when  the  further  course  more 
often  leads  to  the  retroperitoneal  nodes  and  kidneys. 

Cerebral  metastases  occur  in  about  4  per  cent,  of  autopsies.  Any  portion 
of  the  brain  may  be  chosen,  most  frequently  the  cerebellum.  Their  late 
appearance  indicates  an  origin  through  blood-vessels.  The  dura  and  skull  may 
be  affected  when  the  brain  is  free,  suggesting  an  access  by  cranial  lymphatics. 

In  a  notable  group  of  cases  paraplegia  develops  early  in  the  course  of 
mammary  carcinoma  from  dural  or  spinal  metastasis.  Very  remarkable 
are  the  cases  of  diffuse  carcinoma  of  spinal  and  cerebral  meninges,  of  which 


531 

Peabody's  report  from  this  laboratory  is  illustrative.  The  tumor-cells  in 
flat  strands  and  groups  extend  from  the  cauda  to  the  vertex.  Humbert  and 
Alexieff  have  collected  several  cases  of  this  type. 

The  part  played  by  the  blood-vessels  in  the  dissemination  of  mammary 
carcinoma  is  distinctly  less  than  that  of  the  lymphatics.  Invasion  of  veins 
is  commonly  observed  about  cancerous  lymph-nodes,  in  the  deep  fascia,  and 
less  often  in  the  breast  itself.  It  becomes  a  prominent  feature  in  very 
cellular  and  rapid  growths  with  which  also  the  metastases  are  more  wide- 
spread. The  occurrence  of  metastases  sometimes  early,  in  the  brain,  spinal 
cord,  spleen,  bone-marrow,  and  heart  muscle,  indicate  that  intravenous  foci 
often  escape  the  encapsulation  by  fibrin  and  organization  described  by  M.  B. 
Schmidt.  Cases  of  general  miliary  carcinoma  also  indicate  dissemination 
at  least  in  part  by  the  blood-vessels  (Petit). 


FIG.  236. — Mammary  cancer.     Alveolar  carcinoma  invading  vein. 

Regressive  Phenomena. — Regression  in  mammary  carcinoma  is  often 
observed  in  the  older  lesions.  Partial  or  complete  atrophy  of  tumor-cells, 
with  cicatrization,  occurs  especially  in  cutaneous  nodules  and  ulcers  when 
internal  metastases  are  growing  actively.  It  is  commonly  assumed  that 
the  lymph-nodes  are  capable  of  destroying  not  only  embolic  cells,  which 
may  be  granted,  but  even  established  secondary  tumors,  an  event  which 
must  be  held  excessively  rare  or  even  as  yet  unproved.  Handley  accounts 
for  the  discontinuous  character  of  lymphatic  permeation  by  assuming  that 
perilymphatic  fibrosis  causes  pressure  atrophy  of  tumor-cells  in  advancing 
segments  of  invaded  lymphatics,  so  that  the  zone  of  active  growth  is  ring- 
shaped  rather  than  disk  shaped.  Union  of  cancerous  fractures  occurred  in 
several  cases  in  the  Middlesex  Hospital  series. 


532  NEOPLASTIC  DISEASES 

A  constitutional  immunity  is  the  only  satisfactory  explanation  for 
the  resistance  which  some  subjects  exhibit  to  the  progress  of  a  disease, 
whose  course  varies  from  a  few  weeks  to  20  years.  The  slow  atrophic  scir- 
rhus  is  the  best  illustration  of  a  repressed  and  yet  progressive  carcinoma. 
In  Hodenpyl's  case  in  which  large  superficial  tumors  disappeared,  I  found 
the  liver  almost  completely  replaced  by  hyaline  connective  tissue  with  com- 
paratively few  active  foci  in  the  extremely  emaciated  body.  Gould  and 
Mackay  have  reported  cases  of  apparently  complete  disappearance  of 
advanced  mammary  cancer  with  restoration  of  health,  but  histological 
studies  of  .the  tissues  of  such  subjects  are  still  wanting.  Osier  records 
shrinkage  of  a  spinal  metastasis  with  relief  of  paraplegia. 

Clinical  Varieties. — The  clinical  course  of  mammary  carcinoma  is  in- 
fluenced by  the  conditions  of  origin  and  the  structure  of  the  tumor;  by  the 
age,  susceptibility,  and  physiological  condition  of  the  patient;  and  by  many 
intercurrent  factors.  Most  prominent  is  the  influence  of  structure  and  con- 
ditions of  origin,  and  most  current  clinical  classifications  show  a  definite  rela- 
tion to  these  features.  Age  has  a  pronounced  influence  on  most  anatomical 
varieties.  The  relatively  malignant  course  of  most  structural  types  of  the 
disease  in  young  subjects  is  uniformly  recognized.  The  cellular  varieties 
belong  to  the  early  decades,  the  scirrhous  forms  to  the  late  periods.  Yet  there 
are  many  exceptions  to  this  general  rule.  Cystic  adenocarcinoma  and  colloid 
tumors  are  of  relatively  late  occurrence.  In  some  old  and  resistant  persons 
the  disease  seems  to  reach  a  certain  limit  of  growth.  I  have  observed  an 
apparently  stationary  large  adenocarcinoma  of  10  years'  duration  in  a  woman 
of  80  years  who  suffered  little  apparent  inconvenience.  The  very  marked 
aggravations  in  the  disease  produced  by  gestation  and  lactation  are  com- 
monly observed.  Cancer  may  apparently  arise  during  gestation  and  prove 
fatal  before  its  termination.  While  there  are  doubtless  marked  variations 
in  the  susceptibility  of  patients  to  the  progress  of  the  disease,  the  nature  of 
this  constitutional  element  is  as  obscure  here  as  elsewhere. 

A  possible  reflex  influence  of  the  ovaries  led  Beatson  to  perform  ovari- 
otomy in  two  young  subjects.  The  results  were  disappointing.  Lett  in  99 
inoperable  cases  saw  notable  amelioration  in  23  per  cent.,  slight  change  in 
13  per  cent.  Rarely,  as  in  the  cases  of  Quinard  and  of  Reynes,  distinct  in- 
hibition appears  to  follow  castration. 

More  or  less  striking  clinical  peculiarities  have  led  to  the  recognition  of 
several  clinical  varieties  of  mammary  cancer. 

(1)  Cystadenocarcinoma  corresponds  in  part  to  a  specific  anatomical  type 
arising  in  mammary  cysts  or  large  ducts.     It  occurs  after  the  chief  age  of 
incidence  and  in  many  elderly  women  who  have  nursed  children  (Bowlby, 
Delbet).     A  circumscribed  tumor  appears  in  the  center,  less  often  in  the 
periphery,  of  the  gland.    It  is  preceded  by  an  intermittent,  serous  or  bloody 
discharge  from  the  nipple,  which  may  temporarily  reduce  the  size  of  the 
tumor.    A  definite  tumor  may  be  difficult  to  demonstrate,  especially  in  fat 
subjects,  or  the  growths  may  be  multiple.    The  progress  is  slow  and  growth 
may  be  inhibited  for  long  periods.    Invasion  of  lymphatics  and  nodes  is  de- 
layed until  the  tumor  capsule  is  perforated,  or  the  breast  invaded  or  the 
skin  eroded.    As  previously  pointed  out,  there  are  many  grades  of  malignancy 
.observed  in  the  late  stages  and  atypical  forms  of  this  tumor,  but  many  of 
them  are  comparatively  benign,  and  they  furnish  the  highest    proportion 
of  successful  extirpations,  as  well  as  the  most  difficult  field  for  properly  ad- 
justed surgical  treatment. 

(2)  Medullary  or  encephaloid  is  the  term  commonly  applied  to  the  aver- 
age bulky,  soft,  cellular  tumor  which  pursues  the  course  of  very  malignant 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


533 


mammary  cancer.  The  majority  of  these  tumors  are  duct  carcinomas,  but 
the  clinical  group  includes  also  cellular  acinar  carcinomas,  malignant  adeno- 
carcinomas,  and  pseudosarcomas.  They  are  characterized  by  the  occurrence 
at  relatively  early  age,  by  their  considerable  or  large  bulk,  fungating  form, 
rapid  progress,  early  invasion  of  skin,  muscle,  and  lymph-nodes,  extensive 
dissemination,  and  early  cachexia.  Ulceration,  necrosis,  hemorrhage,  and 
gangrene  may  be  prominent.  Yet  some  of  them  by  attracting  attention 
early  may  be  cured  by  radical  operation,  so  that  the  formidable  appearance 
is  no  bar  to  active  measures. 


FIG.  237. — Disseminating  carcinoma  of  breast.     Extensive  invasion  of  skin  reaching 
beyond  line  of  incision  on  both  sides.     Miliary  carcinoma  of  pectoral  muscle. 

(3)  Acute  Carcinosis. — Very  rapid  progress  with  local  inflammatory 
signs,  fever,  and  early  intoxication  are  observed  in  a  remarkable  group  of 
cases  occurring  at  early  ages  and  notably  in  gestation.  The  process  begins 
actively  and  one  or  both  breasts  rapidly  increase  in  size  without  localized 
tumor  formation.  There  is  well-marked  hyperemia,  local  heat,  and  slight 
tenderness.  The  consistence  is  uniformly  firm,  but  the  tissues  about  the  breast 
or  over  the  chest  and  back  may  be  edematous.  The  lymph-nodes  are  swollen 
from  the  first  and  invaded  probably  very  early.  After  reaching  a  certain 
stage  the  subsequent  course  may  vary.  Some  cases  are  rapidly  fatal  with 
generalization  or  pneumonia,  as  in  Billroth's,  6  weeks;  Aitken's,  38  days  (?); 


534 


NEOPLASTIC  DISEASES 


and  Schmidt's,  3  months.  The  shortest  duration  I  have  observed  was  4 
months.  Others  are  subacute,  but  succumb  within  a  year  with  very  wide- 
spread lymphatic  and  visceral  metastases.  A  patient  of  Delbet's  survived 
amputation  first  of  one  breast  then  of  the  other  for  3  years.  In  2  cases  I 
found  this  clinical  course  with  large-cell  duct  carcinoma,  in  one  with  a  tumor 
composed  of  diffuse  hyperchromatic  round  and  polyhedral  cells. 

(4)  Scirrhous  carcinoma  is  an  ill-defined  anatomical  variety,  but  clinically 
quite  characteristic.  The  majority  of  mammary  cancers  are  distinctly 
fibrous  in  much  of  their  growth,  but  the  typical  scirrhus  is  a  small  and  very 
hard  acellular  process  which  usually  fails  to  enlarge  the  organ  and  often 
results  in  atrophy  and  shrinkage.  It  is  a  form  frequently  assumed  by  local 
recurrences.  A  trophic  scirrhus  occurred  in  7.9  per  cent,  of  Gross'  series, 
and  chiefly  but  not  always  in  elderly  subjects.  The  breast  is  usually  flat, 
hard,  and  nodular.  The  skin  is  commonly  adherent,  the  nipple  retracted, 


FIG.  238. — Mammary  carcinoma  arising  on  chronic  mastitis  and  involving  nipple  and 

ducts. 

and  the  breast  becomes  fixed  to  the  chest.  Superficial  erosion  of  the  epider- 
mis or  ulceration  may  occur.  The  progress  is  very  slow  and  may  be  pro- 
longed 10  or  even  20  years.  Yet  the  typical  small  scirrhous  carcinoma  is  also 
notable  for  the  extensive  dissemination  in  lymph-nodes  and  distant  organs 
which  occurs  in  some  cases.  Hence  the  breast  always  requires  careful  exami- 
nation in  cases  of  visceral  carcinoma  of  uncertain  origin. 

The  skin  may  become  the  seat  of  very  numerous  secondary  nodules  or 
small  ulcerating  tumors  derived  from  a  scirrhous  tumor  in  the  breast.  In  a 
notable  case  of  Handley's  scores  of  nodular  tumors  and  excavated  ulcers 
covered  the  skin  from  chin  to  navel,  illustrating  the  effects  of  wide  dissemina- 
tion in  the  deep  fascia  with  multiple  excursions  to  the  derma  through  the 
vertical  lymphatics.  These  cases  were  described  by  Velpeau  as  "scirrhus 
pustuleux."  Moderate  grades  of  the  cutaneous  eruption  are  relatively  com- 
mon in  recurrent  cases.  The  nodules  may  disappear  at  one  point  while  develop- 
ing at  another. 

Cancer  en  cuirasse  develops  in  the  late  stages  of  cases  in  which  the  early 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


535 


history  is  variable,  but  some  cases  follow  primary  scirrhous  carcinoma  and 
maintain  this  character  throughout.  The  pronounced  cases  show  deep 
thickening  and  wooden  induration,  eroded  spots,  ulcerated  areas,  reddish 
and  brownish  discoloration  of  the  skin  over  a  wide  area,  including  arm, 
neck,  chest,  and  even  encircling  the  trunk,  with  pain,  elephantiasis,  and 
embarrassment  of  respiration.  The  typical  condition  is  rare,  and  many 
authors  have  described  imperfect  copies  of  the  startling  pictures  this  condi- 
tion may  present. 

(5)  Fibrocarcinoma  following  chronic  mastitis  constitutes  one  of  the 
most  definite  of  the  clinical  entities  in  mammary  cancer.  After  a  variable 
period  of  chronic  induration  of  one  or  both  breasts,  which  often  escapes  the 
attention  of  the  patient,  one  or  more  areas  of  the  organ  become  very  hard, 


FlG.  239. — Chronic  diffuse  productive  mastitis,  with  many  small  cysts,  and  a  single 

nodule  of  carcinoma. 


the  skin  becomes  dimpled  and  adherent,  the  nipple  often  retracted.  A 
definite  tumor  being  difficult  to  define,  the  suspicion  of  carcinoma  is  delayed, 
the  growth  slowly  increases,  often  pain  is  added,  the  breast  becomes  adherent 
to  the  muscle,  and  the  axillary  nodes  enlarge.  The  progress  may  be  very 
slow  and  usually  extends  over  several  months  before  its  serious  nature  is 
realized,  or  it  may  develop  actively  while  remaining  hard  and  fibrous.  The 
familiar  picture  of  fibrocarcinoma  without  marked  tumor  formation  is  thus 
unfolded. 

It  is  especially  in  this  group  of  cases  that  errors  of  diagnosis,  expectant 
treatment,  and  indecision  of  patient  and  physician  prove  costly.  Many 
of  these  cases  recur  after  early  operation,  and  when  they  have  infiltrated  the 
breast  or  reached  the  lymph-nodes  they  form  one  of  the  least  favorable  for 


536 


NEOPLASTIC  DISEASES 


successful  treatment.  Very  small  fibrocarcinomas  occur  which  cannot  be 
definitely  located  by  palpation,  but  which  early  give  rise  to  well-marked 
tumors  in  the  axillary  nodes.  Occasionally  the  dissection  of  the  amputated 
breast  has  been  pronounced  negative,  but  subsequent  recurrence  in  the  lymph- 
nodes  proves  that  a  carcinoma  has  been  overlooked. 

(6)  Mucoid  carcinoma  is  a  relatively  benign  form  which  has  been  discussed 
in  the  anatomical  section. 

When  the  different  subvarieties  of  mammary  cancer  have  been  sufficiently 
distinguished  little  remains  of  the  so-called  banal  form  of  the  disease.  Such 
a  result  is  desirable  owing  to  the  individual  character  of  the  various  clinical 
forms  of  this  protean  malady. 

The  simple  diagnosis,  "mammary  cancer,"  must  be  regarded  as  inade- 
quate. 


FIG.  240. — Cicatrizing  carcinoma  in  an  atrophic  breast.     Bulky  metastasis  in  axillary 

lymph-node. 

Mammary  Carcinoma  in  Males. — Since  the  thesis  of  Hourteloup,  1872, 
carcinoma  in  the  male  breast  has  attracted  much  attention.  The  estimates 
of  its  frequency  have  varied  from  0.86  per  cent,  of  all  mammary  cancers 
(Williams)  to  6  per  cent,  by  La  Forgue.  Of  269  tumors  of  the  male  breast,  244 
were  carcinoma  and  3  sarcoma  (Schuchardt).  Contributing  factors  ob- 
served include  repeated  trauma,  zona,  chronic  eczema,  and  attempts  at 
nursing  (Baumgartner,  Lit.).  It  occurs  at  slightly  later  age  than  in  women, 
but  has  been  observed  at  20  years.  Poirier  saw  affection  of  both  breasts. 
Unusual  development  and  activity  of  the  breast  are  predisposing  conditions. 
Owing  to  the  prominence  of  the  large  canals,  duct  cancer  is  relatively  fre- 
quent, and  the  scirrhus  type  is  often  followed,  but  cellular  tumors  are  not 
uncommon.  Williams  classified  89  of  100  cases  as  of  acinar  or  alveolar 
structure.  Chronic  inflammatory  processes  may  long  precede  the  develop- 
ment of  the  tumor  which  is  slow  and  insidious.  When  fully  established  the 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  537 

process  is  less  malignant  than  in  women,  the  growth  is  persistent,  many  of 
the  features  of  ordinary  mammary  cancer  are  observed,  and  local  or  general 
metastases  may  develop.  Of  16  fatal  cases  Williams  found  the  average  dura- 
tion 61  months,  in  13  unoperated  cases,  38  months.  Recurrences  were  notably 
early,  average  period  9.7  months. 

Development  of  Surgical  Treatment. — Moore  introduced  the  modern 
operation  for  mammary  cancer  in  1867,  when  he  contended  that  recurrences 
were  due  not  to  blood  infection,  but  to  incomplete  extirpation  of  the  tumor. 
He  recommenced  a  general  removal  of  the  breast,  skin,  fat,  axillary  nodes, 
and  pectoral  muscle.  He  even  undermined  the  skin-flaps.  His  views  were 
supported  by  Lister  and  Banks.  Gross  adduced  convincing  statistics  show- 
ing the  necessity  of  removing  the  axillary  nodes  in  every  case,  and  he  excised 
the  skin  widely,  looking  for  aberrant  lobules  of  the  gland,  and  portions  of 
the  pectoral  muscle  if  suspicious.  The  free  excision  of  underlying  muscle 
followed  Heidenhain's  demonstration  of  the  invasion  of  deep  intermuscular 
lymphatics.  Stiles  limited  the  excision  of  skin,  enlarged  the  ablation  of 
mammary  fat  tissue,  and  excised  all  underlying  muscle. 

Halsted  excised  the  sternal  half  of  the  pectoral  and  divided  the  clavicular 
portion  and  pectoralis  minor  in  order  to  expose  the  upper  axilla.  He  had 
three  successful  results  after  removal  of  supraclavicular  nodes.  Handley 
limits  the  excision  of  skin,  greatly  extends  that  of  the  muscles  and  aponeu- 
roses  to  a  circle  10  inches  in  diameter,  and  clears  the  epigastric  space. 

Many  other  surgeons  in  England,  France,  Germany,  and  America  have 
contributed  observations  influencing  the  present  accepted  form  of  the  opera- 
tion. Statistical  reports  of  the  improving  results  obtained  have  shown  that 
the  wider  the  operative  field,  the  better  the  result.  The  proportion  of  cases 
presenting  themselves  at  the  Middlesex  Hospital  with  recurrence  fell  from 
54.5  per  cent,  in  1858  to  1875  to  13.8  per  cent,  (plus  operative  mortality  of 
1.5  per  cent.)  after  1894.  Survival  of  recurrent  cases  after  operation  decreased 
from  34  to  26  months,  partly  because  of  the  increased  scope  of  cases  judged 
operable.  The  same  improvement  appears  in  De  Page's  report  of  cases  well 
after  3  years  in  different  periods:  From  1865  to  1875,  9.4  per  cent.;  1875  to 
1885,  10  per  cent.;  1885  to  1895,  33.8  per  cent.;  1895  to  1905,  46.5  per  cent. 
Walther's  statistics  from  Paris  hospitals  gave  52  per  cent,  of  cures  after  3 
years. 

The  effects  of  late  recurrences  are  illustrated  in  Le  Dentu's  table  showing 
47.45  per  cent,  well  after  4  years,  but  only  6.77  per  cent,  known  to  survive 
after  19  years.  Many  others  could  not  be  traced. 

Surgical  statistics  may  be  made  more  significant  by  more  detailed  atten- 
tion to  the  gross  anatomy  and  microscopical  structure  of  the  tumor.  Statis- 
tical studies  include  encapsulated  adenocarcinoma,  miniature  cancers  or 
even  precancerous  lesions,  and  early  circumscribed  duct  cancers,  all  of  which 
may  be  eradicated  by  ablation  of  the  breast,  along  with  the  highly  malig- 
nant forms  of  the  disease.  It  is  possible  to  select  cases  which  will  give  too 
per  cent,  of  recoveries  and  others  which  will  invariably  prove  fatal.  Too 
often  the  radical  operation  is  performed  on  comparatively  innocent  growths 
and  the  good  result  attributed  to  the  sacrifice  of  tissue.  No  uniform  rule 
can  guide  in  the  excision  of  skin  when  some  cases  show  cutaneous  invasion 
over  a  very  wide  area,  others  none  at  all.  It  would  be  interesting  to  know 
but  is  impossible  to  state  how  much  a  constitutional  resistance  influences 
a  favorable  result  after  some  very  wide  excisions.  Experimental  and  clin- 
ical data  strongly  urge  great  caution  against  producing  mechanical  emboli 
in  blood-  and  lymph-vessels  by  vigorous  preparation  of  the  skin  and  blunt 
dissection,  especially  in  those  advanced  cases  subjected  to  wide  excision. 


538  NEOPLASTIC  DISEASES 

General  Prognosis. — The  prognosis  in  mammary  cancer  can  be  estimated 
only  after  consideration  of  the  many  factors  involved,  including  the  age  of  the 
patient,  the  duration  and  extent  of  the  disease,  the  structural  type  and  posi- 
tion of  the  tumor,  and  the  condition  of  the  patient.  According  to  Handley 
the  condition  is  inoperable  when  there  is  extensive  ulceration  of  the  skin; 
with  tumors  adherent  to  chest;  when  axillary  nodes  are  fixed;  with  edema  of 
arm;  when  supraclavicular  nodes  are  involved;  when  there  are  signs  of  dis- 
tant metastases;  and  in  acute  carcinosis. 

The  proportion  of  cases  presenting  themselves  as  inoperable  was  estimated 
by  Primrose  at  32  per  cent.,  after  an  average  duration  of  the  disease  of  14 
months,  and  by  Deaver  at  25  per  cent.  Before  30  years  of  age  mammary 
cancer  is  extremely  fatal,  so  that  some  surgeons  prefer  not  to  operate  during 
this  period.  Schwartzoff  reports  15  such  cases  all  rapidly  fatal  in  spite  of 
early  operation,  yet  Deaver  reports  three  cures  in  patients  under  30  years. 
In  aged  women,  on  the  other  hand,  the  disease  usually  runs  a  prolonged  course, 
and  according  to  Deaver  many  of  the  patients  with  well-established  cancer 


FIG.  241. — Mammary  cancer.     Postoperative  recurrence. 

live  longer  with  palliative  instead  of  operative  treatment.  In  obese  subjects 
with  much  fat  invasion  of  the  breast  and  atrophy  of  parenchyma,  small 
tumors  very  often  metastasize  early  and  give  disappointing  operative  results. 

The  position  of  the  tumor  is  often  of  importance.  The  most  favorable 
position  is  at  the  nipple.  Aberrant  tumors  in  axillary,  sternal,  or  xiphoid 
prolongations  are  frequently  atypical  and  anaplastic,  and  the  initial  exten- 
sions are  relatively  inaccessible.  Small  deep-seated  tumor  masses  may  de- 
velop on  the  under  surface  of  the  breast,  immediately  invade  the  pectoral 
fascia  or  muscle,  and  soon  reach  the  deep  nodes  or  chest  wall. 

The  duration,  extent,  and  structural  type  of  the  tumor  are  the  common 
factors  influencing  the  results  of  operation.  They  may  be  taken  together  in 
considering  the  sources  of  recurrence. 

Recurrences. — Recurrent  tumors  develop  in  the  skin,  in  the  outlying 
lymph-nodes,  and  in  distant  organs.  In  each  instance  they  develop  from 
undisturbed  tumor  foci  or  loose  tumor-cells  which  have  escaped  removal. 
In  or  under  the  skin  recurrent  tumors  may  arise  from  aberrant  portions  of 
the  breast  in  axillary,  sternal,  or  epigastric  region,  of  which  Williams  col- 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST 


539 


lected  29  cases.  Many  incisions  supposed  to  surround  the  breast  really  pass 
through  outlying  portions  of  the  organ  which  are  not  distinctly  aberrant. 
L.  Heidenhain  long  ago,  and  later  Stiles,  pointed  out  that  all  portions  of  the 
breast  in  carcinoma  must  be  removed  and  that  many  recurrences  are  due  to 
failure  to  accomplish  this  object  and  to  the  late  development  of  carcinoma 
in  such  remnants  of  the  organ.  Cancer  may  develop  anew  in  the  opposite 
breast. 

In  young  subjects  recurrences  develop  earlier  (average  i\  months)  than 
in  patients  over  65  years  (8^  months)  (Durand).  In  the  malignant  histo- 
logical  forms  recurrences  are  earlier  and  more  frequent  than  in  relatively 
benign  cases,  but  the  more  important  influence  is  the  extent  of  the  disease. 
Both  these  rules  are  amply  apparent  in  operative  statistics.  Mucoid  carci- 
noma is  notable  for  the  long  delay  in  recurrences.  Of  47  recurrences  Williams 
recorded  before  3  months,  4;  i  year,  17;  2  years,  10;  3  years,  6;  4  years,  2; 
after  4  years,  8.  Ransohoff  collected  a  series  of  very  late  recurrences.  Thirty- 
seven  cases  of  which  26  were  local  occurred  after  7  years,  others  at  late  periods 
up  to  25  years.  Recurrence  in  brain,  spine  or  liver,  alone,  after  10  to  13  years 
was  observed  by  Bull. 

The  striking  influence  on  prognosis  exerted  by  the  type  of  carcinoma  is 
illustrated  in  Halsted's  table. 


Cases. 

Cures. 

Per  cent. 

Cancer  cysts  

6 

2 

33-3 

Adenocarcinoma        

~\2 

24 

7S-O 

Medullary  carcinoma          .... 

25 

12 

48.0 

Circumscribed  scirrhus 

28 

IT. 

46.4. 

Small  infiltrating  scirrhus  
Large  infiltrating  scirrhus  .... 

80 

39 

30 

8 

35-5 
20.5 

Total  

2IO 

89 

42.4 

In  this  series  the  neck  operation  was  performed  119  times.  Of  44  cases 
in  which  both  axillary  and  supraclavicular  nodes  were  found  microscopically 
to  be  involved,  3  were  definitely  cured.  Pilcher  reports  3  cured  cases  of  this 
type. 

The  influence  of  the  extent  of  the  disease  was  even  more  notable. 


No. 

Cured,  per  cent. 

Weil  3  years. 

Axilla  and  neck  negative  

60 

75-O 

85 

Axilla  positive,  neck  negative. 
Axilla  and  neck  positive  

no 
4.0 

24-5 
7.  5 

31 
IO 

At  the  Massachusetts  General  Hospital  Greenough  reports  that  of  236 
cases  with  palpable  axillary  nodes  only  1 2  per  cent,  were  cured  by  operation, 
while  of  275  similar  cases  Finsterer  reports  only  (12)  4.3  per  cent,  cured.  I 
believe  that  the  last  figures  represent  the  average  success  obtained  by  surgical 
treatment,  which  means  that  when  a  woman  presents  an  established  mam- 
mary cancer  with  axillary  nodes  palpably  infected  she  has  about  one  chance 
in  25  of  being  cured  by  operation. 

In  mucoid  carcinoma  Gaabe  found  53.8  per  cent,  of  3-year  recoveries. 


540 


NEOPLASTIC  DISEASES 


The  influence  of  improving  operative  technic  is  strikingly  shown  in  De 
Page's  report  (1907): 

RECURRENCES  AFTER  OPERATION  (DE  PAGE) 


Local. 

Lymph-nodes. 

Distant. 

1865-75 

76.O 

6.0 

7    5 

1875-85 

72    O 

6   2 

IO   O 

1885-05. 

45.  5 

8.4 

IQ   O 

180^—  IQO5 

2Q.  O 

o.o 

27    O 

Many  authors  have  stated  their  belief  that  the  extent  of  the  disease 
rather  than  the  extent  of  the  operation  determines  the  prognosis.  It  is 
regarded  as  proved  that  loose  tumor-cells  may  become  implanted  in  the 
wound  and  give  rise  to  recurrent  nodules.  The  implantation  experiments 
of  Bergmann  and  Hahn,  and  the  occurrence  of  tumors  at  the  site  of  injection 
of  tumor  vaccine,  favor  this  view,  while  the  location  of  nodules  exclusively 
in  the  line  of  incision  is  highly  suggestive.  An  equally  or  even  more  impor- 
tant source  of  cutaneous  recurrence  is  the  incomplete  removal  of  infected, 
cutaneous,  and  deep  lymphatics,  while  the  mechanical  displacement  of  tumor- 
cells  from  invaded  into  normal  lymphatics  is  probably  rather  common.  The 
persistence  of  cutaneous  recurrences  in  spite  of  the  best  modern  technic 
seems  to  justify  the  use  of  various  adjuvants  to  surgery,  which  may  destroy 
superficial  cell  groups,  and  not  a  few  operators  claim  to  secure  better  results 
by  #-ray,  radium,  fulguration,  or  escharotics  at  or  soon  after  operation 
(Ochsner,  Cabot,  Deaver). 

Recurrence  in  the  lymph-nodes  and  muscles  is  largely  under  the  control 
of  the  operator,  and  the  conditions  governing  their  appearance  have  been 
fully  indicated  in  discussion  of  the  paths  of  dissemination.  It  is  notable 
that  this  form  of  dissemination  has  been  reduced  to  a  minimum. 

The  increased  proportion  of  visceral  recurrences  has  been  referred  chiefly 
to  the  increased  scope  of  operability,  but  it  seems  quite  possible  that  mechan- 
ical dissemination  of  tumor-cells  may  account  for  some  of  the  distant  recur- 
rences. It  may  be  suggested  also  that  the  removal  of  a  tumor  withdraws 
the  natural  local  barriers  against  it  and  may  leave  the  system  in  a  less  favor- 
able position  to  inhibit  the  growth  of  vagrant  cells.  Gaylord  (1916)  offers 
experimental  evidence  to  show  that  prolonged  anesthesia  and  hemorrhage 
reduce  the  resistance  to  cancer.  Against  such  a  possibility  stands  an  apparent 
increased  tenure  of  life  of  operative  cases  even  after  recurrence.  The  average 
duration  of  life  in  untreated  cases  was  placed  by  Paget  at  4  years,  by  Ode- 
kop  at  29  months,  by  Sprengel  at  27  months.  After  operation  Handley's 
recurrent  cases  lived  an  average  of  29.6  months  and  many  others  were  cured. 
Reports  of  Sibley,  Baker,  Gross,  and  Williams  give  an  average  life  in  un- 
operated  cases  of  34  months,  of  operated  cases  52  months. 

The  operative  mortality  was  estimated  by  Delbet,  1898,  to  average  about 
5  per  cent.,  but  in  many  clinics  it  is  now  much  less.  De  Page  reports  2.8 
per  cent.  (1906).  M.  Richardson  lost  4  patients  in  1500  breast  operations. 

Regarding  the  significance  of  these  statistics  the  following  comments  seem 
to  the  writer  permissible. 

(i)  The  figures  (4  years  to  27  months)  are  too  divergent  to  permit  accu- 
rate conclusions  regarding  the  natural  duration  of  mammary  cancer.  The 
attempt  to  establish  an  average  duration  of  this  disease  should  be  replaced 


EPITHELIAL  AND  OTHER  TUMORS  OF  THE  BREAST  541 

by  the  systematic  classification  of  cases  according  to  the  factors  known  to 
influence  prognosis.  The  total  duration  of  life  in  all  forms  of  this  disease  is  of 
no  clinical  significance. 

(2)  The  comparison  of  operated  and  unoperated  cases  is   sophistical. 
The  choice  of  operable  cases  tends  to  throw  into  the  untreated  class  the 
majority  of  rapid  and  unfavorable  cases. 

(3)  Statistics  favor  the  conclusion  that  operation,  on  the  whole,  shortens 
life   in   recurrent   cases,    although   sometimes   rendering   it   more   tolerable. 
Handley's  recurrent  cases  lived  29.6  months,  while  in  the  above  series  the 
duration  of  life  of  unoperated  cases  was  27,  29,  34,  and  48  months  respectively. 
This  conclusion  is  strengthened  by  theoretical  considerations,  as  well  as  by 
observations  on  the  rapid  course  of  many  recurrent  cases.    It  is  clearly  proved 
in  many  instances  by  the  increasing  anaplasia  exhibited  in  the  structure  of 
recurrent  tumors. 

(4)  The  high  proportion  of  clinical  cures  from  the  modern  operation  has 
resulted  largely  from  the  earlier  recognition  of  cancer  and  the  inclusion  of  a 
larger  number  of  minute  carcinomas  or  precancerous  lesions  in  the  operated 
class. 

(5)  The  choice  of  therapeutic  measures  should  not  be  made  under  the 
impression  that  the  duration  of  the  untreated  disease  is  27  months  and  that 
40  per  cent,  of  operated  cases  are  cured.    Since  the  duration  of  the  disease 
may  vary  from  6  wreeks  to  25  years  and  the  favorable  results  of  operation 
from  o  to  100  per  cent.,  the  first  essential  in  treatment  is  accurate  diagnosis 
and  prognosis  of  each  individual  case. 

(6)  In   estimating   the   economic  importance  of   the   surgical   treatment 
of  mammary  cancer  there  must  be  charged  up  the  cost  of  acquiring  surgical 
skill,    and    the    deplorable    conditions    following    local    recurrence.      There 
can  be  no  doubt  that  operation  shortens  life  and  aggravates  the  terminal 
suffering  in  the  great  majority  of  recurrent  cases.    Most  of  those  who  deal 
with  the  great  number  of  these  unfortunate  patients  would"  welcome  a  judi- 
cious limitation  of  the  scope  of  operability  in  this  disease. 

From  clinical  and  pathological  studies  I  have  drawn  the  impression  that 
in  dealing  with  mammary  cancer  surgery  meets  with  more  peculiar  difficul- 
ties and  uncertainties  than  with  almost  any  other  form  of  the  disease.  The 
anatomical  types  of  the  disease  are  so  numerous,  the  variations  in  clinical 
course  so  wide,  the  paths  of  dissemination  so  free  and  diverse,  the  difficulties 
of  determining  the  actual  conditions  so  complex,  and  the  sacrifice  of  tissue  so 
great  as  to  render  impossible  in  a  majority  of  cases  a  reasonably  accurate 
adjustment  of  means  to  ends. 

The  scope  of  the  operative  field  having  apparently  reached  a  limit,  the 
chief  hope  for  a  reduction  in  the  mortality  from  mammary  carcinoma  lies 
in  its  prevention  and  earlier  diagnosis. 

Both  these  objects  point  to  the  excision  of  many  breasts  before  carcinoma 
has  become  established  in  the  clinical  sense.  The  growing  tendency  to 
remove  the  breast  for  recognized  chronic  mastitis  or  suspected  carcinoma, 
while  probably  sacrificing  some  organs  unnecessarily,  has  justified  itself 
in  the  writer's  material  by  securing  the  early  removal  of  some  miniature  car- 
cinomas and  more  precancerous  lesions.  In  this  field  too  much  reliance 
should  not  be  placed  on  the  examination  of  resected  areas  and  nodules. 
When  the  condition  of  the  organ  becomes  sufficiently  suspicious  to  demand 
a  partial  excision  for  diagnosis  it  is  usually  safer  to  excise  the  whole  breast, 
make  the  diagnosis  complete,  and  remove  a  source  of  anxiety  or  actual 
danger. 

The  use  of  x-ray  and  radium  in  the  treatment  of  mammary  cancer  has  been 


542  NEOPLASTIC  DISEASES 

widely  employed  in  recent  years,  and  with  so  much  success  that  these  agents 
cannot  be  disregarded  in  any  competent  discussion  of  this  subject. 

Local  recurrences  in  the  chest  wall,  opposite  breast,  axilla  and  supra- 
clavicular  space,  and  elsewhere  very  often  regress  and  disappear  completely 
under  x-ray  therapy.  Pleural  extensions  seem  to  be  controlled  to  some  ex- 
tent. Whether  the  life  of  the  patient  is  definitely  prolonged  in  such  casesr 
in  most  of  which  the  disease  is  generalized,  may  be  doubted,  but  the  local 
conditions  are  very  much  ameliorated. 

Thorough  treatment  by  ac-ray  to  the  limit  of  skin  tolerance  before  and 
shortly  after  operation  has  been  endorsed  by  all  who  have  employed  it  system- 
atically. So  great  has  been  the  regression  of  the  tumor  after  such  preliminary 
treatment  in  many  cases  as  to  indicate  that  the  limit  of  operability  may  well 
be  reduced  in  borderline  cases  in  favor  of  the  #-ray.  Striking  histological 
changes  in  tumors  so  treated  support  the  conclusion  that  such  treatment  has 
a  powerful  effect  on  the  local  tumor,  but  the  possibility  that  metastases  may 
occur  from  regressing  and  even  quiescent  tumors  must  be  considered. 

As  a  rule,  radium  is  more  effective  with  mammary  cancer  than  the  it-ray, 
with  which  it  is  often  advantageously  combined.  In  the  hands  of  several 
observers  the  insertion  of  radium  into  the  tumor  and  its  extensions,  followed 
by  external  radiation,  has  caused  marked  regression  and  even  standstill  of  the 
local  growths  in  advanced  inoperable  cases.  The  pursuit  of  this  method  in 
operable  cases,  in  which  there  is  some  contraindication  to  operation,  offers 
a  very  important  field  of  study. 


CHAPTER  XXVII 

CANCER  OF  UTERUS,  VULVA,  VAGINA 
CANCER  OF    UTERUS 

General  Etiology  and  Classification. — Statistics  may  be  cited  to  show 
that  the  uterus  is  first  in  the  list  of  organs  affected  by  primary  cancer.  Welch 
collected  (from  the  literature)  over  31,000  cases  of  cancer,  of  which  29.5  per 
cent,  were  of  the  uterus  and  21.4  per  cent,  of  the  stomach.  Orth  states  that 
uterine  cancer  forms  30  per  cent,  of  all  those  occurring  in  women,  and  Birch- 
Hirschfeld  places  it  first  in  order  of  frequency.  The  British  statistics  of 
Williams  gave  38  per  cent.,  31.4  per  cent.,  and  22.5  per  cent,  in  1868,  1888, 
1900.  The  U.  S.  Census,  1911,  shows  a  very  marked  predominance  of  can- 
cer of  the  stomach  and  liver  over  cancer  of  the  female  generative  organs, 
viz.,  17,365  to  6707.  The  uterus  is  still  probably  the  most  frequent  seat  of 
the  disease  in  women.  Kaufmann,  dealing  with  the  material  of  the  Basel  and 
Gottingen  institutes,  found  cancer  of  the  uterus  in  a  smaller  proportion, 
14.75  Per  cent,  and  15.59  Per  cent,  of  the  total  in  both  sexes,  and  Borst  places 
the  uterus  fourth  in  the  list  of  organs.  Owing  chiefly  to  better  separation  of 
sarcoma,  myoma,  and  cancer  of  the  vagina  and  ovaries  from  cancer  of  the 
uterus,  the  cases  of  the  latter  disease  have  tended  to  diminish  in  statistical 
observations  (Weinberg). 

About  10  per  cent,  of  uterine  cancers  affect  the  corpus  (Koblanck).  R. 
Williams,  however,  finds  the  proportion  of  corpus  carcinoma  in  clinical  ma- 
terial much  lower,  while  Backer  and  Blumenfeld  found  it  at  autopsy  below 
3  per  cent. 

The  frequency  of  uterine  cancer  must  be  referred  in  general  partly  to  its 
anatomical  and  physiological  characteristics,  more  especially  to  its  exposure 
to  various  forms  of  trauma  and  irritation.  Cervical  carcinoma  is  strongly 
influenced  by  childbirths,  which  average  over  5  in  such  patients  (Gusserow, 
Koblanck,  Williams).  While  carcinoma  seldom  develops  in  scars,  yet  re- 
peated cervical  lacerations  disturb  the  normal  structure  and  functions  of 
this  tissue,  interfere  with  its  nutrition,  and  expose  its  weakened  structure 
to  chronic  irritation  and  inflammation.  A  chronic  endocervicitis  precedes 
cancer  in  the  great  majority  of  cases  (34  out  of  48,  Polese),  and  the  routine 
examination  of  this  tissue  reveals  abnormalities  in  the  morphology  and  posi- 
tion of  the  epithelium  which  constitute  precancerous  conditions.  The  most 
prominent  of  these  conditions  is  the  cervical  erosion,  many  of  which  show 
suspicious  hypertrophy  and  heterotopia  of  the  lining  epithelium.  Beckmann 
saw  the  development  of  carcinoma  in  an  erosion  which  he  had  treated  for 
5  years. 

For  corpus  carcinoma  the  chief  definite  etiological  factor  is  the  associa- 
tion with  myoma,  10  per  cent,  of  which  are  combined  with  carcinoma  (Ols- 
hausen).  Taussig,  in  a  personal  communication  from  the  Mayo  Clinic, 
learned  that  of  40  cases  of  corpus  carcinoma  there  were  10  associated  with 
myomas.  Local  hyperemia,  chronic  endometritis,  and  ulceration  of  the  mu- 
cosa  are  frequent  concomitants  of  myoma  which  favor  the  development  of 
carcinoma  (Winter,  Sutton).  The  carcinomas  which  arise  from  adenomyoma, 
localized  or  diffuse,  present  peculiar  anatomical  and  clinical  features  which 
usually  permit  of  their  identification.  Genital  tuberculosis  has  been  ob- 

543 


544  NEOPLASTIC  DISEASES 

served  with  carcinoma  in  several  instances  (Koblanck),  but  as,  in  Cullen's 
cases,  the  association  may  be  accidental. 

Age.--—  Uterine  cancer  chiefly  affects  child-bearing  women  in  the  fifth 
decade,  but  occurs  from  the  second  to  the  eighth  decades.  Cervical  cancer 
appears  rather  earlier  than  disease  of  the  corpus.  A  peculiar  case  of  carcino- 
sarcoma  of  the  cervix  in  a  child  of  2  years  is  reported  by  Rosenstern,  and 
several  cases  in  very  young  subjects  are  collected  by  Engelhorn.  Cervical 
carcinoma  in  a  child  of  7  years  is  described  by  Glockner. 

Two  main  histological  and  clinical  varieties  of  uterine  carcinoma  are 
recognized:  (i)  Squamous-cell  carcinoma  of  the  cervix,  and  (2)  glandular 
carcinoma  of  the  body.  The  vaginal  portion  of  the  cervix  is  almost  exclu- 
sively the  seat  of  epidermoid  carcinoma;  in  the  cervical  canal  the  two  types 
meet  and  intermingle,  while  glandular  carcinoma,  or  malignant  adenoma, 
predominate  in  the  corpus.  These  relations  naturally  accord  with  the  struc- 
ture of  the  organ,  squamous  epithelium  lining  the  portio  and  extending  a 
variable  distance  up  the  canal;  high  cylindrical  cells  of  pavement  type  line 
the  corrugated  surface  and  gland  ducts  of  the  cervical  canal;  and  specific 
glandular  epithelium  covers  the  endometrium  and  forms  its  glands. 

Anatomy  of  Cervical  Carcinoma. — The  earliest  stages  of  the  disease  are 
seldom  recognized  grossly.  Very  small  tumors  appear  in  the  form  of  (i) 
a  hard  nodule  in  the  substance  of  the  cervical  lip,  or  (2)  a  circumscribed 
indurated  ulcer  of  portio  or  cervical  canal,  or  (3)  more  diffuse  low  papillary 
outgrowths,  covering  a  portion  of  the  lip  or  canal. 

As  usually  observed  the  lesion  is  more  advanced  and  exhibits  (i)  an  ex- 
tensive induration  and  swelling  of  the  cervix;  (2)  an  excavated  ulcer,  or  (3) 
extensive  papillary  or  cauliflower  outgrowths  covering  much  of  the  canal 
and  portio. 

Three  stages  of  the  progress  of  the  lesion  are  emphasized  by  Cullen:  (i) 
Induration  without  loss  of  tissue;  (2)  disintegration,  and  (3)  excavation. 

The  established  and  advanced  process  varies  greatly  according  to  the 
predominance  of  certain  of  these  tendencies.  In  one  group  of  cases  there  is 
wide  superficial  extension  of  the  process,  and  the  whole  canal  and  even 
portions  of  the  endometrium,  the  posterior  fornix,  and  much  of  the  vagina 
are  covered  by  polypoid  or  cauliflower  outgrowths.  These  may  become 
bulky  and  obstruct  the  canal,  causing  retention  of  secretions  or  filling  the 
vagina.  Ulcerating  carcinoma  produces  wide  excavations  of  tissue  in  the 
cervix  and  vagina,  or  completely  destroys  the  cervix,  and  may  perforate 
into  the  bladder  or  rectum,  or  both. 

Infiltrating  carcinoma  thickens  the  cervix,  extends  along  the  vagina, 
and  up  the  canal  into  the  endometrium,  causing  obstruction  to  the  canal 
with  pyometra,  firmly  fixing  the  uterus  to  the  parametria,  and  invading 
the  bladder  and  rectum.  In  some  cases  the  entire  uterine  mucosa  and  part 
of  the  wall  is  replaced  by  tumor  tissue  extending  from  the  cervix,  and  eventu- 
ally becoming  excavated. 

Ruge  and  Veit  distinguish  sharply  between  cancers  of  the  portio  vaginalis 
and  those  of  the  cervical  canal.  Their  distinctions  are  anatomical  and 
clinical.  Squamous-cell  tumors  and  adenocarcinoma  frequently  arise  from 
both  regions.  Portio  cancer  produces  marked  thickening  with  induration 
of  one  lip  or  the  whole  lower  portion  of  the  cervix,  while  the  canal  long  re- 
mains intact.  Cervical  tumors  involve  the  canal  from  the  first  and  may 
long  spare  the  portio  while  extensively  thickening  the  whole  length  of  the 
cervix  and  ultimately  excavating  it.  The  portio  carcinoma  arises  super- 
ficially and  tends  to  involve  the  vaginal  mucosa  and  wall,  often  by  a  pro- 
gressive hypertrophy  and  cancerous  transformation  of  normal  epithelial 


CANCER  OF  UTERUS,  VULVA,  VAGINA 


545 


papillae.  Contact  metastases  are  also  claimed  to  occur.  On  the  other  hand, 
portio  carcinoma  seldom  invades  the  canal  and  never  beyond  the  os  internum, 
while  metastases  in  the  endometrium  have  not  been  demonstrated. 

Cervical  carcinoma  may  be  regarded  as  a  true  uterine  tumor  which  does 
not  tend  to  invade  the  portio  or  vagina,  although  the  whole  cervix  may  be 
excavated.  It  readily  invades  the  peritoneum.  In  a  series  of  cases  metas- 
tases in  the  endometrium  have  been  observed  (Winter,  Lit.),  for  which  several 
modes  of  origin  are  under  discussion,  including  multiple  primary  growths, 
contact  implantation,  and  extension  through  the  lymphatics. 


FIG.  242. — Island  of  beginning  carcinoma  in  a  cervical  erosion. 

Structure  and  Histogenesis. — In  cervical  carcinoma  two  histological 
types  of  structure  appear,  epidermoid  carcinoma  and  adenocarcinoma,  but 
the  two  types  are  often  combined.  The  most  frequent  form  presents  cords 
of  pavement  epithelium  in  which  neither  alveoli,  pearls,  spine-cells,  nor 
hornification  are  demonstrable.  Rarely  adult  acanthoma  is  observed  with 
abundance  of  pearls  and  much  hornification.  These  structures  usually  affect 
the  portio  and  early  ulcerate. 

The  earliest  cervical  carcinoma  that  I  have  seen  consisted  of  localized 
downward  growth  of  hypertrophied  papillae  in  portions  of  chronic  erosions. 
35 


546 


NEOPLASTIC  DISEASES 


Since  heterotopia  of  the  epithelium  was  missing  these  cases  might  be  desig- 
nated as  precancerous.  In  one  case  a  localized  indurated  patch,  i|  X  i  cm. 
in  the  lower  cervical  canal,  was  composed  of  atypical  hypertrophied  squamous 
epithelium  with  elongated  papillae  extending  to  a  depth  of  25  mm.  In 
another  case  a  chronic  erosion  showed  early  squamous  epithelioma  of  its 
edges  and  beginning  neoplastic  overgrowth  and  metaplasia  of  cylindrical 
cells  in  the  gland  ducts.  Early  stages  in  the  development  of  carcinoma  of 
the  cervix  are  described  by  Waldeyer,  Ruge  and  Veit,  Cullen,  Kermauner, 
Stone,  and  others. 

The  established  tumor  is  usually  composed  of  columns  of  transitional 
epithelium  with  cells  of  large  dimensions,  polyhedral  or  rounded,  without 
a  trace  of  pearl  formation  or  keratosis.  Giant-cells  are  commonly  present. 
The  stroma  is  usually  scanty,  vascular,  and  infiltrated  by  mononuclear 
or  eosinophile  leukocytes.  It  may  be  completely  wanting  in  certain  areas 
so  that  neighboring  columns  of  cells  cohere.  Evidently  this  structure  is 


FIG.  243. — Atypical  epithelial  overgrowth  in  cervix  uteri. 

produced  by  the  growth  of  the  epithelial  layer  as  a  whole,  which,  in  order 
to  accommodate  its  enlarged  dimensions,  becomes  variously  folded,  incurved 
or  everted,  thus  producing  a  bulky  tumor  of  essentially  papillary  type. 
Lateral  outgrowths  from  the  original  layer  progressively  complicate  the 
picture,  but  the  cells  do  not  early  split  off  in  small  groups  as  in  acanthoma, 
so  that  lymphatic  involvement  is  relatively  late.  The  presence  of  free 
lying  foci  of  pus  surrounded  by  tumor-cells,  and  the  abundant  growth  of 
blood-vessels  in  elongated  papillae,  are  structural  features  resulting  from  this 
mode  of  growth.  From  the  same  point  of  view  Ruge  has  described  these 
tumors  as  carcinoma  evertens  and  carcinoma  invertens,  the  former  growing 
outward  in  papillary  form,  the  latter  inward,  pushing  and  invading  the  tissues 
before  it.  This  structure  produces  the  majority  of  the  papillary  or  cauli- 
flower, superficial  or  deep,  and  widely  distributed  tumors  of  the  cervix. 
Their  histogenesis  has  been  traced  to  the  stratified  epithelium  lining  the 
cervical  canal  and  the  ducts  of  the  glands.  The  distribution  of  this  type 


CANCER  OF  UTERUS,  VULVA,  VAGINA 


547 


of  epithelium  is  subject  to  considerable  variations,  and  it  is  probable  that 
before  and  during  the  development  of  carcinoma  the  cylindrical  epithelium 
is  transformed  into  stratified  cells,  or  replaced  by  these  cells  from  a  lower 
level.  This  metaplasia  may  extend  even  to  the  endometrium  and  its  phases 
may  often  be  traced  in  chronic  erosions. 

Changes  in  the  endometrium  occur  in  many  cases  of  cervical  carcinoma. 
Abel  and  Landau  describe  a  form  of  glandular  and  interstitial  hypertrophy, 
with  warty  projections  of  enlarged  and  dilated  glands,  overgrowths  of  spindle- 
and  epithelial  cells,  and  exudation  of  round  cells  in  the  stroma.  These 
changes  constitute  chronic  endometritis.  A  transformation  of  cylindrical 
epithelium  into  stratified  flat  or  polyhedral  cells  is  a  form  of  epithelial 
metaplasia  seen  with  cervical  carcinoma  (Kraus)  and  in  chronic  endometritis. 

Adenocarcinoma,  reproducing  the  alveoli  of  the  cervical  glands,  occurs 
in  a  small  proportion  of  cervical  carcinomas.  They  first  appear  as  submucous 
nodules  in  cervix  or  portio,  but  in  their  later  stages  they  reach  the  surface  as 
papillary,  cauliflower,  or  ulcerating  growths  which  cannot  be  distinguished 


FIG.  244. — Fungating  epidermoid  carcinoma  of  the  cervix. 

from  other  types  of  cervical  tumors.  At  the  same  time,  their  structure 
tends  to  approach  that  of  epidermoid  carcinoma.  The  tumor  process  begins 
in  the  ducts  of  fundi  of  one  or  more  cervical  glands,  where  the  cells  multiply, 
become  stratified,  and  often  assume  squamous  characters.  Cullen  pictures 
a  very  early  but  probably  secondary  focus  of  origin  of  carcinoma  affecting  the 
superficial  cells  of  the  cervical  lining.  The  alveoli  have  become  elongated, 
dilated,  and  filled  with  tumor-cells  which  have  usually  lost  their  cylindrical 
form.  Yet  the  alveolar  arrangement  is  long  retained  and  reasserts  itself  in 
lymphatic  metastases.  Large  alveoli  filled  with  tumor-cells,  forming  second- 
ary alveoli,  is  a  common  structural  type  of  cervical  adenocarcinoma.  In 
advanced  and  in  some  early  cases  there  is  the  usual  variety  of  structures  of 
established  carcinoma,  including  alveolar,  diffuse,  and  scirrhous  types. 

Adeno-acanthoma. — Tumors  composed  of  glandular  and  squamous  ele- 
ments are  often  designated  as  adenocancroids,  or  adeno-acanthoma.  They 
arise  in  the  portio,  cervical  canal,  or  in  the  endometrium,  and  their  histo- 
genesis  has  formed  the  topic  of  much  discussion  (Frankel,  Wiener,  Hitsch- 


548 


N EOF LAST  1C  DISEASES 


mann,,  Offergeld,  Hauser,  Buttner).  It  is  now  rather  apparent  that  such 
structures  do  not,  as  a  rule,  signify  a  multicentric  origin  from  cylindrical  and 
squamous  cells,  and  do  not  require  an  original  heterotopia  of  squamous 
cells,  but  that  metaplasia  of  cylindrical  tumor-cells  into  squamous  is  a  fre- 
quent characteristic  of  uterine  growths  as  of  some  other  processes  in  the 
endometrium.  Hitschmann  has  shown  that  the  metaplasia  is  complete, 
producing  spine-cells  and  keratohyalln.  On  the  other  hand,  Hauser  reports  a 
case  of  adenocarcinoma  of  the  cervix  with  separate  acanthoma  of  the  portio, 
showing  that  with  multicentric  origin  the  tumors  may  remain  separate. 
Finally,  in  several  cases  the  histological  study  strongly  suggested  that  the 
adenocancroid  developed  from  a  double  origin,  and  not  through  metaplasia 
(Hofmeier,  Buttner,  Sitzenfrey).  In  a  chronic  erosion  I  have  observed  rarely 


FIG.  245. — Adenocarcinoma  of  fundus  uteri  developing  over  point  of  greatest  pressure 

from  a  myoma. 

acanthoma  arising  from  the  squamous  lining  and  precancerous  changes  in  a 
neighborhing  group  of  cervical  glands.  It  thus  appears  that  a  variable  histo- 
genesis  must  be  assumed  for  the  cervical  adeno-acanthomas. 

The  Cervical  Erosion. — The  facility  with  which  cylindrical  mucous  cells  and  squam- 
ous cells  replace  each  other  in  the  cervix  appears  in  the  study  of  erosions  and  pseudo- 
erosions.  Ruge  and  Veit  concluded  that  the  mucous  cells  lining  pseudo-erosions  were 
the  transformed  basal  cells  of  the  squamous  layer.  Meyer  and  Adair  fail  to  find  evi- 
dences of  this  transformation,  and  Meyer  states  that  true  mucous  lining  cells  always 
develop  from  the  glands  of  the  pseudo-erosion.  He  finds  that  erosions  always  result 
from  inflammation  and  are  attended  by  extrusion  of  the  glands  into  cervical  tissue  and 
a  replacement  of  squamous  by  cylindrical  gland  epithelium.  Schottlander  holds  that 
the  proliferating  glands  may  pierce  the  squamous  lining  of  the  cervix.  In  healing,  the 
squamous  epithelium  from  edges  or  persistent  islands  grows  beneath  the  mucous  cells, 
even  into  the  glands,  causing  exfoliation  of  gland-cells  and  eventually  complete  replace- 


CANCER  OF  UTERUS,  VULVA,  VAGINA 


549 


raent  by  squamous  cells,  if  the  lesion  heals  completely.  The  attendant  overgrowth 
readily  gives  rise  to  papillomas  and  adenomas,  and  these  and  other  secondary  changes 
determine  the  different  features  of  chronic  erosions,  as  simple,  papillary,  cystic,  and 
glandular.  Fischel  holds  that  the  pseudo-erosion  of  the  adult  is  usually  in  part  a  con- 
genital condition.  The  indifferent  epithelium  of  the  fetal  cervix  differentiates  in  the 
third  month  into  glandular  and  squamous  types,  the  latter  covering  much  of  the  cer- 
vical canal.  Later  the  glands  and  mucous  cells  encroach  upon  the  squamous  lining 
and  often  extend  over  segments  of  the  portio,  producing  the  congenital  pseudo-erosion 
of  infants.  At  birth  the  squamous  cells  begin  to  regain  their  position  in  the  canal, 
undermining  the  mucous  layer,  so  that  both  types  of  epithelium  are  often  seen  in  con- 
tiguity. Meyer  recognizes  persistent  congenital  erosions.  Most  authors  accept  the 
direct  transformation  of  mucous  into  squamous  lining  cells,  and,  in  this  respect  Meyer's 
view,  which  sharply  separates  the  two  cells  types,  is  probably  too  rigid.  The  influence 
of  simple  ectropion  is  also  emphasized  by  many,  especially  for  multiparse.  All  these 
observations  bear  directly  on  the  histogenesis  and  variable  structure  of  cervical  car- 
cinoma. 

Mucous  adenocarcinoma  of  the  cervix  is  rare.     Miller  collected  5  cases 
in  which  the  alveoli  were  filled  or  distended  with  mucus,  while  the  stroma  was 


FIG.  246. — Adeno-acanthoma  of  endometrium. 

unaffected.  In  Albrecht's  case  there  was  extensive  diffuse  infiltration  of 
the  cervix,  corpus,  parametrium,  and  lymph-nodes.  In  Cullen's  case  the 
tumor  involved  both  cervix  and  corpus.  For  these  cases  an  origin  from  an 
aberrant  group  of  intestinal  or  ovarian  glands  is  suggested  by  Williams. 

Atypical  Forms  of  Cervical  Carcinoma, — (a)  Scirrhous  carcinoma  of  the 
cervix  has  been  described  by  several  observers  who  had  to  deal  with  over- 
growths of  cellular  or  fibrous  stroma  and  corresponding  suppression  of  eipthe- 
lial  cells,  which  here  may  assume  a  small  spindle  form  (Wagner,  Gebhard, 
Cullen).  This  structure  usually  occurs  in  late  cases,  and  signifies  a  local 
inhibition  of  tumor  growth.  As  in  other  localities,  the  outlying  areas  of  the 
tumor  may  exhibit  undiminished  vitality. 

(b)  Simple  Adenoma  or  Cystadenoma  of  the  Cervix. — The  cervix  is  occa- 
sionally the  seat  of  a  characteristic  adenoma  composed  of  regular  alveoli  lined 
by  a  single  layer  of  cylindrical  cells,  reproducing  the  structure  of  the  normal 
cervical  glands  (Ruge,  Veit).  While  many  of  these  tumors  are  benign,  some 
recur  locally,  and  have  produced  metastases  in  the  vagina.  The  microscopic 
structure  has  also  revealed  adenocarcinomatous  and  carcinomatous  changes 


550  NEOPLASTIC  DISEASES 

(Ruge,  Krukenberg).  Winter  interprets  these  tumors  as  a  slowly  developing 
adenoma  of  cervical  glands  with  carcinomatous  tendencies.  Stone  describes 
precancerous  changes  in  these  glands. 

(c)  Endothelioma. — Unusually  small  tumor-cells  growing  in  long  narrow 
columns  or  in  small  groups,  or  diffusely,  may  give  the  appearance  of  endothe- 
lioma,  and  hence  have  led  several  authors  to  assume  an  endothelial  origin  for 
certain   cervical   tumors   (Kroemer,   Graefe,   R.   Meyer,   Poworecke).    Since 
the  gross  appearance  of  these  tumors  is  identical  with  that  of  certain  epithe- 
liomas,  and  since  they  are  usually  quite  malignant,  it  seems  most  probable 
that   they   represent   atypical   forms   of   epithelioma    (see   Endothelioma   of 
Uterus). 

(d)  Perithelioma. — In  certain  rapidly  growing  and  atypical  epitheliomas  of 
the   cervix  the  cells  become  arranged  about  blood-vessels,   giving  a  peri- 
theliomatous    structure.      Hansen    describes    an    intravascular    hemangio- 
endothelioma.    The  existence  in  the  uterus  of  a  tumor  of  vasoformative  cells 
is  uncertain. 

(e)  Sarcomatoid  structures  are   sometimes   seen   in  portions   of   early   or 
advanced  cervical  carcinoma,  but  they  are  more  frequently  observed  in  the 
corpus  (Forssner). 

The  cells  have  no  definite  squamous  or  glandular  character,  they  grow 
diffusely  with  little  stroma,  and  giant-cells  may  be  numerous.  The  gross 
appearance  of  such  tumors  is  nevertheless  rather  characteristic  of  carcinoma, 
and  thorough  microscopical  study  may  reveal  epithelial  and  alveolar  struc- 
tures. In  all  such  cases  the  gross  appearance  of  theilesion  should  weigh 
strongly  in  the  diagnosis.  Tumors  of  this  type  are  described  by  Cullen  and 
many  others,  and  they  are  sometimes  wrongly  called  carcinosarcoma  (see 
Sarcoma  of  Uterus). 

Precancerous  Changes  in  the  Cervix. — The  alterations  in  structure  which 
precede  the  development  of  definite  carcinoma  of  the  cervix  have  been 
variously  interpreted.  Schauenstein,  Sitzenfrey,  and  Schottlander  describe 
as  characteristic  of  beginning  carcinoma  the  following  changes: 

(1)  The  appearance  of  groups  of  irregular,  hypertrophied  epithelial  cells 
with    hyperchromatic    nuclei,    with   irregularity   and   indistinctness    of    cell 
borders. 

(2)  Loss  of  regular  stratification  of  cell  layers,  especially  of  the  proliferating 
basal  cells.    Schottlander  also  emphasizes  the  importance  of  marked  nuclear 
granulation. 

The  significance  of  these  changes  is  contested.  Heurlin  and  Pick  inter- 
pret them  as  atypical  hypertrophy  and  regeneration.  Yet  when  to  them  is 
added  the  features  of  (3)  downward  growth  of  epithelial  papillae  and  definite 
heterotopia,  there  is  little  doubt  that  one  has  to  deal  with  the  early  stages  of 
carcinoma.  In  a  uterus  partly  lined  by  squamous  cells,  Sitzenfrey  describes 
early  downward  growth  of  squamous-cell  groups  and  cylindrical  cell  alveoli 
into  a  tissue  infiltrated  with  round  cells,  a  condition  which  must  be  accepted 
as  beginning  carcinoma.  Rubin  pictures  extremely  early  but  quite  definite 
proliferation  of  atypical,  cylindrical,  and  squamous  cells  on  the  surface 
and  in  the  glands  of  old  erosions,  and  the  routine  study  of  such  erosions  re- 
veals many  phases  of  such  precancerous  lesions.  Schauenstein's  cases  illus- 
trate extensive  epidermization  of  the  canal  and  corpus,  and  downward  growth 
of  atypical  papillae  at  a  few  points.  In  my  own  material  the  changes  consist 
chiefly  of  epidermization  of  ducts  and  fundi  of  glands,  with  atypical  pro- 
liferation of  both  squamous  and  cylindrical  cells.  Pronai  would  not  insist 
on  heterotopia  and  downward  growth  of  epithelium,  but  describes  as  early 
carcinoma  a  flat  extension  over  cervix  of  foci  of  atypical  epithelium.  Yet 


CANCER  OF  UTERUS,  VULVA,  VAGINA 


551 


there  is  a  condition  of  epidermization  of  the  canal  which  seems  to  have  no 
definite  tendency  to  develop  into  carcinoma.  It  need  not  be  assumed  that 
every  case  presenting  the  above  changes  will  necessarily  develop  cancer, 
focal  epidermization  often  remaining  stationary,  but  it  is  highly  important 
to  recognize  that  the  majority  of  cervical  cancers  develop  from  such  altered 
cells.  When  atypical  hypertrophic  and  hyperchromatic  cells  are  growing 
downward  from  the  epidermis  or  fill  enlarged  gland  alveoli  the  diagnosis  of 
beginning  carcinoma  is  justified. 

Stone  has  shown  that  several  different  anatomical  forms  of  cervical  car- 
cinoma develop  from  equally  specific  precancerous  lesions,  such  as  leuko- 
plakic  patches,  areas  of  epidermization  in  erosions,  atypical  cervical  polyps, 
and  adenomatoid  overgrowth  of  cervical  glands. 

Anatomy  of  Corpus  Carcinoma. — The  rather  numerous  anatomical  forms 
of  this  group  of  tumors  may  be  divided  into  (i)  circumscribed  and  (2)  diffuse 
growths  (Ruge  and  Veit).  The  latter  usually  represent  the  advanced  stages 


FIG.  247. — Beginning  epidermoid  carcinoma  of  uterus. 

of  the  former,  but  it  is  probable  that  certain  diffuse  tumors  originate  over 
a  very  wide  area,  and  present  specific  features  from  their  inception. 

The  earliest  stages  of  the  circumscribed  growths  appear  as  low  thickenings 
of  a  segment  of  the  mucosa,  usually  in  the  fundus,  or  at  one  horn,  or  near  the 
os  internum.  Very  soon  there  is  a  definite  outgrowth  reaching  into  the  cavum, 
with  papillary  or  polypoid  projections.  Some  tumors  long  remain  distinctly 
papillary  and  are  designated  as  papillary  adenoma,  or  adenocarcinoma 
(Lindquist,  Kaufmann).  The  circumscribed  tumors  are  usually  well  demar- 
cated from  the  adjoining  mucosa,  sometimes  very  sharply,  but  others,  espe- 
cially early  forms,  grade  off  insensibly.  In  advanced  stages  they  produce 
bulky  growths  which  destroy  the  cavum,  and  invade  the  wall. 

The  diffuse  tumors  either  originate  from  a  wide  area  or  early  extend 
laterally  in  all  directions.  They  are  more  frequent  than  the  circumscribed 
forms,  Huerlin  finding  in  his  series  29  diffuse  tumors,  15  circumscribed  and 
2  papillary,  and  of  these  9  covered  the  entire  mucosa,  18  others  at  least 
one-half.  Other  authors  classifv  as  diffuse  onlv  those  tumors  which  involve 


552 


NEOPLASTIC  DISEASES 


the  entire  endometrium.  The  character  of  the  advancing  edge  should  here 
be  considered.  The  cervical  canal  is  very  rarely  involved  in  corpus  carcinoma, 
although  a  short  cervix  in  an  atrophic  uterus  may  suggest  a  cervical  lesion,  the 
cervical  mucosa  may  be  partly  undermined,  and  rarely  it  may  show  implan- 
tation metastasis. 

A  marked  general  enlargement  of  the  uterus  results  from  the  diffuse 
thickening  of  the  mucosa,  for  these  tumors  produce  considerable  bulk  of 
tissue  before  invading  the  wall.  Or  the  enlargement  may  be  due  to  myomas 
which  are  often  associated  with  malignant  adenoma,  less  frequently  with 
carcinoma.  Rarely  there  is  hypertrophy  of  the  muscular  wall  (Theilhaber, 
Hollinger).  When  fully  established  both  localized  and  diffuse  growths  may 
be  sharply  denned  from  the  muscular  wall  which  gradually  becomes  thin 
while  still  free  from  invasion. 


FIG.  248. — Adenocarcinoma  involving  the  entire  endometrium. 

The  integrity  of  the  myometrium  is  the  chief  factor  in  the  favorable 
prognosis  of  many  uterine  cancers.  In  early  stages  the  growth  may  be  strictly 
limited  to  the  mucosa,  and  Vassmer  has  reported  the  successful  eradication 
of  the  disease  by  the  curet.  Eventually  the  thin  wall  is  perforated,  sub- 
peritoneal  nodules  appear,  and  the  peritoneal  cavity,  or  bladder,  or  rectum 
may  be  invaded.  In  more  malignant  cases  there  is  an  early  tendency  toward 
invasion  of  the  myometrium  by  groups  of  tumor  alveoli,  and  the  whole  wall 
may  thus  be  infiltrated  and  thickened.  Rarely  a  deep  invasion  of  adeno- 
carcinoma  occurs  early  at  one  point;  and  in  such  areas  I  have  seen  the  sub- 
serous  tissue  reached  by  infiltration  along  vessels  from  a  flat  tumor  2  cm.  in 
diameter.  Gravity  figures  in  the  early  extension  of  corpus  carcinoma  so 
that  the  vagina  from  the  introitus  to  the  fornix  may  be  the  seat  of  secondary 
ulcerating  growths  through  blood-  and  lymph-vessels. 


CANCER  OF  UTERUS,  VULVA,  VAGINA 


553 


Secondary  changes  in  the  tumor  mark  the  advanced  stages,  and  include 
excessive  polypoid  formation,  ulceration,  necrosis,  and  calcine  deposits. 
These  degenerative  changes  may  greatly  alter  the  gross  and  microscopical 
appearance.  Pyometra  occurs  rarely.  Loose  calcined  myomas  were  found 
by  Cullen  and  Thorn,  in  cases  of  carcinoma. 

In  the  late  stages  the  growth  may  extend  into  the  parametrium,  ovaries, 
tubes,  and  lymph-nodes,  beyond  which  its  progress  is  very  similar  to  that  of 
cervical  adenocarcinoma. 

Structure  of  Corpus  Carcinoma. — Corpus  carcinoma  appears  in  several 
distinct  histological  varieties. 


FIG.  249. — Adenocarcinoma  involving  cervix  and  lower  half  of  fundus  uteri. 

(i)  Malignant  adenoma,  the  most  frequent  type,  presents  greatly  en- 
larged and  elongated  alveoli,  giant  reproductions  of  the  uterine  glands,  lined 
by  several  compact  layers  of  cuboidal  and  cylindrical  cells.  The  cell  bodies 
are  usually  paler  than  the  normal  lining  cells,  but  the  large  hyperchromatic 
nuclei  give  a  dark  staining  character  to  the  gland  linings.  There  is  much 
variation  in  the  number  and  depth  of  the  cells  in  the  tumor  alveoli.  Some 
tumors  rigidly  maintain  the  pattern  of  the  enlarged  uterine  glands  and  in  the 
lymph-nodes,  liver,  and  spleen  the  same  orderly  but  malignant  structure 
persists.  Secondary  alveoli  form  by  convolutions  of  the  lining  within  the 
distended  alveolus  and  yield  a  structure  characteristic  of  a  large  group.  In 


554 


NEOPLASTIC  DISEASES 


all  these  cases  the  stroma  is  greatly  reduced  and  adjacent  alveoli  become 
contiguous,  and  may  fuse. 

(2)  Papillary  adenocarcinoma  is  a  form  assumed  by  certain  tumors  which 
probably  arise  from  superficial  cells  or  adenoid  forms.  They  may  closely 
resemble  in  structure  and  gross  appearance  the  coarser  papillomas  of  the 
bladder,  but  are  usually  more  diffuse  and  compact  (Cullen).  Many  adeno- 
carcinomas  exhibit  a  certain  papillary  tendency  in  their  superficial  portions. 
Various  stages  of  malignant  transformation  of  benign  polyps  are  observed. 
Special  interest  attaches  to  one  group  of  polypoid  carcinomas  because,  while 
the  curetings  show  carcinoma,  the  extirpated  uterus  retains  no  trace  of  the 
disease.  This  situation  may  arise  when  a  polypoid  tumor  attached  by  a 
narrow  pedicle  is  completely  removed  by  the  curet  (Gessner,  Ladinski, 
Lit.).  Of  Ladinski's  cases  I  found  one  to  be  an  atypical  embryonal  adeno- 
carcinoma, another  was  malignant  adenomyoma. 


. 


FIG.  250. — Acanthoma  of  endometrium  with  extensive  hornification. 

(3)  Alveolar  carcinoma  is  rare  in  the  uterus,  but  some  tumors  early  show 
solid  masses  of  cells  forming  alveoli  and  smaller  cell  groups  infiltrating  spaces 
and  vessels.     Extremely  small,  numerous,  and  indistinct  alveoli  may  form, 
giving  a  structure  that  is  almost  or  quite  diffuse.    These  structures  are  more 
aggressive  than  the  malignant  adenoma,  and  they  are  subject  to  degenerative 
changes  which  may  lead  to  the  diagnosis  of  giant-cell  or  round-cell  sarcoma. 

(4)  Squamous  cells  may  form  a  prominent  element  in  adenocarcinoma  of 
the  corpus,  and  in  rare  cases  they  predominate  over  the  glandular  structure 
and  produce  a  true  adeno-acanthoma.     While  in  many  cases  neither  spine- 
cells  nor  keratohyaline  granules  are  demonstrable,  in  others  both  these  criteria 
of  true  squamous  epithelium  are  present,  and  pearl  formation  is  added. 
The  squamous  cells  usually  appear  in  foci  in  the  alveolar  lining  where  the 
sharp  transformation  of  cylindrical  into  flat  cells  may  be  followed.     Such 
cell  foci  usually  fail  to  show  hornification.    Or  the  tumor  may  be  composed 
exclusively  of  large  and  small  groups  of  squamous  cells  without  hornification. 


CANCER  OF  UTERUS,  VULVA,  VAGINA 


555 


Rarely  all  the  characters  of  adult  acanthoma  are  observed.  At  least  three 
primary  acanthomas  of  the  corpus  have  been  described,  all  in  elderly  women 
(Gebhard,  Kaufmann,  Flaischlen).  As  secondary  changes  one  may  find 
hyaline  degeneration  of  masses  of  squamous  cells  or  calcification  of  pearls 
(C.  psammosum,  Hitschmann).  In  elderly  subjects  in  which  the  uterus  is 
probably  the  seat  of  an  old  leukoplakia,  squamous-cell  acanthoma  may  develop 
in  many  superficial  foci  or  diffusely,  giving  an  opaque,  warty  appearance  in 
the  gross  and  leading  to  infiltration  of  the  mucosa.  Some  of  these  cases 
probably  represent  an  extension  of  a  cervical  acanthoma  (Ruge,  Benckiser). 
A  combination  of  this  superficial  acanthoma  with  adenocarcinoma  is  described 
by  E.  Kaufmann,  who  holds  that  one  has  to  deal  with  a  double  origin  from 
previously  altered  superficial  lining  cells  and  from  gland-cells. 


FIG.  251. — Atypical  proliferation  of  uterine  glands  in  a  case  of  myoma  uteri. 

The  histogenesis  of  corpus  carcinoma  presents  many  difficulties,  and  in 
spite  of  much  labor  the  exact  origin  of  the  different  histological  types  remains 
uncertain.  Although  Gebhard  claimed  that  malignant  adenomas  arise  from 
hypertrophied  glands  in  chronic  endometritis,  this  simple  history  has  not 
received  verification.  Most  observers  fail  to  find  the  transformation  from 
simple  hypertrophied  gland-cells  to  the  neoplastic.  On  the  contrary,  most 
early  adenomas  show  a  sharp  demarcation  from  the  surrounding  glands, 
and  Heurlin,  in  44  cases,  failed  to  find  any  transitions  or  any  signs  of  glandular 
hypertrophy  in  the  endometrium.  Such  observations  indicate  that  adenoma 
uteri  arises  in  a  circumscribed  group  of  glands  and  extends  laterally  by  dis- 
placing the  normal  glands  even  over  the  whole  endometrium.  The  frequent 
association  of  adenocarcinoma  with  myoma  suggests  that  the  originating 


556  NEOPLASTIC  DISEASES 

glands  may  be  in  some  way  connected  with  a  myomatous  area  or  other  devel- 
opmental anomaly.  But  aside  from  the  rare  and  peculiar  carcinomas  derived 
from  adenomyomas,  there  are  no  facts  to  support  this  hypothesis.  Hence 
one  is  forced  to  the  conclusion  that  adenoma  arises  from  the  normal  glands 
of  the  endometrium  under  conditions  which  cannot  be  accurately  denned, 
but  which  are  probably  associated  with  a  peculiar  local  irritation.  Doca  de- 
scribes early  multiple  adenocarcinomatous  foci  in  the  hypertrophic  mucosa 
in  a  case  of  myoma  uteri.  Here  the  hyperemia  and  local  irritation  of  myoma 
appear  to  have  caused  the  neoplastic  overgrowth  of  normal  glands.  I  have 
seen  3  cases  of  carcinoma  arising  in  the  hypertrophied  glands  overlying  the 
most  prominent  points  of  submucous  myomas.  One  of  these  myomas  was 
calcined. 

The  papillary  adenocarcinomas  have  been  traced  with  considerable  cer- 
tainty to  proliferating  superficial  cells  (Cullen),  but  here  again  no  morpho- 
logical signs  of  a  tissue  predisposition  are  usually  observed.  An  exception 
to  this  rule  occurs  in  the  forms  of  adenocarcinoma  arising  from  polyps.  The 
transformation  of  benign  polpyi  into  malignant  tumors  of  the  corpus  by 
proliferation  and  metaplasia  of  lining  and  gland-cells  has  repeatedly  been 
observed.  Heurlin  describes  the  implantation  of  carcinoma  from  such  a 
malignant  polyp  upon  the  opposite  side  of  the  uterus,  and  somewhat  similar 
implantations  are  reported  by  Noble  and  Flaischlen. 

The  mode  of  extension  of  the  common  adenoma  and  adenocarcinoma  is 
still  under  discussion.  While  most  of  these  tumors  present  well  demarcated 
edges,  the  gradual  inclusion  of  normal  glands  in  the  tumor  area  may  often  be 
observed  in  the  uterus  as  in  the  stomach  and  colon.  It  is  difficult  to  account 
for  certain  very  diffuse  tumors  on  any  other  basis.  Lancereaux  observed 
a  diffuse  tumor  covering  the  entire  endometrium  and  the  mucosa  of  both 
tubes  (Cit.  by  Williams).  Heurlin's  view  in  this  matter  is  certainly  too  ex- 
treme. Likewise  for  the  adenocarcinomas  which  arise  after  epidermization 
of  the  endometrium,  an  origin  from  multiple  foci  of  altered  superficial  or 
gland-cells  and  a  gradual  extension  of  the  process  must  be  accepted.  In  the 
vicinity  of  all  these  tumors  there  are  often  observed  signs  of  collateral  hyper- 
plasia,  low  papillary  projections  of  vessels  from  the  stroma  capped  by  epi- 
thelium, and  groups  of  squamous  cells. 

The  most  definite  origin  of  any  corpus  carcinoma  is  that  of  the  rare  tumors 
derived  from  circumscribed  or  diffuse  adenomyoma.  Arising  in  circum- 
scribed adenomyomas,  the  carcinoma  produces  a  submucous  or  intramural 
tumor  which  tends  to  infiltrate  deeply  and  extend  to  neighboring  tissues, 
often  with  extensive  metastases  (E.  Kaufmann,  Roily,  Dillmann,  Cullen). 

Diffuse  adenomyomatosis  gives  origin  to  characteristic  forms  of  uterine 
cancer.  The  uterus  is  uniformly  enlarged  and  most  of  the  myometrium  is 
the  seat  of  a  diffuse  myomatous  process  in  which  are  many  gland  alveoli 
exhibiting  more  or  less  neoplastic  character.  Often  they  present  the  struc- 
ture of  an  orderly  adenoma,  with  large  alveoli  lined  by  one  or  more  layers  of 
cylindrical  cells.  In  this  form  they  are  capable  of  producing  metastases, 
which  I  have  observed  in  the  ovary.  Islands  of  squamous  cells  may  also  be 
present.  Or  the  epithelial  elements  may  yield  various  forms  of  adenocar- 
cinoma or  carcinoma  (Winter,  Schwab,  Heurlin).  Myomas  are  frequently 
the  seat  of  metastatic  carcinoma  from  ovarian  sources. 

Precancerous  Changes  in  the  Corpus. — From  the  processes  which  tend 
distinctly  to  develop  into  cancer  of  the  endometrium  must  be  excluded  fa 
simple  increase  in  the  cell  layers  lining  the  surface  or  glands.  In  chronic 
glandular  endometritis  multiplication  of  regular  cell  layers  lining  the  glands 
has  repeatedly  been  observed  without  any  indication  of  a  cancerous  tendency 


CANCER  OF  UTERUS,  VULVA,  VAGINA  557 

(Borst,  Cullen,  Heurlin).  Likewise  a  simple  overgrowth  of  surface  epithe- 
lium with  partial  or  complete  epidermization  cannot  be  regarded  as  a  definite 
approach  toward  a  neoplastic  process  (Heurlin,  Lit.).  Yet  the  distinction 
between  such  benign  overgrowth  and  a  progressive  malignant  process  is 
extremely  difficult,  and  opinions  differ  as  to  the  essential  morphology  of  this 
early  form  of  corpus  carcinoma. 

Leukoplakia  uteri  is  a  term  often  applied  to  this  epidermization  of  the 
endometrium  (Gebhard).  It  occurs  under  a  variety  of  conditions.  After 
curettage,  especially  when  the  uterus  has  been  treated  with  escharotics  and 
styptics,  the  regeneration  of  surface  epithelium  may  yield  groups  or  a  con- 
tinuous lining  of  stratified  flat  cells  (Werth,  Sitzenfrey).  In  certain  cases, 
especially  in  atrophic  uteri,  this  epidermization  may  progress  extensively 
with  atrophy  of  the  mucosa,  and  scaly  material  with  cholesterin  may  gather  in 
quantities  in  the  cavum,  producing  the  condition  observed  by  E.  Kaufmann, 
as  cholesteatoma  uteri. 

Rarely  diffuse  benign  epidermization  occurs  as  a  form  of  endometritis 
(Zeller,  Borst).  It  has  often  been  observed  in  connection  with  chronic  pyo- 
metra.  In  epdermoid  carcinoma  of  the  cervix  much  of  the  lower  endome- 
trium may  be  found  covered  with  stratified  cells,  which  may  be  regarded 
either  as  an  extension  of  the  tumor  process  or  as  an  independent  process 
affecting  the  endometrium.  In  many  cases  of  adenocarcinoma  of  the  corpus, 
especially  when  arising  from  polypi,  extensive  epidermization  of  the  endo- 
metrium has  been  observed  (Hofmann,  Hitschmann).  Here  the  process 
may  affect  not  only  the  adenocarcinoma,  but  other  portions  of  the  endo- 
metrium. Finally,  since  islands  of  squamous  epithelium  may  occur  in  the 
normal  fetal  endometrium,  it  may  be  assumed  that  its  occurrence  in  the 
adult  is  sometimes  only  a  result  of  such  early  malformation  (Ribbert,  R. 
Meyer) . 

The  decision  regarding  the  malignancy  of  uterine  epidermization  must 
in  each  instance  be  based  on  its  finer  peculiarities.  In  definitely  malignant 
processes  there  are  irregularity  in  cell  form  and  arrangement,  atypical  mitoses, 
hypertrophy  and  hyperchromatism,  and  often  pearl  formation.  One  may 
very  well  insist,  with  Heurlin,  on  heterotopia  as  an  essential  sign  of  malig- 
nant qualities,  of  which  Oeri's  cases  furnish  examples.  Such  conditions  are 
true  early  carcinomas.  On  the  other  hand,  in  the  absence  of  such  definite 
signs  of  early  carcinoma,  extensive  epidermization  must  still  be  regarded  with 
suspicion  and  classed  among  precancerous  changes. 

Course  of  Uterine  Cancer. — From  the  nature  of  the  initial  symptoms  of 
carcinoma  it  is  obvious  that  the  disease  must  exist  for  some  time  before  it 
attracts  attention,  and  since  the  rate  of  progress  must  vary  considerably, 
observations  on  the  duration  of  the  disease  when  first  recognized  must  have 
a  somewhat  uncertain  value.  Under  these  circumstances  the  early  recogni- 
tion of  uterine  cancer  is  a  very  difficult  clinical  problem.  Winter  claims  to 
have  observed  13  per  cent,  of  his  cases  in  the  first  month  of  symptoms,  30  per 
cent,  in  the  second  to  third  months,  27  per  cent,  in  the  fourth  to  sixth  months, 
8  per  cent,  after  one  year.  Hammer  recognized  50  per  cent,  of  cervical  cases 
in  the  first  3  months,  but  only  19  per  cent,  of  corpus  carcinoma.  Taylor  found 
that  in  50  per  cent,  of  the  cases  the  symptoms  had  lasted  less  than  3  months, 
in  40  per  cent,  between  3  and  6  months,  and  in  only  10  per  cent,  for  more 
than  6  months.  The  rapid  progress  of  the  disease  is  illustrated  by  Macken- 
rodt's  observations,  who  found  the  disease  beyond  the  uterus  in  half  of  18 
cases  examined  within  4  weeks  after  the  earliest  definite  symptoms.  After 
the  second  month  20  per  cent,  of  his  cases  were  inoperable,  after  6  months 
40  per  cent.  Waldstein  points  out  that  cases  are  very  apt  to  fall  into  advanced 


558 


NEOPLASTIC  DISEASES 


inoperable  and  localized  operable  tumors  if  observed  during  the  first  year. 
Early  age,  pregnancy,  special  susceptibility,  a  malignant  structure,  and  a 
location  in  the  cervical  canal  are  more  important  factors  than  the  duration 
of  the  disease.  Cervical  carcinoma  yields  symptoms  earlier,  but  the  estab- 
lished forms  of  corpus  carcinoma  give  more  urgent  manifestations. 

A  serous  or  mucous  discharge  is  the  earliest  symptom,  long  preceding  the 
tumors  arising  from  erosions,  or  many  of  the  corpus  carcinomas,  and  being 
established  early  in  deep  cervical  tumors.  It  results  from  the  preexisting 
inflammation,  from  excessive  mucous  secretion  of  affected  glands,  and  from 
exudates  from  eroded  surfaces.  Only  when  fetid  and  mixed  with  blood, 
in  the  more  advanced  stages,  can  it  be  regarded  as  highly  significant. 


FIG.  252. — Uterine  adenocarcinoma  penetrating  the  wall  of  the  uterus  by  way  of  the  peri- 
vascular  lymphatics. 

Bleeding,  irregular,  at  the  climacteric,  after  slight  trauma,  or  spontaneous, 
or  as  prolonged  metrorrhagia,  is  also  an  early  symptom  in  the  majority  of 
cases. 

Aside  from  the  uterine  colic  of  early  corpus  carcinoma,  pain  is  a  late  symp- 
tom, denoting  ulceration,  or  invasion  of  sensitive  structures,  usually  beyond 
cervix  or  endometrium. 

A  definite  stage  of  the  established  disease  is  reached  by  the  invasion  of  the 
parametrium,  which  usually  occurs  by  continuous  extension  on  one  or  both 
sides,  through  lymph-spaces,  lymph-vessels,  nerve-trunks,  and  occasionally 
by  the  veins.  Isolated  carcinomatous  foci  also  develop  in  the  lymph-nodes, 
about  the  vessels  and  in  the  looser  tissues  of  the  parametrium,  but  the  para- 
metrium may  be  thickened  while  still  free  from  carcinoma  (Scheib,  Samson). 


CANCER  OF  UTERUS,  VULVA,  VAGINA  559 

In  such  tissue  one  finds  thickening  and  sclerosis  of  vessels,  perivascular 
lymphocytic  infiltration,  development  of  many  new  lymph-nodules,  and 
edema.  Bacterial  infection  of  the  parametrium  by  staphylococcus  or  strepto- 
coccus has  often  been  demonstrated  (Veit,  Bumm,  Fromme). 

The  period  of  lymphatic  invasion  varies  greatly  with  the  location  and 
type  of  the  disease,  but  is  relatively  early  in  cervical  carcinoma.  It  has  been 
present  in  more  than  half  (43  to  73  per  cent.)  of  patients  coming  to  operation 
(Scheib).  In  later  stages  the  parametrium  is  perforated  and  peritoneal 
nodules  form,  chiefly  in  the  sac  of  Douglas.  Diffuse  carcinoma  of  the  peri- 
toneum, peritonitis,  and  ascites  are  occasionally  observed. 

Lymphatic  Invasion. — The  course  of  the  lymphatics  has  been  carefully  studied  by 
many  observers  with  reference  to  the  extensions  of  carcinoma.  Two  main  groups  of 
lymphatics  from  (i)  the  body  and  (2)  the  cervix  are  demonstrable,  between  which, 
however,  there  are  rather  free  and  variable  anastomoses. 

The  main  cervical  vessels  follow  the  uterine  artery  through  the  parametrium,  meet- 
ing small  nodes  in  the  broad  ligament  and  at  the  region  where  the  artery  crosses  the 
ureter,  and  further  on  the  iliac  nodes  in  front  of  the  external  iliac  artery  and  about  the 
obturator  foramen.  From  this  plexus  other  vessels  pass  along  the  ureter  to  the  hypo- 
gastric  vessels  and  nodes.  A  posterior  plexus  passes  forward  and  backward  along  the 
sacro-uterine  ligament,  around  the  rectum,  and  to  nodes  at  the  promontory  of  the 
sacrum  (Sappey,  Kroemer,  Poirier,  Lucas-Championniere). 

The  lymphatics  of  the  corpus  begin  in  the  mucosa,  pass  upward  and  outward  and 
leave  the  uterus  in  4  to  5  trunks  just  beneath  the  tubes,  pass  through  the  broad  liga- 
ment, anastomosing  with  the  ovarian  plexus  and  about  the  ovarian  artery  in  the  pelvic 
ovarian  ligament,  to  end  in  lumbar  nodes  above  the  bifurcation  of  the  aorta.  From 
the  middle  of  the  corpus  other  vessels  mingle  with  those  from  the  cervix,  reach  the  iliac 
nodes,  and  some  pass  along  the  round  ligament  to  the  inguinal  nodes  (Sappey,  Bruhns). 
These  six  groups  of  nodes,  parametrial,  iliac,  hypogastric,  sacral,  lumbar,  and  inguinal, 
form  the  regional  nodes  of  the  uterus.  Beyond  them  there  are  rich  communications 
with  each  other  and  with  the  vessels  of  the  bladder,  rectum,  kidney,  and  abdomen 
(Baisch). 

Uterine  carcinoma  as  a  whole  cannot  be  classed  among  the  tumors  which 
early  invade  the  lymph-nodes.  Postmortem  observations  often  suggest  the 
striking  tendency  of  the  disease  to  remain  localized,  either  to  the  uterus,  or  to 
this  organ  and  its  immediate  vicinity,  including  the  regional  nodes  and  the 
tissues  actually  destroyed  by  the  tumor.  The  autopsy  records  collected 
by  Kroemer  showed  the  lymph-nodes  free  in  66  per  cent,  of  the  fatal  cases. 
There  is,  however,  much  variation  in  the  course  of  the  disease.  As  a  rule, 
tumors  of  the  fundus  long  remain  confined  by  the  muscular  wall,  while  cervi- 
cal carcinoma  early  infiltrates  the  cervix  and  invades  the  parametrium. 
Baisch  found  the  regional  nodes  involved  in  only  4  of  24  cases  of  corpus  car- 
cinoma, and  Cullen  regularly  found  the  nodes  free.  The  duration  and  the 
type  of  the  disease  are  doubtless  the  controlling  factors  in  the  rapidity  of 
extension,  but  their  influence  does  not  appear  seriously  to  alter  the  above  rule, 
so  that  permanent  operative  cures  of  corpus  carcinoma  are  often  observed 
(Doderlein,  Fritsch,  Landau,  Cullen).  In  cervical  carcinoma  the  early  in- 
volvement of  the  parametrium  and  its  nodes  was  fully  demonstrated  by 
Kundrat,  who  in  160  cases  found  this  structure  involved  in  55  per  cent., 
while  Lamaris  and  Kermauner  saw  such  extension  in  57.5  per  cent.,  Baisch 
in  36  per  cent.,  Schauta  in  64  per  cent.  From  a  large  series  of  reports  of 
various  types  of  cases  Baisch  concludes  that  the  regional  nodes  are  involved 
in  33  per  cent,  of  operable  cases  of  cervical  carcinoma;  when  the  parametrium 
is  macroscopically  free  the  nodes  are  affected  in  5  to  1 6  per  cent.,  and  with 
invaded  parametrium  the  nodes  are  Affected  in  50  per  cent,  of  the  cases. 
Rarely  the  regional  nodes  are  said  to  escape,  while  more  distant  ones  are  in- 
volved, as  in  Schauta's  postmortem  material.  V.  Herff  also  reports  such  a 


560  NEOPLASTIC  DISEASES 

case,  but  these  isolated  instances  do  not  alter  the  rule  that  uterine  carcinoma 
extends  progressively.  The  invasion  may  be  by  continuous  permeation, 
or  sound  tissue  may  separate  the  nodes  from  the  cervix  (Kundrat).  Rarely 
extensive  lesions  may  fail  to  involve  the  nodes  (Cullen),  but  in  many  cases 
they  were  already  involved  with  cervical  lesions  which  had  the  appearance 
of  simple  erosions,  or  consisted  of  a  small  circumscribed  nodule  (Baisch,  Lit.). 
It  has  repeatedly  been  shown  that  only  microscopical  examination  is  a  safe 
guide  to  the  conditions  of  both  swollen  and  small  lymph-nodes.  Distinct 
metastatic  nodules  in  the  uterine  wall  may  develop  from  cervical  cancer 
(Blau,  Winter). 

Among  Sampson's  27  cases  he  found  only  10  in  which  the  parametrium 
was  free.  The  direct  extension  of  the  disease  through  fine  lymphatics 
is  the  most  frequent  manner  in  which  this  tissue  is  invaded  by  cancer, 
occurring  in  14  of  17  cases  in  which  parametrial  extension  was  found.  Metas- 
tases  in  the  lymph-nodes  of  the  parametrium  were  also  present  in  6  of  these 
cases.  Of  much  clinical  importance  is  the  fact  that  the  parametrium  may  be 
cancerous  while  the  pelvic  nodes  are  free,  demonstrating  that  the  parame- 
trium may  be  able  to  check  the  disease  for  a  time.  Hence  if  one  can  remove 
the  entire  local  growth  it  may  be  possible  to  cure  a  certain  percentage  of 
such  cases.  Induration  of  the  parametrium  without  cancerous  invasion 
occurred  in  i  case,  while  in  3  cases  the  parametrium  was  invaded,  but  felt 
normal  on  palpation.  Of  19  lymph-nodes  examined,  9  were  found  invaded. 
Gellhorn,  from  a  full  review  of  the  literature  and  from  his  own  experience, 
concludes  that  cervical  carcinoma  involves  the  pelvic  nodes  in  less  that  one- 
third  of  all  cases.  R.  Peterson  examined  the  lymph-nodes  removed  in  29  of 
a  series  of  51  cases  and  found  invasion  in  only  5.  At  autopsy  on  cervical 
carcinoma  the  striking  feature  is  the  usual  limitation  of  the  disease  to  the 
pelvis  or  even  to  the  uterus  and  immediately  contiguous  tissues.  In  these 
respects  cervical  carcinoma  follows  the  usual  rule  of  acanthoma,  viz.,  to 
destroy  the  originating  tissue,  extend  with  induration  and  ulceration  to  the 
first  barrier  of  lymph-nodes,  and  then  cease  its  progress.  There  are,  however, 
highly  anaplastic  epidermoid  carcinomas  and  glandular  carcinomas  of  the 
cervix  which  extend  widely. 

Many  efforts  have  been  made  to  establish  a  relation  between  prognosis 
and  the  structure  of  the  tumor,  from  which  it  appears  that  the  transitional 
cell  cervical  carcinomas  are  distinctly  more  malignant  than  the  squamous 
epitheliomas  of  the  portio.  Thus  when  the  parametrium  is  free  Baisch  finds 
invaded  lymph-nodes  in  30  per  cent,  of  cervical  carcinomas,  but  in  only  10 
per  cent,  of  portio  acanthomas. 

Pregnancy  has  an  unfavorable  influence  on  the  course  of  many  uterine 
carcinomas,  but  this  influence  is  not  always  apparent.  The  age  of  the  patient 
is  also  of  some  importance.  Between  20  and  30  years  the  course  of  the 
disease  is  often  unusually  rapid.  Kroemer  finds  the  everted  cauliflower 
growths  of  the  cervix  and  portio  are  of  slight  malignancy;  the  deep  unicentric 
nodules  are  more  so;  while  the  diffuse  forms  are  highly  malignant.  Cullen 
and  Lubarsch  attribute  special  infiltrative  powers  to  the  tumors  composed  of 
small  cells,  a  view  which  accords  with  the  small  size  of  the  cells  in  many  highly 
anaplastic  growths. 

The  microscopical  study  of  pelvic  and  other  lymph-nodes  has  revealed 
the  occasional  presence  in  normal  nodes  of  structures  resembling  isolated 
carcinomatous  alveoli.  These  structures  appear  as  single  or  multiple  well- 
formed  alveoli  lined  by  cylindrical  or  ciliated  cells.  They  have  been  inter- 
preted as  inclusions  of  the  Wolffian  duct  (Borst),  or  as  groups  of  altered 
lymphatic  endothelium  (R.  Meyer).  They  are  usually  located  in  the  tra- 


CANCER  OF  UTERUS,  VULVA,  VAGINA  561 

beculae  where  embolic  cancer-cells  are  not  found,  but  when  situated  in  the 
parenchyma  they  may  be  difficult  to  distinguish  from  carcinomatous  cell 
groups  (Sheib,  Lit.).  Carcinomatous  invasion  of  nodes  is  usually  preceded 
by  parenchymatous  hypertrophy,  and  often  by  catarrhal  or  exudative  lymph- 
adenitis. Streptococcus  infection  of  such  nodes  appears  to  be  rather  promi- 
nent in  cases  of  uterine  carcinoma,  and  may  give  rise  to  suppuration  and 
peritonitis  after  operation  (Ruhle). 

The  clinical  course  of  the  advanced  disease  is  dominated  by  the  secondary 
invasion  of  neighboring  organs.  The  bladder  is  invaded  by  direct  extension 
from  the  cervix,  and  the  wall  is  infiltrated  with  the  formation  of  metastatic 
nodules  in  the  submucosa,  or  more  often  with  ulceration,  necrosis,  and  fistulae. 
Invasion  of  the  bladder  is  relatively  common,  Williams  finding  it  in  56  of 
75  autopsies,  while  in  29  vesico vaginal  fistulae  had  formed. 

The  natural  termination  of  most  cases  of  uterine  cancer  is  through  uremia 
from  occlusion  of  the  ureters.  This  termination  very  frequently  occurs  while 
the  disease  remains  well  localized  in  the  pelvis.  These  important  structures 
are  commonly  invaded  from  without  through  the  parametrium,  and  while  the 
wall  long  resists  destruction,  partial  or  complete  occlusion  is  readily  estab- 
lished by  cancerous  infiltration  or  by  inflammatory  processes.  The  ureter 
may  also  be  invaded  by  extension  through  the  bladder  wall,  and  it  may  be 
occluded  by  inflammation  extending  upward  from  the  bladder.  Dilatation 
of  the  ureter,  hydronephrosis,  and  chronic  nephritis  with  gradual  suppression 
of  the  renal  function  regularly  follow.  Suppurative  nephritis  may  arise  in 
cases  complicated  by  cystitis. 

The  rectum  is  often  compressed  by  infiltration  of  the  wall  and  recto- 
vaginal  fistulae  form  in  not  a  few  advanced  cases  (6  per  cent.,  Beckmann). 

With  invasions  of  bladder  or  rectum  the  pelvic  connective  tissue  is 
usually  involved,  with  compression  of  vessels  and  edema  of  vulva  and  lower 
limbs. 

Visceral  metastases,  while  occurring  in  many  cases,  are  often  conspicuous 
by  their  absence.  Yet  the  disease  may  become  widely  generalized,  and 
secondary  tumors  have  been  observed  in  many  organs.  Since  visceral 
deposits  occur  chiefly  in  the  terminal  stages  of  the  disease,  they  are  not 
distinctly  influenced  by  the  location  or  type  of  the  original  disease,  but  the 
more  adult  acanthomas  rarely  extend  beyond  the  pelvis.  In  rare  instances 
there  is  early  and  very  wide  extension  through  the  lymphatics,  with  continuous 
permeation  through  the  abdominal  and  thoracic  nodes  to  the  supraclavicular 
and  cervical  regions. 

The  liver  has  been  invaded  through  the  portal  vessels  and  by  retrograde 
lymph  flow  in  5  to  15  per  cent,  of  autopsies. 

The  lungs  have  been  invaded  probably  through  the  blood-vessels  in  5  to 
7  per  cent.  Pleural  metastases  extend  from  bronchial  nodes  in  rare  instances. 
Offergeld  collected  56  cases  of  peritoneal  metastases  located  in  a  great  variety 
of  positions,  and  he  found  records  of  7  secondary  tumors  in  the  thyroid,  n 
in  the  adrenals,  31  (2.39  per  cent.)  in  the  kidney,  5  in  the  pancreas.  The 
brain  is  rarely  affected  (Williamsky  0.2  per  cent.).  A  few  cases  of  carcino- 
matous meningitis  have  occurred  from  uterine  cancer.  The  bones  are  in- 
volved in  many  cases. 

Characteristic  cachexia  in  uterine  cancer  develops  in  the  terminal  stages 
of  the  generalized  disease,  but  when  the  lesion  is  localized  in  the  pelvis 
cachexia  is  missing,  the  nutrition  may  remain  surprisingly  good,  and,  if 
infection  can  be  avoided,  death  follows  from  uremia.  Local  and  general 
infection,  usually  by  streptococcus,  may  be  a  prominent  feature.  Fever 
is  almost  always  due  to  infection  and  local  necrosis  of  tissue. 
36 


562  NEOPLASTIC  DISEASES 

The  mortality  from  uterine  cancer  is  very  high.  Jacobson,  from  an 
elaborate  analysis,  shows  that  of  the  women  who  enjoy  the  services  of  the 
best  American  operators  35  per  cent,  are  inoperable,  the  operative  mortality 
is  15.17  per  cent.,  after  5  years  8.39  per  cent,  are  well,  and  i  per  cent,  of  the 
total  are  permanently  cured.  Cullen  states  that  of  cervical  cases  50  per 
cent.,  and  of  corpus  cases  16  per  cent.,  are  inoperable  when  first  seen. 

In  an  effort  to  extend  the  field  of  operability  Ries  and  J.  G.  Clark 
proposed  the  more  radical  operation  which  was  developed  especially  by 
Mackenrodt  and  Wertheim,  but  the  results,  at  first  encouraging,  have  proved 
unsatisfactory.  Mackenrodt's  original  72  per  cent,  of  successes  fell  first  to 
42  per  cent.,  then  after  8  years  to  22  per  cent.,  and  after  10  years  to  12  per 
cent.  Wertheim's  statistics  have  suffered  a  similar  revision.  The  widest 
discrepancies  exist  between  the  claims  made  of  permanent  cures,  as  Macken- 
rodt, 58  per  cent.;  Rosthorn,  2.65  per  cent.  Operable  carcinoma  of  corpus 
offers  a  better  prognosis,  prominent  clinics  reporting  53  per  cent,  of  perma- 
nent cures  of  this  form  of  the  disease  (Koblanck).  In  a  series  of  103  cases, 
Cullen  reports  16  per  cent,  of  cures  of  adenocarcinoma  of  cervix,  21  per  cent, 
for  acanthoma  of  cervix,  and  66  per  cent,  for  corpus  carcinoma.  Yet  in  the 
latter  group  fall  many  comparatively  benign  tumors. 

In  America  the  Wertheim  operation  has  never  been  distinctly  popular 
because  of  the  feeling  that  the  additional  cases  saved  by  this  method  do 
not  justify  the  higher  mortality.  Some  support  of  the  extraradical  operation 
in  advanced  cases  has  come  from  a  few  paradoxical  cures.  Thus  Scheib 
collected  14  cases  which  remained  well  for  several  years  although  the  regional 
nodes  had  been  involved.  From  the  economic  standpoint  it  must  be  con- 
sidered that  a  competent  Wertheim  operation  is  beyond  the  reach  of  the 
great  majority  of  the  population  and  that  all  the  phases  of  the  cost  of  acquir- 
ing technical  skill  should  be  counted  in  estimating  its  utility.  Because 
of  these  considerations  a  marked  change  has  occurred  during  the  last  few 
years  in  the  aspects  of  surgical  treatment  of  uterine  cancer,  most  surgeons 
preferring  to  reduce  the  scope  of  operability  and  others  abandoning  all 
operations  for  uterine  cancer,  in  favor  of  radium  and  x-ray  treatment. 
Earlier  diagnosis  has  doubtless  contributed  to  improving  surgical  statistics 
and  is  equally  important  for  radium  therapy.  In  these  directions  lies  the 
hope  of  real  advance  in  the  therapeutics  of  uterine  cancer. 

EPIDERMOID  CARCINOMA  AND  EPITHELIAL  TUMORS  OF  VULVA 

These  tumors  are  peculiar  because  of  the  special  conditions  under  which 
they  originate,  their  relatively  great  malignancy,  and  the  late  period  of 
life  at  which  they  commonly  arise. 

Carcinoma  of  the  vulva  is  not  a  rare  disease,  forming  10  per  cent.,  ac- 
cording to  Gurlt,  of  all  cancers  in  women.  The  majority  of  the  tumors  are 
epidermoid  carcinomas  arising  from  the  mucous  membrane  of  the  vulva, 
but  the  clitoris  is  also  a  frequent  source  of  epithelioma,  and  glandular  cancers 
develop  from  the  sweat-glands  and  from  the  gland  of  Bartholin.  It  is  most 
frequent  in  the  sixth  decade  (Dittrich),  but  has  been  observed  in  a  girl  of 
20  years  (Arnot). 

The  disease  first  appears  as  (i)  a  thickening  of  the  epidermis  which  soon 
exhibits  cracks  and  fissures,  or  (2)  a  localized  papule,  vesicle,  or  wart,  or  (3) 
deeper  tumors  of  sweat-glands  or  of  Bartholin's  gland  precede  the  appearance 
of  superficial  lesions.  The  initial  lesions  may  be  multiple  (Fromme).  The 
chief  seat  of  the  disease  is  in  the  follicles,  in  the  sulci  between  the  labia,  and 
about  the  urethral  orifice.  Sitzenfrey  traced  the  origin  of  one  case  to  the  duct 


CANCER  OF  UTERUS,  VULVA,  VAGINA  563 

of  Bartholin's  gland.  Two  notable  conditions,  pruritus  and  leukoplakia, 
often  antedate  the  malignant  process. 

Pruritus  is  a  very  common  precursor  of  carcinoma  of  the  vulva,  but  its 
source  is  not  always  clear.  Dittrich  reports  a  case  of  pruritus  lasting  12 
years  due  to  a  benign  wart,  which  terminated  in  epidermoid  carcinoma. 
Weir  observed  a  long  period  of  pruritus  in  a  young  girl,  associated  with 
kraurosis  and  ending  in  epithelioma.  Frequently  the  pruritus  exists  for 
several  months  before  the  carcinoma  is  discovered.  The  parakeratosis  and 
round-cell  infiltration  of  the  corium  in  pruritus  are  distinctly  favorable  to 
the  development  of  epithelioma. 

The  relation  of  kraurosis  and  leukoplakia  of  the  vulva  to  epithelioma 
was  first  pointed  out  by  Weir  and  later  emphasized  by  Butlin,  Jung,  Franque, 
and  many  others.  A  syphilitic  origin  is  not  always  demonstrable,  but  some 
form  of  local  infection  or  irritation  is  usually  present.  It  produces  a  pearly 
white,  warty  condition  of  the  mucosa  which  appears  at  many  discrete  points 
or  affects  nearly  the  whole  orifice.  The  condition  begins  as  a  chronic  inflam- 
mation of  the  mucous  membrane  with  thickening,  edema,  and  cellular  infil- 
tration of  the  corium,  and  hypertrophy  and  keratosis  of  epithelium,  and  it 
results  later  in  extensive  sclerosis  and  atrophy  of  the  corium  with  contrac- 
tures  (Peter).  From  one  or  more  points  or  from  a  broad  area  of  this  lesion 
epithelioma  develops. 

Other  local  conditions  related  to  the  disease  are  psoriasis,  syphilitic  scars, 
elephantiasis,  abscess,  and  various  forms  of  trauma. 

When  fully  developed  the  carcinoma  appears  as:  (i)  a  prominent  warty 
or  lobulated  tumor;  (2)  a  deep  ulcer;  or  (3)  a  diffuse  infiltration.  In  the  ulcer- 
ating cases  a  severe  infection  is  often  added  which  greatly  complicates  the 
local  condition,  causes  enlargement  of  inguinal  nodes  on  one  or  both  sides, 
and  hastens  the  progress  of  the  disease.  Involvement  of  lymph-nodes  has 
been  observed  as  early  as  3!  months  from  the  beginning  of  the  disease  and 
has  been  delayed  for  more  than  3  years.  Schwarz  found  that  the  swollen 
inguinal  nodes  were  invaded  by  cancer  in  only  about  one-half  of  his  cases. 
Dittrich  finds  that  involvement  of  lymph-nodes  occurs  in  about  50  per  cent, 
of  the  cases  during  the  second  6  months  of  the  disease.  Extensions  occur 
along  the  deep  tissues  to  pubic  bones,  to  the  pelvis,  and  through  inguinal 
and  pelvic  lymph-nodes  of  one  or  both  sides.  Fritsch  saw  extensive  growth 
about  the  urethra.  The  vaginal  mucosa  usually  escapes  involvement,  but 
the  vaginal  wall  may  be  invaded  and  even  the  cervix  uteri.  Local  metastases 
occur  about  the  anus,  in  the  abdominal  wall,  and  in  the  thighs.  General 
metastases  have  been  observed  in  abdominal  nodes,  lungs,  heart,  liver,  spleen, 
and  kidneys  (Kustner). 

Implantation  by  contact  on  the  opposite  labium  has  been  reported  by 
several  observers,  but  the  probability  of  an  extension  through  the  lymphatics 
is  not  eliminated  (Dittrich,  Lit.). 

The  course  of  vulvar  carcinoma  is  usually  rapid  and  terminates,  if  with- 
out operation,  as  a  rule  within  2  years  after  the  discovery  of  the  lesion.  Des- 
champs  observed  a  fatal  case  terminating  in  4  months.  The  explanation 
of  this  rapid  course  is  probably  to  be  found  in  the  abundant  vascular  and 
lymphatic  supply  of  the  tissues,  in  the  late  discovery  of  the  disease,  and  in 
complicating  infections.  Dittrich  found  no  recorded  case  in  which  the  pa- 
tient remained  free  from  recurrence  for  over  6  years.  Several  cases  showed 
recurrence  after  5  years.  H.  Schultze  in  114  cases  found  14  free  from  recur- 
rence after  5  years.  Yet  it  is  probable  that  not  a  few  cases  recognized  early 
have  been  cured  by  operation.  It  may  also  be  noted  that  in  many  cases 
the  early  stages  of  the  disease  may  be  slow  and  that  several  years  may  elapse 


564  NEOPLASTIC  DISEASES 

before  the  lymph-nodes  become  involved  and  the  growth  becomes  accelerated. 
Kaufmann,  Teller,  and  Rupprecht  report  cases  of  long  duration.  Rupprecht 
gives  a  comparatively  favorable  prognosis  for  superficial  lesions,  and  reports 
cures  after  invasion  of  the  nodes. 

Structure. — Epithelioma  of  the  vulva  usually  presents  a  structure  of 
narrow  cords  and  columns  of  relatively  undifferentiated  squamous  cells. 
Hornifi cation  and  pearl  formation  are  not  prominent.  The  malignant 
clinical  character  of  the  process  is  often  apparent  in  the  histological  structure. 
In  the  advanced  stages  the  proportions  of  cells  and  stroma  varies,  and  some 
authors  speak  of  scirrhous  and  encephaloid  types.  Pick  and  H.  Ruge  state 
that  adenoma  of  the  sweat-glands  may  become  malignant  and  pursue  the 
course  of  epitheHoma  of  vulva.  The  structure  of  the  benign  tumor  recalls 
that  of  the  sweat-glands  (tubular  adenoma),  and  the  malignant  form  occurs 
as  an  adenocarcinoma.  Bartholin's  gland  is  the  source  of  rare  adenomas  and 
adenocarcinomas  (Veit,  Lit.).  These  tumors  usually  reach  larger  dimensions 
than  epitheHoma  and  present  an  adenoid  structure  (Chaboux).  Many  cases 
of  melanoma  of  the  vulva  are  recorded  (P.  Meyer,  Hinselmann,  Lit.). 

EPIDERMOID  CARCINOMA  OF  VAGINA 

Primary  epidermoid  carcinoma  of  the  vagina  is  a  comparatively  rare 
condition,  forming  0.24  per  cent.  (Schwarz)  or  0.19  per  cent.  (Gurlt)  of  all 
carcinomas,  or  about  0.43  per  cent,  of  all  carcinomas  in  women  (R.  Williams). 
Secondary  carcinoma,  however,  is  rather  common,  the  vagina  being  invaded 
in  most  cases  of  cervical  cancer,  and  from  the  bladder,  rectum,  ovaries,  and 
other  more  distant  organs.  The  chief  age  of  incidence  is  between  30  and  40 
years,  but  Winckel  saw  7  cases  between  20  and  30  years  and  many  occur 
late  in  life.  Cases  reported  in  infants  are  of  doubtful  nature. 

Exciting  factors  include  the  irritation  of  pessaries  which  have  been  directly 
connected  with  vaginal  carcinoma  in  several  reported  cases  (Wille,  Lit.); 
the  traumatism  of  repeated  childbirth,  a  factor  emphasized  by  West  and 
Bernard;  and  leukoplakia,  which  has  been  observed  to  precede  carcinoma 
in  rare  cases  discussed  by  Reclus,  Bex,  and  v.  Franque. 

In  form  and  location  vaginal  carcinoma  appears  as:  (i)  a  papillary  or 
(2)  infiltrating  growth  arising  (a)  chiefly  on  the  posterior  wall  of  the  upper 
segment,  (7>)  on  the  anterior  wall  and  about  the  urethra,  (c)  on  lateral  wall, 
(d)  in  the  fornix,  whence  it  invades  both  cervix  and  vagina,  producing  the 
"epitheliome  luminaire"  of  Pozzi,  (e)  in  the  lower  segment  and  invading  the 
vulva,  and  (/)  as  an  annular  or  diffuse  infiltration  of  much  of  the  vaginal 
wall  (Olshausen). 

The  initial  stages  of  the  lesion  are  rarely  observed,  but  appear  as  single 
or  multiple  warts;  as  an  elastic  nodule  in  the  epithelial  tissue;  or  as  a  flat 
infiltration.  In  advanced  stages  cauliflower,  villous,  highly  vascular,  and 
more  frequently  ulcerated  tumors  form.  Schwartz  described  a  multiple 
fungoid  epithelioma  of  upper  vaginal  segment  and  cervix. 

The  extensions  of  vaginal  carcinoma  are  determined  by  the  location  of 
the  lesion.  Ulceration  often  occurs  early,  the  muscular  wall  offering  little 
resistance.  With  or  without  ulceration  extension  through  the  lymphatics 
is  established  early  in  the  disease.  From  the  upper  segment  the  lymphatics 
enter  the  iliopelvic  chain  and  join  with  those  of  the  cervix  uteri;  from  the 
middle  segment  the  vessels  enter  the  lowest  nodes  of  the  iliopelvic  and  hypo- 
gastric  groups;  while  from  the  lower  portion  drainage  is  toward  the  inguinal 
nodes  (Poirier,  Bruhns).  Along  these  channels  the  nodes  become  enlarged, 
vessels  are  constricted  with  edema,  and  the  urethra  may  become  obstructed 
with  cystitis  and  hydronephrosis.  Ulceration  produces  fistulous  tracts  to 


CANCER  OF  UTERUS,  VULVA,  VAGINA  565 

rectum  or  bladder.  Extensive  suppuration  and  peritonitis  may  develop. 
The  broad  ligaments,  uterine  wall,  ureters,  and  ovaries  may  be  infiltrated. 
Metastatic  deposits  have  been  observed  in  the  tubes,  ovaries,  kidneys,  liver, 
lungs,  and  bones. 

The  prognosis  is  very  unfavorable.  R.  Williams  calculated  the  average 
duration  of  life  at  16.5  months,  longest  26.25  months,  shortest  8  months. 
Longer  immunity  from  recurrence  has  followed  extensive  operations  in  early 
cases,  but  no  definite  cure  of  the  established  disease  seems  to  have  been  re- 
corded (Lohnberg).  The  early  cases  respond  well  to  radium. 

Structure  and  Histogenesis. — Vaginal  carcinoma  usually  arises  from  the 
squamous  epithelial  lining  and  takes  the  form  of  acanthoma  or  tubular  epi- 
thelioma.  Pearl  formation  and  hornification  are  not  prominent.  The  upper 
cervical  segment  contains  cysts  and  follicles  lined  by  cylindrical  cells  from 
which  atypical  adenoid  epithelioma  may  develop.  The  variable  structure 
and  origin  of  these  cysts  have  been  discussed  by  Cullen.  Davidsohn  regards 
the  vaginal  glands  as  heterotopic  cervical  or  (below)  vulvar  structures.  R. 
Meyer  traces  the  ampulla  of  Gartner's  duct  into  the  lateral  vaginal  wall, 
where  its  structure  is  often  to  be  seen  in  infants.  He  also  traces  the  forma- 
tion of  follicles  by  the  dipping  down  of  the  basal  layer  of  epithelium  and  re- 
ports several  forms  of  congenital  abnormalities  in  the  epithelial  lining  of  the 
fetal  vagina,  as  well  as  adenocarcinoma  arising  from  such  abnormalities. 
In  the  adult  he  finds  small  cysts  and  aberrant  groups  of  squamous  epithelium 
in  the  submucosa.  In  a  remarkable  case  the  entire  vagina  was  the  seat  of  a 
cystadenofibromatous  degeneration.  To  what  extent  these  abnormalities 
are  concerned  in  the  genesis  of  carcinoma  in  the  adult  remains  to  be  shown, 
but  the  occurrence  of  such  conditions  must  be  considered  in  all  atypical  forms 
of  carcinoma  of  cervix,  vagina,  and  vulva. 

Cylindrical  cell  carcinoma  of  the  vagina  is  reported  by  Pintor  and  by 
Polosson  and  Violet,  and  adenocarcinoma  by  Hoehne  and  Hirsch. 


CHAPTER  XXVIII 
CHORIOMA  (CHORIONEPITHELIOMA) 

Historical. — The  characteristic  anatomical  and  clinical  features  of 
destructive  placental  polyp  were  clearly  described  and  depicted  as  early 
as  1867  by  R.  Volkmann  and  later  by  many  others  (Sanger,  Lit.),  but  the 
nature  and  origin  of  other  highly  malignant  tumors  connected  with  gesta- 
tion proved  to  be  a  much  more  difficult  problem,  chiefly  because  the  absence 
of  a  core  of  the  villus  in  these  tumors  removed  the  chief  basis  for  connecting 
them  with  fetal  structures.  The  idea  gained  currency  that  the  chorion  pro- 
duced only  the  destructive  polyp,  while  the  more  malignant  tumors  arose 
from  decidual  cells,  and  this  view  was  maintained  notably  by  Sanger,  -1888  to 
1891,  who  employed  the  term  "deciduoma  malignum"  or  "sarcoma  deciduo- 
cellulare." 

In  this  group,  I  judge  from  the  literature  of  the  period,  were  included 
the  more  malignant  chorionic  tumors,  certain  sarcomas  of  the  endometrium, 
and  possibly  rare  tumors  of  the  placenta.  The  large  fusiform  and  polyhe- 
dral cells  of  the  decidua  were  supposed  to  give  origin  to  the  tumors,  but 
Pestalozza  thought  the  uterine  muscle  also  contributed  to  the  tumor-cells. 
A  combination  of  deciduoma  with  destructive  hydatid  or  placental  moles 
was  recognized,  especially  by  Gottschalk  and  Schmorl,  but  such  cases  were 
regarded  as  of  complex  origin. 

The  fetal  origin  of  the  tumors  was  maintained  by  a  number  of  authors, 
especially  by  Gottschalk,  who,  however,  believed  that  the  connective  tissue 
of  the  villi  suffered  sarcomatous  transformation.  In  this  situation  Mar- 
chand,  by  a  minute  comparison  of  the  tumor-cells  with  the  fetal  villi,  con- 
cluded that  the  tumors  arose  from  the  chorionic  epithelium,  reproducing  both 
syncytium  and  Langhans'  cells.  At  the  same  time  J.  W.  Williams  inter- 
preted his  case  as  of  exclusive  syncytial  (and  maternal)  origin,  and  thus  was 
led  to  retain  the  term  "deciduoma." 

Marchand's  view  of  the  exclusive  chorionic  origin  of  the  tumors  has  proved 
entirely  correct,  and  has  served  to  connect  the  various  grades  of  prolifera- 
tion of  chorionic  epithelium  in  one  general  class,  while  the  clinical  relations 
of  the  different  forms  of  the  disease  have  been  greatly  elucidated,  especially 
the  connection  with  gestation  and  hydatid  mole.  Marchand  divided  the 
tumors  into  two  main  classes,  typical  and  atypical,  the  former  covering  the 
actively  growing  and  metastasizing  tumors,  the  latter  designating  certain 
less  active  or  degenerating  forms  composed  chiefly  of  large  giant-cells.  In 
1910  it  seemed  to  the  writer  that  the  anatomical  and  clinical  distinctions 
long  recognized  to  exist  between  destructive  moles,  typical  chorionic  car- 
cinoma, and  atypical  degenerating  tumors  deserved  definite  emphasis,  and 
he  proposed  for  them  the  terms  "chorioadenoma,"  "choriocarcinoma,"  and 
"syncytial  endometritis."  Subsequent  experience  has  confirmed  this  conclu- 
sion and  interpretation. 

In  recent  years  many  authors  have  contributed  numerous  details  of  our 
knowledge  of  the  origin,  course,  and  treatment  of  the  disease,  and  numerous 
monographic  studies  have  appeared  (Pestalozza,  Veit,  Teacher,  Risel,  Frank, 
Schmauch). 

566 


CHORIOMA  (CHORIONEPITHELIOMA)  567 

Etiology. — The  frequency  of  malignant  proliferation  of  chorionic  epithe- 
lium cannot  at  present  be  determined.  The  number  of  reported  cases  has 
increased  notably  in  recent  years,  so  that  Pollasson  and  Violet  (1914)  were 
able  to  collect  455.  Findley  thought  that  about  16  per  cent,  of  hydatid  moles 
were  malignant.  Senarclens  found  that  of  49  hydatid  moles,  3  (13  per  cent.) 
developed  chorioma,  while  4  others  died  of  other  complications.  In  the 
cases  collected  by  Pollosson  and  Violet  the  disease  occurred  in  the  following 
relations  to  pregnancy:  after  moles,  203  (44  per  cent.);  abortion,  135  (30  per 
cent.);  labor  near  term,  99  (22  per  cent.);  ectopic,  12;  doubtful,  6.  Multiple 
gestations  seem  to  increase  the  liability  to  the  disease,  since  Ollivier  Baure- 
gard  in  178  cases  found  that  66  had  borne  more  than  5  children,  while  22 
were  nulliparae.  Curtis  and  Oui  noted  an  average  of  7  confinements,  and  a 
minimum  of  3,  in  women  between  40  and  53  years  suffering  from  destructive 
placental  mole.  The  average  periods  of  occurrence  have  been  estimated  as 
8  weeks  after  hydatid  mole,  7  weeks  after  abortion,  and  5  weeks  after  labor  at 
term. 

Destructive  mole  usually  yields  symptoms  between  4  and  5  months  after 
the  last  menstruation.  Briquet  found  that  in  14  of  30  abortions  followed  by 
chorioma  and  in  17  of  35  hydatid  moles,  the  age  of  the  ovum  was  3  to  4  months. 
The  age  of  the  patients  has  been  from  17  to  58  years.  At  either  extreme  of 
age  the  probability  of  a  teratomatous  origin  must  be  considered. 

Latent  chorioma  has  occurred  in  some  remarkable  cases  in  which  the 
disease  appeared  several  years  after  the -last  gestation.  This  interval  was 
3  to  4  years  in  several  cases,  5  years  in  Caturani's  case  and  10  years  in  Polano's 
(Outerbridge,  Lit.).  The  capacity  of  fetal  villi  to  maintain  their  existence 
in  the  uterus  for  a  long  period  is  indicated  by  Ries'  observation  of  intact 
villi  in  a  superficial  uterine  sinus  18  years  after  the  last  pregnancy.  It  is, 
of  course,  possible  to  doubt  the  accuracy  of  the  history  in  this  case.  Yet 
the  villi  had  become  fused  with  and  were  nourished  by  the  walls  of  the  veins. 

Gross  Anatomy  and  Structure. — Three  main  types  of  the  disease  may  be 
distinguished  by  gross  and  microscopical  structure,  while  between  these  there 
are  transition  cases. 

(1)  Chorio-adenoma  destruens.    Destructive  placental  mole. 

(2)  Choriocarcinoma. 

(3)  Syncytioma  and  syncytial  endometritis. 

(i)  Chorio-adenoma  Destruens. — The  destructive  recurring  and  perforat- 
ing placental  mole  yields  a  characteristic  gross  appearance.  The  uterus  is 
usually  much  enlarged,  reaching  at  times  a  length  of  13  to  17  cm.  (Huguenin). 
The  wall  is  thick  and  honeycombed,  or  a  definite  cavity  appears  in  tjae  mus- 
culature, or  a  transverse  or  longitudinal  septum  separates  tumor  cavity 
from  uterine  canal  (Volkmann).  In  advanced  cases  the  serous  surface  may 
present  nodular  elevations  due  to  subserous  veins  distended  by  tumor  masses, 
and  similar  extensions  may  be  traced  into  parametrium,  tube,  cervix,  and 
vagina.  Perforation  of  the  wall  has  been  recorded  in  7  cases  (Curtis,  Lit.). 
In  Waldo's  case  hemorrhage  appeared  to  be  controlled  by  a  fringe  of  omen- 
turn,  and  the  patient  recovered.  All  the  others  died.  In  Engstrom's  cases 
separated  vesicles  were  found  on  the  peritoneal  surface. 

The  contents  of  the  uterus  .vary  with  many  circumstances.  When  the 
mole  remains  in  situ  it  presents  the  usual  bulky  tumor  adherent  over  the 
implantation  site  and  altered  by  hemorrhage  or  suppuration.  When  the  mole 
has  been  expelled  coarse  shreds  of  necrotic  tumor  or  larger  lobulated 
masses  resembling  blood-clot  adhere  to  a  portion  of  the  wall,  and  are  con- 
tinuous with  the  distended  sinuses.  Usually  after  curetage  the  tumor  is 
represented  by  a  ragged  cavity  in  the  wall. 


568 


NEOPLASTIC  DISEASES 


The  endometrium  may  be  normal  in  early  cases  or  the  seat  of  implanted 
vesicles  (Moller)  or  extensively  eroded. 

The  gross  diagnosis  of  malignant  mole  may  sometimes  be  approached 
from  inspection  of  the  discharged  material.  The  occurrence  of  great  varia- 
tions in  the  size  of  the  vesicles,  with  many  small  opaque  coherent  nodules, 

in  material  which  comes  away  in  fragments 
with  difficulty  and  in  rather  reduced  amount, 
are  suggestive  signs. 

The  structure  of  chorio-adenoma  is  quite 
specific.  It  presents  an  overgrowth  of  all 
the  elements  of  the  chor ionic  villi,  con- 
nective-tissue core,  Langhans'  cells,  and 
syncytium.  The  connective  tissue  is  com- 
pact cellular,  but  not  very  vascular.  It  may 
be  greatly  increased  in  thickness  and  swollen 
by  edema,  but  mucinous  changes  are  absent 
or  slight.  An  unusual  overgrowth  of  fibro- 
blasts  has  occasionally  suggested  a  sarco- 
matous  tendency.  Neumann  described  rows 
of  large  round  or  elongated  cells  in  the 
stroma,  which  he  derived  from  the  syncytium 
and  regarded  as  a  sign  of  malignancy.  They 
are  by  no  means  constant. 

The  Langhans  cells  appear  in  greatly 
increased  number,  forming  multiple  layers 
at  the  bases  of  villi  and  long  broad  sheets  not 
directly  connected  with  the  villi.  Their  size 
varies  little  from  the  normal,  but  the  nuclei 
are  hyperchromatic.  They  are  sharply  sep- 
arated from  the  overlying  syncytium.  When 
denuded  of  syncytium  they  are  usually  covered 
by  fibrin,  which  suggests  that  they  yield  a 
coagulating  ferment  (Curtis).  These  cells 
present  a  clear  cytoplasm,  contain  glycogen, 
and  rarely  suffer  necrosis. 

The  syncytium  appears  in  the  early  stages 
in  the  form  of  well-nourished  actively  sprout- 
ing  buds   of    strongly   acidophile    cytoplasm 
with     abundant     compact     hyperchromatic 
nuclei.     The   syncytial  buds   may   be   very 
FIG.  253. — Chorio-adenoma.    In-  large  and  abundant  and  constitute  the  chief 
vasion  of  uterine  sinuses.          element    of    the    neoplasm    (Solowij,    Gott- 

schalk).    Some  early  observers  were  thus  led 

to  believe  that  the  tumor  process  resided  exclusively  in  the  syncytium.    A 
pure  syncytioma,  however,  has  not  been  demonstrated. 

In  more  fully  developed  cases  the  syncytium  grows  not  only  in  buds,  but 
in  elongated  sheets  covering  the  increasing  masses  of  Langhans'  cells. 

"Syncytial  wandering  cells"  is  a  term  applied  to  derivatives  of  the  syn- 
cytium, which  are  large  or  giant  polyhedral  cells  occurring  singly  or  in  groups, 
lying  in  the  folds  of  villi,  or  loose  in  the  blood-spaces,  or  infiltrating  the  walls 
of  veins  or  the  musculature.  They  are  present  in  normal  chorions  and  in 
benign  hydatid  moles,  and  are  distinctly  increased  when  a  malignant  mole 
is  altered  by  hemorrhage  or  inflammation.  They  are,  therefore,  less  vigor- 
ous than  either  of  the  other  cell  types,  if  not  distinctly  degenei  ^tive. 


CHORIOMA  (CHORIONEPITHELIOMA) 


569 


The  differential  diagnosis  between  a  benign  and  a  malignant  hydatid 
mole  usually  presents  no  difficulty.  The  distance  separating  the  ordinary 
epithelial  proliferation  of  the  hydatid  mole  from  a  typical  chorio-adenoma 
is  very  great  and  may  be  recognized  at  a  glance,  as  may  be  seen  from  the 
accompanying  figures.  There  is,  however,  an  intermediate  group  of  cases 
in  which  an  unusual  overgrowth  especially  of  syncytial  buds,  less  markedly 
of  Langhans'  cells,  suggests  a  malignant  capacity  and  leaves  the  observer 
in  doubt.  After  encountering  several  of  these  cases  and  learning  of  their 
wholly  favorable  course,  I  have  had  to  extend  my  ideas  of  the  limits  of  epi- 
thelial hyperplasia  in  benign  moles.  There  may  be  very  considerable  over- 
growth of  epithelium  in  moles  which  pursue  a  favorable  course  or  in  which 
an  unfavorable  outcome  results  from  hemorrhage  or  infection.  It  is  possi- 
ble, however,  that  the  same  structure  may  not  always  signify  the  same  degree 
of  penetration  of  the  uterine  sinuses.  In  Waldo's  case  a  perforating  mole 


FIG.  254. — Chorio-adenoma.      Preservation  of  villi,  orderly  syncytium,  and  Langhans' 

cells. 

was  regarded  as  of  benign  structure.  It  must  be  admitted  that  serious  dam- 
age to  the  uterus  may  result  from  hydatid  moles  which  are  not  distinctly 
neoplastic,  but  such  cases  are  extremely  rare,  and  do  not  belong  in  the  present 
category.  In  Solowij's  case,  with  deported  villi  in  the  lung,  it  was  stated 
that  the  epithelium  of  the  villi  in  the  extensively  invaded  uterus  showed 
comparatively  little  proliferation. 

Metastases  in  chorio-adenoma  are  comparatively  rare  and  their  signi- 
ficance is  peculiar.  The  intravascular  position  of  the  infiltrating  villi  favors 
the  separation  of  portions  of  the  epithelium  and  even  of  the  core,  which  be- 
come lodged  in  various  capillary  systems,  including  parametrium,  vagina, 
and  lungs.  As  a  rule,  the  metastases  of  chorio-adenoma  are  limited  to  the 
pelvic  region,  but  occasionally  they  occur  in  the  lung.  In  the  vaginal  wall 
they  form  small  circumscribed  bluish  projecting  tumors.  Several  of  these 
have  been  removed  after  the  expulsion  or  extirpation  of  the  original  tumor 


570 


NEOPLASTIC  DISEASES 


and   the   patient   has   recovered    (Neumann,   Pick,    Engstrom,   Kaufmann). 
The  metastases  consisted  chiefly  of  syncytium. 

Similar  vaginal  tumors  have  occurred  also  with  benign  hydatid  mole. 
In  such  a  case  Pick  found  in  the  vaginal  tumor  segments  of  villi  with  hyaline 
stroma  and  syncytium  largely  necrotic.  In  2  cases  of  abortion  and  3  of  hy- 
datid mole  Dunger  found  mild  proliferative  changes  in  embolic  syncytium. 
It  is  evident,  therefore,  that  vaginal  emboli  do  not  necessarily  signify  the 
presence  of  a  malignant  mole  in  the  uterus.  The  structure  of  the  vaginal 
tumor  is  of  first  importance  in  the  prognosis.  When  actively  growing  Lang- 
hans'  cells  are  present  the  case  may  safely  be  regarded  as  malignant.  I 
have  once  found  only  feebly  proliferating  syncytium  in  a  vaginal  tumor  in  a 
case  which  progressed  unfavorably.  When  the  cores  of  villi  are  present  the 


FIG.  255. — Portion  of  a  benign  hydatid  mole. 

case  is  at  least  relatively  benign,  but  in  Lindfors'  case,  which  was  of  this  type, 
pulmonary  metastases  followed.  It  should  be  remembered  that  normal  villi 
may  be  deported  and  lodged  in  small  veins.  The  structure  of  the  original 
tumor  has  important  bearing  on  the  prognosis  of  vaginal  metastases.  In  15 
cases  with  vaginal  metastases  which  recovered  I  find  that  the  original  tumor 
contained  villi  in  9,  the  structure  was  atypical  (syncytioma)  in  3,  and  in- 
definitely described  in  2.  In  Schlagenhaufer's  case  the  structure  was  pos- 
sibly that  of  choriocarcinoma  with  excess  of  vacuolated  syncytium. 

Pulmonary  metastases,  as  indicated  by  the  symptoms  of  cough  and  hemop- 
tysis, occurred  in  7  recovering  cases  of  chorioma  collected  by  Fleischmann. 

(2)  Choriocarcinoma. — The  majority  of  cases  of  chorioma  pursue  a  fatal 
course,  are  marked  by  a  characteristic  structure  in  which  villi  are  absent,  and 


CHORIOMA  (C MORION EPITHELIOM A) 


571 


the  epithelial  growth  is  anaplastic  and  disorderly.    They  produce  wide-spread 
metastases,  and  are  best  designated  as  "chorionic  carcinoma." 

In  choriocarcinoma  the  uterus  is  only  moderately  enlarged  and  may 
appear  normal  in  size,  but  is  usually  the  seat  of  a  relatively  small  compact, 
opaque,  infiltrating  tumor,  commonly  located  at  the  placental  site.  In  a 
few  cases  no  tumor  has  been  demonstrable  in  the  uterus,  it  having  been  re- 
moved with  the  placenta  or  by  the  curet,  or  the  growth  has  arisen  in  tube 
or  ovary.  Schmorl  reported  a  case  of  malignant  chorioma  in  the  organs, 


FlG.  256. — Benign  hydatid  mole.     Slight  epithelial  proliferation. 

appearing  first  in  the  vagina,  18  weeks  after  normal  labor  with  a  normal 
uterus. 

The  chorionic  carcinoma  is  locally  aggressive.  It  invades  the  sinuses 
without  distending  them  as  does  the  dissecting  mole,  it  splits  up  the  mus- 
culature, and  it  rapidly  traverses  or  perforates  the  wall,  traveling  mainly 
by  the  sinuses.  While  often  infiltrated  with  blood,  the  uterine  tumor  is  usually 
cellular  and  compact,  but  friable.  It  is  not  capable  of  complete  removal  by 
the  curet,  except  possibly  in  very  rare  cases. 

The  structure  is  rather  uniform  and  highly  characteristic.     The  tumor 


572 


NEOPLASTIC  DISEASES 


FIG.  257. — Benign  hydatid  mole.     Moderate  proliferation  of  syncytium. 


FIG.  258. — Benign  hydatid  mole.    The  numerous  Langhans'  cells  belong  to 
the  early  periods  of  gestation. 


CHORIOMA  (CHORIONEPITHELIOMA) 


573 


FIG.  259. — Cross-section  through  a  uterus  the  seat  of  choriocarcinoma. 


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FIG.  260.— Structure  of  vaginal  nodule  in  Polano's  case  of  latent  choriocarcinoma. 


574 


NEOPLASTIC  DISEASES 


consists  of  bands  and  masses  of  acidophile  syncytium  commingled  in  dis- 
orderly relations  with  islands  of  actively  growing  Langhans'  cells.  The 
stroma  of  villi  is  absent,  showing  that  the  cells,  as  in  other  carcinomas,  are 
capable  of  growing  apart  from  their  ordinary  sources  of  nutrition.  The  pro- 
portions of  the  two  cell  types  vary,  but  both  are  always  represented.  The 
syncytium  may  appear  in  abundant  isolated,  elongated,  and  coherent  buds 
resembling  the  malignant  mole,  or  it  may  form  diffuse  sheets  with  large  ves- 
icular nuclei  and  resemble  giant  squamous  epithelium.  A  preponderance 

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FIG.  261. — Choriocarcinoma.     Above,  masses  of  syncytial  cells  resembling  squamous 
epithelium.     Below,  group  of  Langhans'  cells. 

of  orderly  syncytium  belongs  to  the  less  anaplastic  growths.  Some  authors, 
as  L.  Fraenkel,  have  surmised  that  variations  in  the  type  of  syncytium  in 
chorioma  signify  a  varying  origin  from  villi,  or  endothelium,  or  uterine  epi- 
thelium. Lebret  and  others  describe  pseudochoriomas  arising  from  the  uterine 
epithelium.  Yet  there  is  no  satisfactory  evidence  that  the  syncytium  of 
choriocarcinoma  has  more  than  one  source,  which  is  from  villi. 

The  Langhans  cells  may  appear  in  compact  masses  sheathed  by  syn- 
cytium and  differing  little  from  the  normal  type,  or  in  the  more  anaplastic 


CHORIOMA  (CHORIONEPITHELIOMA) 


575 


tumors  these  cells  are  hypertrophied,  nuclei  hyperchromatic,  and  the  separa- 
tion from  syncytium  is  imperfect.  Mitoses  are  limited  to  the  Langhans 
cells. 

In  the  sinuses  the  tumor  masses  may  lie  loosely  or  they  become  adherent 
to  the  walls  and  infiltrate  through  the  endothelium.  Fibrin  masses  are 
often  mingled  with  the  tumor-cells,  especially  in  the  sinuses,  and  here  many 
of  the  syncytial  wandering  cells  appear.  In  all  forms  of  chorioma  infiltra- 
tion of  the  uterine  wall  by  syncytial  wandering  cells  is  more  marked  than  in 
normal  gestation  or  hydatid  mole. 

Reactive  inflammation  occurs  about  necrosing  portions  of  choriocar- 
cinoma  and  has  been  interpreted  as  a  sign  of  local  regression. 

Metastases  in  choriocarcinoma  are  of  early  occurrence  and  in  advanced 
cases  are  invariably  present.  Among  455  cases  of  all  types  of  chorioma  col- 
lected by  Pollosson  and  Violet  vaginal  metastases  occurred  in  93,  pulmonary 
in  133,  cerebral  in  40. 

They  may  appear  first  in  the  vaginal  veins  and  prove  to  be  the  initial 
symptom.  On  excision  these  tumors  present  the  usual  malignant  structure. 


FIG.  262. — Choriocarcinoma  invading  uterine  sinus. 

In  the  lungs  they  form  multiple  protuberant  hemorrhagic  nodules,  well 
circumscribed  by  the  walls  of  the  veins  in  which  they  lie.  Here  the  structure 
often  varies  from  that  of  the  uterine  growth,  syncytium  is  scanty  or  absent, 
Langhans'  cells  small  and  abundant,  and  the  structure  may  be  difficult  to 
separate  from  other  cellular  carcinomas.  In  liver,  brain,  spleen,  and  kidney 
the  tumors  resemble  those  in  the  lungs. 

(3)  Syncytioma.  Atypical  Chorioma  of  Marchand.  Syncytial  Endome- 
tritis. — In  a  limited  group  of  cases  the  uterus  fails  to  present  a  well-defined 
tumor  process  of  the  type  of  chorio-adenoma  or  choriocarcinoma,  but  a  por- 
tion or  the  whole  of  the  wall  of  the  cavum  is  infiltrated  by  many  large  or 
giant  acidophile  cells  of  the  general  type  of  syncytial  wandering-cells.  To 
this  process  the  term  "syncytioma"  is  applied.  In  Schmauch's  list  about  5 
per  cent,  of  the  fatal  ca'ses  were  of  this  type.  The  uterus  is  usually  much 
enlarged  and  may  contain  a  bulky  mass  composed  of  uterine  stroma  infiltrated 
with  the  above 'cells  mingled  with  much  fibrin,  and  necrotic  detritus,  and 
swollen  by  exudate  and  hemorrhage.  The  writer's  case  9  illustrates  this 
condition.  Or  the  process  may  be  limited  to  a  small  area  of  mucosa  (v.  Velits). 
Or  the  entire  wall  may  be  thickened,  as  in  Cullen's  case,  but  a  definite  intra- 


576 


NEOPLASTIC  DISEASES 


uterine  tumor  is  wanting.    Rarely  the  process  extends  through  the  wall  into 
the  broad  ligament. 

The  walls  of  vessels  are  swollen  and  infiltrated  by  large  cells.  The  stroma 
contains  lymphocytes,  plasma-cells,  leukocytes,  blood,  and  fibrin.  A  reac- 
tive growth  of  endothelial  cells  and  fibroblasts  may  appear.  The  muscle- 
cells  develop  multiple  nuclei  and  split  up  into  acidophile  fragments  which 
resemble  syncytial  wandering-cells.  In  3  cases  I  have  been  unable  to  trace 
any  participation  of  uterine  epithelium.  The  decidual  cells  probably  partic- 
ipate in  the  process  or  form  the  main  element  in  certain  cases  in  which  the 
lesion  is  diffuse.  Such  a  condition  is  that  described  by  Cullen  in  which  the 
uterus,  as  large  as  a  5  months'  pregnancy,  was  lined  by  a  thick,  irregular, 
largely  necrotic  tissue  covering  the  entire  endometrium.  Here  many  areas  of 
degenerating  decidual  cells  were  described.  In  many  cases  it  is  difficult  to 


FIG.  263. — Giant-cells  in  syncytioma. 

distinguish  between  decidual  cells  and  wandering  syncytial  cells,  and  this 
difficulty  is  increased  when  the  tissue  is  degenerating  and  infiltrated  by  leuko- 
cytes. 

Progressive  metastases  are  not  observed,  but  Fleischmann  described  a 
vaginal  tumor  presenting  the  structure  of  atypical  chorioma,  which  may 
have  arisen  from  deported  villi. 

The  conditions  included  in  the  category  of  syncytioma  probably  arise 
from  several  antecedent  processes,  and  chiefly  from  abortion,  hydatid  mole, 
and  chorio-adenoma.  It  is  unlikely  that  fully  developed  choriocarcinoma 
ever  suffers  such  extensive  regression  as  to  produce  this  anatomical  picture. 
Excessive  invasion  of  the  uterine  muscle  by  syncytial  wandering  cells  is 
observed  with  retained  chorion,  hydatid  mole,  and  especially  with  chorio- 
adenoma.  After  spontaneous  expulsion  or  imperfect  curetage  of  a  malignant 


CHORIOMA  (CHORIONEPITHELIOMA)  577 

mole  proliferation  of  wandering-cells  may  continue,  and  when  hemorrhage  and 
infection  follow,  the  condition  called  syncytioma  may  apparently  develop. 
When  the  process  has  perforated  the  wall  it  must  have  resulted  from  a  dis- 
secting malignant  mole  which  has  undergone  the  spontaneous  regression 
which  many  observations  show  may  overtake  this  process. 

Whatever  may  be  the  original  conditions  which  result  in  excessive 
infiltration  by  syncytial  wandering-cells,  it  is  clear  that  the  disease  is  not  a 
progressive  neoplasm,  but  a  regressive  and  inflammatory  process  appearing 
in  various  stages  and  after  variable  antecedents.  I  have  elsewhere  considered 
at  some  length  the  observations  supporting  this  view  (S.  G.  O.,  1910). 

When  the  syncytial  wandering-cells  are  abundant,  well  nourished,  and 
form  more  or  less  compact  sheets,  a  partial  neoplastic  quality  is  suggested 
and  the  term  syncytioma  may  be  employed.  When  the  lesion  is  more  diffuse 
and  complicated  by  exudative  and  productive  inflammation  it  appears  to  be 
well  designated  as  syncytial  endometritis. 

The  remarkable  extent  to  which  the  syncytial  wandering-cells  may  invade  the 
uterine  wall  in  normal  gestation  has  been  emphasized  by  many  observers  and  especially 
by  R.  Meyer.  He  shows  that  these  cells  may  be  extremely  abundant  in  the  superficial 
portions  of  the  musculature,  often  approaching  the  form  of  decidual  cells,  invading  the 
walls  and  even  the  lumen  of  veins,  and  extending  to  the  serosa.  While  normally  dis- 
appearing shortly  after  gestation,  in  various  pathological  conditions,  as  carcinoma, 
myoma,  retroversion,  or  mole,  they  persist  and  multiply  by  mitotic  division,  yielding  a 
picture  which  may  readily  be  mistaken  for  sarcoma.  Their  behavior  indicates  active 
ameboid  properties.  An  imperfect  development  of  decidua  favors  deep  invasion  of 
villi  and  syncytial  cells  (Bauereisen). 

Clinical  Course  of  Chorioma. — The  different  forms  of  chorioma  vary 
considerably  in  their  clinical  features. 

Chorio-adenoma  regularly  follows  hydatid  mole,  and  occurs  usually  in 
multipart  over  40  years  of  age.  Of  23  cases  collected  by  Curtis  and  Oui  the 
mole  was  found  in  situ  in  13,  and  had  been  expelled  in  10.  After  expulsion 
of  the  mole  there  may  be  a  period  of  a  few  days  or  a  few  "months  in  which 
the  patient  is  free  from  symptoms.  Hemorrhage,  interpreted  as  profuse 
menstruation  or  metrorrhagia,  or  more  alarming,  is  the  first  symptom.  In 
Pick's  doubtful  case  a  vaginal  nodule  was  first  noticed.  The  bleeding  be- 
gins uniformly  in  the  third  month  of  a  supposed  pregnancy  or  at  any  period 
after  expulsion  of  a  mole.  The  bleedings  become  more  severe  and  if  un- 
checked the  patient  may  succumb  in  2  to  8  months  from  exsanguination.  In 
about  13  per  cent,  of  the  cases  infection  occurs  with  fatal  septicemia.  Rup- 
ture of  the  uterus,  spontaneous  or  from  curetage,  is  an  occasional  fatal 
complication. 

The  treatment  commonly  employed  is  hysterectomy.  It  was  followed  by 
recovery  in  n  of  14  cases,  with  3  deaths  (Curtis).  Manual  extraction  of 
the  mole  and  curetage  were  successful  in  2  cases  reported  by  Herz  and  one 
patient  subsequently  gave  birth  to  a  healthy  child. 

Yet  the  anatomy  of  the  disease  does  not  encourage  the  belief  that  many 
of  these  cases  can  be  completely  freed  of  the  infiltrating  villi  by  the  curet. 
Radium  may  prove  of  value  in  this  condition,  but  the  danger  of  hemorrhage 
and  infection  complicates  its  use. 

Veit  emphasizes  the  necessity  of  minute  examination  of  all  portions  of 
the  placenta  extracted  after  abortion,  mole,  or  normal  gestation,  as  the  best 
means  of  prevention  of  chorioma.  He  would  even  extirpate  the  uterus  when 
the  wall  is  found  to  be  very  thin  over  the  implantation  site  of  a  retained 
placental  remnant,  but  here  microscopical  examination  of  the  tissue  seems 
to  be  a  better  guide. 
37 


NEOPLASTIC  DISEASES 

posed  that  all  emboli  from  uterine  tumors  do  not  succeed  in  producing  meta- 
static  tumors.  Some  may  regress  because  of  local  factors,  while  others  go  on 
growing*  I  have  seen  very  extensive  regression,  hyaline  change,  and  fibrin 
formation  in  a  vaginal  metastasis  in  a  case  which  succumbed  to  cerebral 
invasion.  Yet  this  vaginal  tumor  contained  scattered  small  islands  of  well- 
nourished  Langhans'  cells.  Moreover,  the  disease  in  this  patient  developed 
3  years  after  the  last  gestation.  As  a  rule  the  harmless  emboli  are  found 
embedded  in  fibrin  and  degenerating,  as  is  sometimes  seen  in  the  veins  of  the 
broad  ligament  in  tubal  gestation. 

The  further  question  arises  whether  a  malignant  tumor  may  arise  from 
deported  normal  chorionic  cells.  Schmorl  has  reported  a  case  of  chorio- 
carcinoma  in  the  organs,  appearing  first  in  the  vagina,  18  weeks  after  normal 
labor,  with  a  normal  uterus.  Chorioma  has  frequently  arisen  after  normal 
labor  at  term,  and  since  it  is  unlikely  that  a  malignant  change  in  the  placenta 
can  escape  detection,  the  suspicion  has  arisen,  and  has  been  entertained  by 
Marchand,  that  a  malignant  tumor  may  arise  from  deported  normal  placental 
elements.  Strongly  against  this  possibility  stand  the  frequency  of  partial 
hydatid  degeneration  especially  after  abortion  (80  per  cent.,  Stoerk),  the 
frequent  failure  to  examine  the  placenta,  and  the  occurrence  of  ectopic  or 
teratomatous  chorioma. 

After  abortion  (Schlagenhaufer,  Schmidt)  and  after  hydatid  mole  (Pick, 
Schmidt)  the  uterus  was  found  normal,  but  vaginal  tumors  containing  syn- 
cytium  and  Langhans'  cells  were  excised  and  the  patients  recovered.  In 
these  cases  it  must  be  held  that  the  vaginal  tumors  were  deported  normal 
villi  or  fragments  of  moles,  with,  at  most,  transient  proliferation.  In  3  of 
them  there  were  marked  signs  of  degeneration  in  the  vaginal  tumors,  but  in 
Schmidt's  case,  which  was  reported  rather  soon,  the  tumor  was  depicted  as 
an  active  chorio-adenoma. 

On  the  other  hand,  after  normal  labor  (Schmorl)  and  during  gestation 
at  term  (Walthard)  vaginal  tumors  of  the  type  of  choriocarcinoma  and  the 
uteri  which  proved  to  be  normal,  were  extirpated,  but  the  patients  died  with 
metastases.  In  Lindfors'  case  the  uterus  was  found  normal  at  autopsy. 
These  and  other  cases  collected  by  Risel  are  very  difficult  to  explain,  and 
they  suggest  that  deported  normal  villi  or  their  derivatives  may  develop  into 
choriocarcinoma.  It  should  be  noted  that  in  some  of  the  cases  the  placenta 
was  not  examined,  but  this  objection  does  not  apply  to  Walthard's  observation. 

Ovarian  Changes  in  Chorioma. — In  1895  Marchand  pointed  out  the 
notable  frequency  of  ovarian  cysts  in  chorioma,  and  later  (1905)  Patellani 
found  that  in  68  fully  reported  cases  at  that  date  62,  or  91  per  cent.,  presented 
bilateral  cystic  changes.  This  proportion  is  probably  too  high  unless  one 
includes  marked  grades  of  the  small  cystic  cavities  of  gestation,  but  it  is  quite 
evident  that  pronounced  cystic  changes  in  both  ovaries  are  so  frequenMn 
chorioma  as  to  constitute  a  specific  anatomical  feature  of  the  disease,  and 
one  which  invites  explanation.  In  several  cases  the  cysts  have  receded  after 
successful  extirpation  of  the  tumor  or  the  mole,  but  in  fatal  chorioma  they 
persist. 

The  cysts  may  be  very  numerous  and  small,  or  the  ovaries  may  be  bal- 
looned out  by  roomy  multilocular  chambers  to  the  size  of  an  orange.  The 
contents  are  thin,  yellowish,  serous  fluid  containing  albumins,  lipoids,  and 
a  little  mucin.  The  walls  of  the  large  cysts  are  lined  by  a  deep  layer  of  large 
overnourished  granular  polyhedral  cells  exactly  resembling  lutein  cells  of  the 
early  corpus  luteum. 

The  origin  of  the  cysts  has  not  been  traced  with  entire  certainty.  Most  of  them 
probably  arise  by  distention  and  overgrowth  of  corpora  lutea  of  various  ages  (Jaffe, 


CHORIOMA   'CHORIONEPITHELIOMA} 


581 


Orthmann).  The  small  multiple  cysts  of  gestation  are  not  so  clearly  traced.  Seitz 
regards  them  as  arising  from  the  atresic  follicles  of  the  ovary,  which  begin  to  hyper- 
trophy in  the  sixth  week  of  gestation  up  to  term,  and  he  adheres  to  the  view  that  these 
follicles  have  a  different  significance  from  the  corpora  lutea.  Stockel  finds  that  during 
gestation  the  theca  cells  of  the  follicles  wander  out  into  the  ovarian  stroma  forming 
lutein  cell  groups  from  which  the  small  cysts  arise,  and  Schaller  and  Pforinger  found 
such  cell  groups  so  abundant  as  to  suggest  a  tumor  process.  Whatever  the  origin,  the 
structure  and  behavior  of  the  cysts  indicate  that  they  have  an  identical  significance  in 
representing  a  disorder  of  lutein  secretion. 

L.  Fraenkel  concluded  that  interference  with  the  lutein  function  resulted  in  death 
of  the  ovum  and  chorioma,  since  excision  of  the  corpus  luteum  prevented  implantation 
and  growth  of  the  ovum.  L.  Pick  interpreted  the  cysts  as  evidence  of  hypersecretion 
leading  to  excessive  growth  of  the  chorion. 


FIG.  265. — Choriocarcinoma  of  uterus.     Cystic  ovaries. 

The  suggestions  that  the  cysts  result  from  venous  congestion  (Seitz),  that  they  are 
equally  characteristic  of  normal  pregnancy  (Wallert),  and  that  they  belong  to  the 
ordinary  nutritional  changes  of  pregnancy  (Dunger),  seem  quite  inadequate  explanations. 

Veit  considers  the  possibility  that  a  primary  ovarian  disease  yields  a  diseased  ovum 
which  degenerates  and  entails  abnormal  proliferation  in  the  chorion.  Yet  normal  labor 
may  be  followed  by  chorioma. 

Chorioma  after  tubal  pregnancy  occurred  in  12  cases  collected  by  Risel, 
to  which  may  be  added  later  reports  by  Garkisch  and  Bazy.  None  was  recog- 
nized clinically,  all  were  malignant  forms,  and  all  but  one  fatal.  Ovarian 
pregnancy  seems  to  have  been  the  origin  of  a  fatal  choriocarcinoma  described 
by  Kleinhaus. 

Teratomatous  chorioma  in  the  female  has  been  described  by  Lubarsch, 
Pick,  and  Bock. 


CHAPTER'  XXIX 
CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY 

Ovarian  Cysts. — Simple  cysts  form  in  the  ovary  under  several  conditions. 
They  are  often  small  and  bilateral,  giving  rise  to  a  characteristic  appearance 
designated  as  small  cystic  ovaritis  or  degeneration.  Larger  single  or  multiple 
cysts  of  inflammatory  or  mechanical  origin  pass  under  the  term  "hy drops 
follicularis."  The  first  appearance  of  mild  neoplastic  processes  in  dilated 
follicles  deserves  recognition  by  the  term  "simple  cystoma."  Both  benign  and 
malignant  epithelial  tumors  of  the  ovary  are  usually  cystic  and  thus  form  a 
large  and  important  group  of  varied  and  uncertain  origin.  The  corpus 
luteum  is  a  frequent  source  of  cysts  of  peculiar  type.  A  group  of  combina- 
tion cysts  includes  tubo-ovarian  cystoma,  dermatocystoma,  and  combinations 
of  corpus  luteum  cysts  with  other  forms.  The  simple  dermoid  regularly 
assumes  a  cystic  form,  and  many  teratomas  become  cystic. 

Small  multiple  cysts  (cystic  degeneration)  represent  several  different  ana- 
tomical processes: 

(a)  Chronic  ovaritis  with  thickening  and  fibrosis  of  the  cortex  may  be 
associated  with  dilatation  of  many  follicles  which  appear  as  small  translucent 
elevations  of  the  surface  (Hegar,  Bulius).  It  occurs  chiefly  in  early  sexual 
life,  and  is  interpreted  by  Nagel  as  a  premature  maturation  of  follicles.  Yet 
it  is  observed  also  in  children  and  newborn  infants.  I  have  observed  it  with 
general  edema  of  the  ovary  due  to  torsion.  A  moderate  and  variable  degree 
of  development  of  small  cysts  must  be  regarded  as  physiological  and  occurs 
especially  in  infants  and  in  gestation  (Felix). 

(6)  In  elderly  subjects  the  deeper  portions  of  the  cortex  may  be  the  seat 
of  multiple  small  follicular  cysts  lined  by  overnourished  but  undifferentiated 
epithelium,  v.  Kahlden  regarded  these  structures  as  multiple  adenomas 
and  Walthard  derived  them  from  superfluous  groups  of  germ  epithelium 
which  have  failed  to  develop  into  follicles. 

(c)  Remnants  of  the  primitive  nephros  have  been  identified  in  the  ovary 
and  Babo  traces  certain  multiple  small  cysts  to  these  structures,  v.  Franque 
describes  such  cases,  the  cysts  being  lined  by  flat  epithelium. 

(cT)  Multiple  small  or  minute  translucent  cysts  may  be  found  over  the 
surface  of  ovary  and  tubes  and  their  ligaments,  and  are  lined  by  flat,  or 
ciliated,  or  goblet-cells.  Their  origin  is  probably  not  uniform.  Some 
are  referred  by  Walthard  to  superfluous  undifferentiated  germ  epithelium. 
Others  give  evidence  of  a  proliferation  of  peritoneal  epithelium  with  meta- 
plasia of  the  inclosed  cells.  Pick  regards  them  as  miniature  tumors  which 
reveal  the  great  proliferative  capacity  of  germinal  and  peritoneal  epithelium, 
and  believes  that  they  may  go  on  to  produce  cystadenomas.  They  have 
been  extensively  discussed  and  variously  interpreted  by  Schickele,  v.  Franque, 
R.  Meyer,  and  others. 

Simple  follicular  cysts  (hydrops  follicularis)  arise  from  distention  of 
Graafian  follicles  by  an  inflammatory  serous  exudate.  These  cysts  are  of 
small  size,  seldom  as  large  as  the  fist,  and  when  several  develop  in  the  same 
ovary  they  may  be  mutilocular.  Occasionally  they  fuse  with  lutein  or  der- 
moid cysts.  In  some  cases  the  condition  must  be  interpreted  as  an  exaggera- 
tion of  the  small  cystic  chronic  ovaritis.  The  contents  are  serous  albuminous 

582 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  583 

fluid,  without  pseudomucin,  but  blood  and  fatty  detritus  may  be  added. 
The  wall  is  composed  of  the  distinctly  ovarian  tissue  in  a  state  of  atrophy 
and  fibrosis.  Little  ovarian  stroma  may  be  recognizable  and  the  epithelial 
alveoli  of  cystadenomas  are  missing.  The  follicular  epithelium  is  usually 
destroyed.  Low,  warty,  fibrous  excrescences  may  appear  in  the  inner  wall. 
The  fairly  constant  occurrence  of  inflammation  of  the  pelvic  organs  points 
to  the  inflammatory  origin  of  these  cysts.  Single  or  multiple  cysts  are  ob- 
served in  the  newborn  (Virchow,  Klob,  Waldeyer). 

Simple.  Serous  Cystoma. — This  specific  form  of  ovarian  cyst  is  closely 
related  in  structure  and  identical  in  origin  with  the  simple  follicular  cyst, 
but  differs  from  it  in  the  greater  size,  preservation  and  overgrowth  of  lining 
epithelium,  and  in  the  greater  vitality  of  the  connective  tissue.  These  fea- 
tures justify  the  view  that  the  process  is  essentially  neoplastic.  Although  there 


FIG.  266. — Structure  of  wall  of  simple  cystoma  of  ovary. 

are  transitional  cases  between  the  simple  follicular  cyst  and  the  serous  cyst- 
oma there  is  practical  value  in  distinguishing  between  them.  The  former  loses 
its  epithelial  lining,  its  walls  are  acellular,  and  it  remains  of  comparatively 
small  size.  The  cystoma  grows  to  bulky  dimensions,  its  walls  are  cellular 
and  actively  growing,  and  the  lining  cells  multiply,  even  forming  low  papillary 
projections.  In  size  the  cystoma  is  usually  as  large  as  a  child's  head  and 
may  reach  the  dimensions  of  the  bulky  cystadenoma.  Rarely  it  is  bilateral 
(Olshausen,  Bulius,  Orth).  The  cavity  is  usually  single.  The : contents  are 
serous  fluid,  free  from  mucin,  but  often  mingled  with  blood  or  with  fatty 
detritus  or  crystals.  The  lining  is  of  cylindrical  epithelium,  single  cells  or 
syncytium,  and  these  may  form  low  warty  projections.  The  wall  is  com- 
posed of  cellular,  vascular  connective  tissue  without  epithelial  structures, 
and  it  may  form  nodular  or  papillary  projections  with  the  structure  of  an 


584  NEOPLASTIC  DISEASES 

active  fibroma.  The  simple  cystoma  probably  arises  from  ovarian  follicles, 
but  from  which  form  of  these  structures  is  not  known.  Fully  formed  Graafian 
follicles  may  develop  papillary  ingrowths  (Williams),  and  it  is  probable  that 
some  cystomas  are  of  such  origin.  Hence  many  authors  class  these  cysts 
with  follicular  hydrops.  The  occurrence  of  transition  forms  leading  to  cyst- 
adenoma  indicates  that  some  are  derived  in  the  same  manner  as  cystadenoma, 
from  misplaced  and  embryonal  cell  masses. 

Tubo-ovarian  Cysts. — The  simple  ovarian  cyst  may  communicate  with  a 
fusiform  dilatation  of  the  tube  forming  a  composite  cyst  resembling  in  form  a 
glass  retort.  Such  cysts  may  reach  considerable  dimensions.  The  walls  are 
thin  and  contents  usually  serous.  At  the  ostium  of  the  tube  there  may  be 
one  or  more  folds  on  the  inner  surface  from  which  radiate  the  elongated 
nmbrise  embedded  in  the  inner  wall.  The  tubal  portion  may  present  several 
folds  or  partial  contractions.  The  lining  of  the  ovarian  compartment  is  of 
flat  cells,  that  of  the  tubal  part  is  of  cylindrical  and  sometimes  ciliated  epi- 
thelium. Corpus  luteum  cysts  may  fuse  with  the  tube,  in  which  case  the 
wall  presents  the  usual  feature  of  such  cysts.  Shreds  of  smooth  muscle  per- 
sist in  the  wall  of  the  tubal  portion,  but  the  ovarian  section  is  thin  and  fibrous. 
The  origin  of  the  tubo-ovarian  cyst  is  probably  to  be  referred  to  the  union 
of  an  already  formed  ovarian  cyst  with  the  lumen  of  a  tube  which  has  be- 
come adherent  to  the  cyst  wall  through  chronic  productive  inflammation. 
Evidences  of  this  inflammatory  process  are  regularly  found  in  the  form  of 
adhesions  of  the  cyst,  peritoneal  thickenings,  salpingitis,  and  peri-ovaritis 
(Veit).  The  communication  is  established  by  pressure  atrophy.  The  occur- 
rence of  slight  and  early  dilatation  of  the  tube  accords  with  this  view.  Find- 
ing the  ovarian  remnant  limited  to  a  segment  of  the  wall  in  12  of  18  cases, 
Zahn  concluded  that  the  composite  cyst  arises  chiefly  in  the  tube  with  subse- 
quent involvement  of  the  ovary,  but  the  eccentric  position  of  the  ovarian  rem- 
nant is  common  to  other  ovarian  cysts.  Moreover,  the  ovarian  portion  is 
usually  much  the  larger  (Martin). 

Corpus  Luteum  Cysts. — The  corpus  luteum  is  frequently  the  seat  of  dila- 
tation with  overgrowth  of  lutein  cells,  and  gathering  of  serous  fluid,  which 
produces  cysts.  In  size  the  cysts  are  first  small  and  easily  recognized  by  the 
yellow  layer  of  lutein  tissue.  Later  they  are  found  as  large  as  an  orange  or 
a  child's  head,  but  the  larger  ones  are  often  complicated  by  hemorrhage  or 
suppuration.  While  usually  single  and  unilocular,  they  appear  as  bilateral 
multilocular  cysts  with  hydatid  mole.  The  wall  is  composed  of  atrophic 
ovarian  tissue  and  is  lined  by  a  corrugated  layer  of  yellow  lutein  tissue  which 
is  often  incomplete,  but  seldom  absent.  The  contents  are  clear  serous  fluid, 
but  blood  is  often  extravasated  by  capillary  hemorrhages,  bulky  spontaneous 
bleeding,  or  by  strangulation.  Rupture  of  the  cyst  may  lead  to  retro-uterine 
hematocele  simulating  extra-uterine  gestation  (Lunzer,  Lit.).  Suppuration, 
chiefly  from  gonococcus  infection,  frequently  occurs,  replacing  the  lutein 
tissue  with  granulation  tissue,  and  distending  the  cyst  with  thick  mucopus. 
A  definite  group  of  ovarian  abscesses  are  of  this  origin.  They  are  lined  by 
hypertrophic  granulation  tissue  in  which  are  remnants  of  lutein  tissue, 
eosinophile  leukocytes,  plasma-cells,  and  often  demonstrable  gonococci  (Langer, 
E.  Fraenkel).  Garkisch  observed  tuberculous  infection.  The  lutein-cell 
layer  is  early  subject  to  local  infarction  and  necrosis.  The  structure  reveals 
notable  variations,  indicating  several  modes  of  origin  of  these  cysts.  All 
present  an  outer  coat  of  a  cellular  connective  tissue  derived  from  the  external 
layer  of  the  follicle  or  the  distended  ovary. 

(i)  Many  cysts  show  an  internal  lining  of  hyperplastic  lutein-cells 
covered  by  fibrin.  This  structure  is  best  explained  as  a  dilatation  of  the  cor- 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  585 

pus  luteum  beginning  before  any  regressive  changes  have  set  in,  and  is  ob- 
served in  cysts  of  all  sizes.  It  is  also  observed  in  the  multiple  cysts  arising 
from  atresic  follicles  in  hydatid  moles. 

(2)  The  lining  may  be  composed  of  hyaline  and  lamellated  tissue  beneath 
which  is  a  layer  of  lutein-cells.     Such  cysts  probably  arise  after  pronounced 
regressive  changes  have  occurred  in  the  corpus  luteum.     Many  such  cysts 
contain  chiefly  blood  in  various  stages  of  absorption  and  organization,  and 
should  be  interpreted  as  hematomas  in  corpora  lutea  (Fraenkel,  Orthmann). 

(3)  An  epithelial  lining  is  occasionally  observed,  and  is  composed  of  a 
single  layer  of  cylindrical  or  flat  cells,  which  lie  either  directly  upon  lutein- 
cells  as  in  type  (i),  or  upon  the  hyaline  connective  tissue  as  in  type  (2).    The 
origin  of  this  lining  is  still  undetermined.    If  the  cyst  arises  from  an  atresic 
follicle  the  epithelium  could  be  derived  from  the  cells  of  the  membrana  granu- 
losa.     Ciliated  epithelium  was  found  by  E.  and  L.  Fraenkel,  who  remained 
in  doubt  as  to  its  origin,  but  Pick  and  Pfannenstiel  hold  that  such  cells  must 
have  been  derived  from  the  germinal  epithelium  entering  the  cyst  at  the  time 
of  rupture.    Connective  tissue  may  appear  in  the  centers  of  lutein  cysts  and 
the  flat  character  of  the  lining  cells  is  consistent  with  an  endothelial  origin. 

(4)  Bilateral  multilocular  lutein  cysts  commonly  appear  with  hydatid 
mole  and  chorioma.    Kroemer  finds  them  in  59  per  cent,  of  moles  and  Patel- 
lani  in  90  per  cent.     Since  the  condition  is  probably  an  excessive  grade  of 
the  small  cystic  changes  of  gestation  the  estimated  frequency  will  vary  ac- 
cording to  the  size  of  the  cysts  included.     I  find  them  by  no  means  con- 
stant in  chorioma. 

In  pronounced  cases  the  cysts  reach  large  dimensions,  the  walls  are  thin, 
and  neighboring  cysts  fuse.  The  inner  lining  is  of  remarkable  hypertrophic 
and  hyperplastic  lutein-cells,  which  may  slightly  infiltrate  the  walls.  In 
small  cysts  remnants  of  the  granulosa  cells  may  persist  (Stoeckel).  Lymph- 
cysts  may  appear  in  the  walls. 

The  natural  course  of  the  cysts  is  regression  after  removal  of  the  mole. 
Albert  saw  complete  disappearance  of  large  bilateral  tumors  2  months  after 
expulsion  of  the  mole.  Yet  Pfannenstiel  reports  2  cases  of  rapid  increase  after 
curetage. 

That  a  true  neoplastic  process  exists  in  any  form  of  lutein  cyst  appears 
doubtful,  although  the  morphology  of  some  early  cysts  is  suggestive  of  un- 
restrained overgrowth.  In  the  early  stages  of  some  cystic  corpora  lutea  I 
find  overnourished  alveolar  groups  of  small  lutein-cells  with  hyperchromatic 
nuclei  and  layers  of  such  cells  splitting  up  the  ovarian  tissue.  The  appear- 
ance is  not  distinctive  of  a  true  neoplasm.  The  late  course  of  the  lutein  cysts 
fails  to  develop  the  essential  features  of  a  neoplasm,  as  progressive  growth, 
infiltration,  or  metastases.  The  most  advanced  cases  retain  as  a  rule  the 
cystic  form  and  the  lutein-cells  tend  toward  atrophy.  The  process  must  be 
interpreted  as  a  form  of  overgrowth  due  to  overnutrition,  or  excessive  func- 
tion, aided  by  inflammatory  factors.  The  existence  of  a  true  tumor  of  lutein- 
cells  is  not  thereby  excluded,  but  the  reported  cases  of  lutein-cell  tumors 
are  not  entirely  satisfactory. 

Lutein-cell  Tumors. — The  suggestion  that  the  corpus  luteum  might  give 
rise  to  characteristic  tumors  of  the  ovary  was  first  made  by  Rokitansky  in 
1859  and  later  endorsed  by  Klob  and  by  Klebs.  Since  that  time  several 
authors  with  more  or  less  confidence  have  attributed  the  origin  of  certain 
tumors  to  the  lutein-cells.  Some  of  these  tumors  have  been  described  as 
sarcoma,  others  as  carcinoma  (Kroemer,  Lit.).  Voight's  case  was  a  large 
solid  tumor,  grayish  yellow  on  section,  and  showing  a  perithelial  or  diffuse 
arrangement  of  large  cells  resembling  lutein-cells.  The  tumor  obstructed 


586  NEOPLASTIC  DISEASES 

labor.  Sante  also  reported  a  large  tumor  appearing  in  the  third  month  of 
pregnancy.  It  was  soft,  reddish  yellow,  and  infiltrated  with  blood,  and  the 
section  showed  the  structure  of  alveolar  sarcoma  with  septa  inclosing  areas 
of  cells  many  of  which  had  all  the  characteristics  of  lutein-cells.  Six  months 
later  the  patient  succumbed  with  nodular  tumors  of  omentum.  Grousdew 
found  in  the  walls  of  a  large  cystic  tumor  numerous  groups  of  polyhedral  cells 
which  he  interpreted  as  lutein-cells.  He  concluded  that  the  tumor  arose 
from  the  cells  of  one  of  the  corpora  albicantia.  The  patient  died  with 
peritoneal  recurrence  in  the  form  of  spindle-cell  sarcoma,  at  the  age  of  60. 
Michelazzi  referred  to  the  corpus  luteum  a  large  yellowish  tumor  in  an  elderly 
subject.  Wendeler  speaks  of  an  ovarian  tumor  resembling  a  giant  corpus 
luteum  the  structure  of  which  confirmed  the  diagnosis  of  corpus  luteum 
sarcoma. 

I  have  observed  two  forms  of  tumor-like  overgrowth  of  lutein-cells.  In 
one  the  cells  retain  their  original  characters  and  the  convoluted  layer  of 
the  corpus  luteum.  In  the  other  the  cells  are  smaller,  very  compact, 
and  a  diffuse  growth  obliterates  the  convoluted  layer.  I  have  examined  a 
tumor,  with  Dr.  L.  W.  Strong,  which  strongly  suggests  a  lutein-cell  origin. 
It  measured  af  X  3^  cm.,  was  solid,  yellowish,  encapsulated  in  the  ovary, 
and  resembled  an  enlarged  corpus  luteum.  The  structure  was  that  of  alveo- 
lar sarcoma,  the  septa  and  cells  merging  insensibly.  The  cells  were  large 
and  small,  polyhedral,  with  clear  or  slightly  granular  cytoplasm  and  dense 
borders.  Many  contained  hyaline  acidophile  globules  and  scanty  pigment 
particles. 

While,  as  Seitz  concludes,  the  positive  proof  of  the  lutein-cell  origin  has 
not  been  furnished,  yet  the  gross  appearance  of  these  rounded  yellow  tumors 
and  their  peculiar  structure  render  such  an  origin  probable. 

Considerable  proliferation  of  lutein-cells  often  occurs  in  the  cystic  ovaries 
of  hydatid  mole,  and  Schaller  and  Pforringer  have  described  a  "carcinomatous" 
proliferation  in  such  a  case. 

Adenoma. — Adenomas  of  the  ovary  are  usually  cystic,  but  there  are 
rare  forms  of  solid  and  of  superficial  papillary  tumors.  Two  main  classes  of 
cystic  adenoma  are  distinguished  chiefly  on  the  character  of  the  cyst  contents 
and  on  the  epithelial  structure.  These  are  the  serous  and  the  pseudomucin- 
ous  adenomas.  Both  these  types  may  show  a  glandular  (pseudopapillary)  or 
a  papillary  structure,  and  some  authors,  as  Olshausen  and  Kaufmann,  prefer 
to  classify  the  tumors  upon  this  structural  peculiarity  rather  than  upon  the 
character  of  the  cyst  contents.  Either  plan  requires  the  recognition  of  transi- 
tional cases  and  the  histogenesis  is  not  sufficiently  clear  to  form  a  basis  of 
classification.  In  each  class  also  there  are  pure  benign  adenomas,  adeno- 
carcinomas,  and  carcinomas,  the  structure  varying  in  different  cases  and  in 
different  parts  of  phases  of  the  same  case. 

Serous  Cystadenoma. — The  serous  cystadenomas  form  about  one-third  of 
the  cystic  tumors  of  the  ovary.  In  their  earliest  stages  they  are  probably 
identical  with  the  relatively  small  multiple  cysts  of  V.  Kahlden  and  some  of 
them  probably  begin  as  simple  follicular  cysts.  When  fully  developed  they 
reach  large  dimensions,  but  never  the  very  great  size  of  the  pseudomucinous 
tumors.  Most  of  them  are  pedunculated  growths  lying  in  the  peritoneal 
cavity,  but  the  papillary  type  especially  may  be  largely  intraligamentary, 
displacing  the  pelvic  organs  in  its  growth.  Most  of  these  tumors  are  uni- 
lateral, but  the  more  actively  growing  papillary  forms  frequently  (60  per 
cent.)  affect  both  ovaries  either  as  primary  tumors  or  through  implantation. 
The  wall,  at  first  lobulated,  becomes  smooth  and  tense  as  the  tumor  increases. 
The  simple  adenomas  may  be  translucent,  the  more  active  papillary  growths 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY 


587 


are  opaque,  and  papillary  nodules  appear  on  the  surface  and  vicinity,  while 
malignant  processes  are  indicated  by  numerous  adhesions  and  implantations. 
In  some  tumors  simple  cystic  compartments  may  project  in  isolated  form, 
and  an  exaggeration  of  this  process  gives  rise  to  peculiar  hydatidiform  cystic 
adenomas  composed  of  clusters  of  cysts.  The  walls  of  these  cysts  are  thin, 
the  lining  is  of  ciliated  epithelium,  and  contents  are  serous  (Olshausen). 
Of  9  cases  collected  by  Jayle  and  Bender,  6  sprang  from  the  ovary  and  3  from 
the  posterior  surface  of  the  broad  ligament.  The  extra-ovarian  growths 
probably  arise  from  supernumerary  ovaries.  Somewhat  similar  tumors 
lined  externally  by  epithelium  occasionally  form  by  myxomatous  degenera- 


FIG.  267. — A  large  papillary  cystadenoma  of  ovary. 

tion  of  the  stroma  of  superficial  papillary  adenomas  (Odebrecht).  As  might 
be  expected  from  the  position  of  the  epithelium  some  of  these  tumors  prove 
malignant  (Hoffmeier).  Rarely  the  superficial  papillary  growths  are  ex- 
tremely abundant  and  the  intracystic  growth  much  reduced. 

On  section  one  large  central  cavity  usually  represents  the  fusion  of  original 
multiple  chambers  some  of  which  often  persist  until  the  tumor  reaches  a 
large  size.  The  contents  are  originally  yellowish  alkaline  serous  fluid  rich 
in  albumin,  but  free  from  pseudomucin,  but  later  it  may  contain  increasing 
traces  of  pseudomucin,  epithelial  detritus,  fatty  substances,  and  often  much 
blood  from  rupture  of  the  delicate  papillae.  Sand  grains  of  calcine  deposit 
in  the  wall  and  papillae  may  become  extremely  abundant.  When  papillae 


586  NEOPLASTIC  DISEASES 

labor.  Sante  also  reported  a  large  tumor  appearing  in  the  third  month  of 
pregnancy.  It  was  soft,  reddish  yellow,  and  infiltrated  with  blood,  and  the 
section  showed  the  structure  of  alveolar  sarcoma  with  septa  inclosing  areas 
of  cells  many  of  which  had  all  the  characteristics  of  lutein-cells.  Six  months 
later  the  patient  succumbed  with  nodular  tumors  of  omentum.  Grousdew 
found  in  the  walls  of  a  large  cystic  tumor  numerous  groups  of  polyhedral  cells 
which  he  interpreted  as  lutein-cells.  He  concluded  that  the  tumor  arose 
from  the  cells  of  one  of  the  corpora  albicantia.  The  patient  died  with 
peritoneal  recurrence  in  the  form  of  spindle-cell  sarcoma,  at  the  age  of  60. 
Michelazzi  referred  to  the  corpus  luteum  a  large  yellowish  tumor  in  an  elderly 
subject.  Wendeler  speaks  of  an  ovarian  tumor  resembling  a  giant  corpus 
luteum  the  structure  of  which  confirmed  the  diagnosis  of  corpus  luteum 
sarcoma. 

I  have  observed  two  forms  of  tumor-like  overgrowth  of  lutein-cells.  In 
one  the  cells  retain  their  original  characters  and  the  convoluted  layer  of 
the  corpus  luteum.  In  the  other  the  cells  are  smaller,  very  compact, 
and  a  diffuse  growth  obliterates  the  convoluted  layer.  I  have  examined  a 
tumor,  with  Dr.  L.  W.  Strong,  which  strongly  suggests  a  lutein-cell  origin. 
It  measured  z\  X  3?  cm.,  was  solid,  yellowish,  encapsulated  in  the  ovary, 
and  resembled  an  enlarged  corpus  luteum.  The  structure  was  that  of  alveo- 
lar sarcoma,  the  septa  and  cells  merging  insensibly.  The  cells  were  large 
and  small,  polyhedral,  with  clear  or  slightly  granular  cytoplasm  and  dense 
borders.  Many  contained  hyaline  acidophile  globules  and  scanty  pigment 
particles. 

While,  as  Seitz  concludes,  the  positive  proof  of  the  lutein-cell  origin  has 
not  been  furnished,  yet  the  gross  appearance  of  these  rounded  yellow  tumors 
and  their  peculiar  structure  render  such  an  origin  probable. 

Considerable  proliferation  of  lutein-cells  often  occurs  in  the  cystic  ovaries 
of  hydatid  mole,  and  Schaller  and  Pforringer  have  described  a  "carcinomatous" 
proliferation  in  such  a  case. 

Adenoma. — Adenomas  of  the  ovary  are  usually  cystic,  but  there  are 
rare  forms  of  solid  and  of  superficial  papillary  tumors.  Two  main  classes  of 
cystic  adenoma  are  distinguished  chiefly  on  the  character  of  the  cyst  contents 
and  on  the  epithelial  structure.  These  are  the  serous  and  the  pseudomucin- 
ous  adenomas.  Both  these  types  may  show  a  glandular  (pseudopapillary)  or 
a  papillary  structure,  and  some  authors,  as  Olshausen  and  Kaufmann,  prefer 
to  classify  the  tumors  upon  this  structural  peculiarity  rather  than  upon  the 
character  of  the  cyst  contents.  Either  plan  requires  the  recognition  of  transi- 
tional cases  and  the  histogenesis  is  not  sufficiently  clear  to  form  a  basis  of 
classification.  In  each  class  also  there  are  pure  benign  adenomas,  adeno- 
carcinomas,  and  carcinomas,  the  structure  varying  in  different  cases  and  in 
different  parts  of  phases  of  the  same  case. 

Serous  Cystadenoma. — The  serous  cystadenomas  form  about  one-third  of 
the  cystic  tumors  of  the  ovary.  In  their  earliest  stages  they  are  probably 
identical  with  the  relatively  small  multiple  cysts  of  V.  Kahlden  and  some  of 
them  probably  begin  as  simple  follicular  cysts.  When  fully  developed  they 
reach  large  dimensions,  but  never  the  very  great  size  of  the  pseudomucinous 
tumors.  Most  of  them  are  pedunculated  growths  lying  in  the  peritoneal 
cavity,  but  the  papillary  type  especially  may  be  largely  intraligamentary, 
displacing  the  pelvic  organs  in  its  growth.  Most  of  these  tumors  are  uni- 
lateral, but  the  more  actively  growing  papillary  forms  frequently  (60  per 
cent.)  affect  both  ovaries  either  as  primary  tumors  or  through  implantation. 
The  wall,  at  first  lobulated,  becomes  smooth  and  tense  as  the  tumor  increases. 
The  simple  adenomas  may  be  translucent,  the  more  active  papillary  growths 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY 


587 


are  opaque,  and  papillary  nodules  appear  on  the  surface  and  vicinity,  while 
malignant  processes  are  indicated  by  numerous  adhesions  and  implantations. 
In  some  tumors  simple  cystic  compartments  may  project  in  isolated  form, 
and  an  exaggeration  of  this  process  gives  rise  to  peculiar  hydatidiform  cystic 
adenomas  composed  of  clusters  of  cysts.  The  walls  of  these  cysts  are  thin, 
the  lining  is  of  ciliated  epithelium,  and  contents  are  serous  (Olshausen). 
Of  9  cases  collected  by  Jayle  and  Bender,  6  sprang  from  the  ovary  and  3  from 
the  posterior  surface  of  the  broad  ligament.  The  extra-ovarian  growths 
probably  arise  from  supernumerary  ovaries.  Somewhat  similar  tumors 
lined  externally  by  epithelium  occasionally  form  by  myxomatous  degenera- 


FIG.  267. — A  large  papillary  cystadenoma  of  ovary. 

tion  of  the  stroma  of  superficial  papillary  adenomas  (Odebrecht).  As  might 
be  expected  from  the  position  of  the  epithelium  some  of  these  tumors  prove 
malignant  (Hoffmeier).  Rarely  the  superficial  papillary  growths  are  ex- 
tremely abundant  and  the  intracystic  growth  much  reduced. 

On  section  one  large  central  cavity  usually  represents  the  fusion  of  original 
multiple  chambers  some  of  which  often  persist  until  the  tumor  reaches  a 
large  size.  The  contents  are  originally  yellowish  alkaline  serous  fluid  rich 
in  albumin,  but  free  from  pseudomucin,  but  later  it  may  contain  increasing 
traces  of  pseudomucin,  epithelial  detritus,  fatty  substances,  and  often  much 
blood  from  rupture  of  the  delicate  papillae.  Sand  grains  of  calcific  deposit 
in  the  wall  and  papillae  may  become  extremely  abundant.  When  papillae 


588  NEOPLASTIC  DISEASES 

appear  on  the  surface  of  the  tumor  they  may  give  rise  to  implantation  metas- 
tases  over  the  adjoining  peritoneum.  This  type  of  dissemination  occurs 
in  many  of  these  tumors,  and  its  extent  and  severity  accords  with  the  his- 
tological  signs  of  malignancy.  Ascites  regularly  accompanies  these  implan- 
tations. In  general,  the  serous  cystadenomas  differ  from  the  pseudomucin- 
ous,  in  their  smaller  size,  the  greater  frequency  of  bilateral  tumors,  the 
tendency  to  produce  metastases,  the  predominance  of  ciliated  epithelium, 
and  the  usual  absence  of  pseudomucin  in  the  contents. 

Structure. — The  lining  cells  are  cylindrical  or  cuboidal  epithelium  which 
has  a  more  granular  character  than  the  clear  cells  of  the  pseudomucinous 
adenoma.  In  the  simpler  tumors  the  cell  layers  are  single,  lying  upon  a  rich 
stroma.  In  the  more  active  growths  the  cells  increase  in  number,  their  form 
becomes  irregular,  secondary  papillae  develop,  the  wall  is  honeycombed, 
and  sections  of  the  compact  papillae  may  present  a  glandular  appearance. 
A  papillary  structure  predominates  over  the  glandular.  In  more  malignant 
areas  the  growth  of  cells  may  be  more  diffuse  and  less  dependent  upon  the 
stroma.  In  most  cases  ciliated  epithelium  may  be  found  and  sometimes  it 
is  uniformly  present.  Calcine  granules  may  appear  within  or  between  the 
epithelium  or  stroma-cells  (psammoma).  They  occur  at  all  stages  and  have 
little  relation  to  the  vitality  of  the  growth.  The  stroma  forms  low,  thick 
buds  or  longer  cellular  and  vascular  branching  twigs.  Occasionally  it  is 
finely  villous.  Very  abundant  and  cellular  stroma,  suggesting  a  sarcomatous 
property,  is  limited  chiefly  to  distinctly  adenocarcinomatous  tumors. 

The  course  of  the  serous  cystadenoma  is  slow  and  relatively  benign.  The 
simple  tumors  are  uniformly  benign,  unilateral,  and  do  not  produce  local 
metastases  or  recur  after  extirpation.  They  may  cause  pressure  symptoms, 
but  local  peritonitis,  adhesions,  and  ascites  are  rare.  The  more  active  tumors 
with  rich  development  of  papillae  are  clinically  more  serious.  While  slowly 
growing,  and  requiring  3  to  15  years  to  reach  bulky  dimensions,  the  tu- 
mor capsule  may  at  any  time  be  perforated  and  ascites  and  implantation 
metastases  follow.  Likewise  their  frequent  intraligamentary  position  and 
bilateral  occurrence  give  rise  to  more  severe  pressure  symptoms.  Recur- 
rent ascites  marks  the  course  of  many  cases  and  may  require  paracentesis 
over  a  period  of  many  years,  during  which  there  is  progressive  anemia  and 
emaciation.  Pyr-Smith  records  229  tappings  in  9  years,  and  Peaslee  665 
in  13  years.  The  peritoneum  becomes  thickened  and  opaque,  adhesions 
form,  and  implantation  metastases  occur  in  13  per  cent.  (Pfannenstiel).  In 
Peaslee's  case  they  were  absent.  Rupture  of  the  cyst  and  discharge  of  the 
serous  contents  and  tumor  fragments  are  rarely  observed.  It  may  be  fol- 
lowed by  a  slight  fever,  or  by  prolonged  chronic  peritonitis  (Werder).  As  a 
rule  the  implantations  develop  from  papillae  on  the  surface  or  growing  through 
the  wall  without  rupture. 

Implantation  metastases  occur  early  or  late  and  remain  localized  or  extend 
over  a  large  portion  of  the  peritoneum.  Their  course  varies  with  the  general 
malignancy  of  the  tumor,  but  their  fate  cannot  always  be  predicted  from  the 
structure  of  the  original  tumor,  since  some  adenomatous  tumors  have  given 
rise  to  carcinomatous  implantations.  In  a  well-known  group  the  metastases 
disappear  after  extirpation  of  the  tumor.  This  favorable  outcome  occurs 
almost  exclusively  with  structures  which  are  comparatively  non-malignant 
and  in  which  the  lining  cells  of  the  papilla?  are  but  slightly  atypical  and 
appear  in  single  rows.  This  spontaneous  retrogression  has  been  observed  by 
many  writers  and  is  described  with  anatomical  details  by  Froschel,  Bumm, 
H.  Freund,  E.  Fraenkel,  Pfannenstiel,  and  others.  It  seems  probable  that 
regression  of  tumor  fragments  disseminated  by  operation  occurs  very  fre- 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  589 

quently  (Olshausen).  Even  without  the  removal  of  the  primary  tumor  the 
implanted  nodules  may  regress  (E.  Fraenkel,  Werder).  Several  factors 
seem  to  combine  in  this  result.  Chief  among  them  is  the  low  vitality  of  the 
transported  cells  which  tend  to  atrophy.  A  chronic  inflammatory  process 
usually  incloses  the  nodule  in  fibrin,  granulation  tissue,  or  multiplying  endo- 
thelium,  which  cuts  off  the  nutrition  of  the  tumor-cells.  The  nodule  becomes 
flat  and  fibrous,  and  finally  disappears,  leaving  a  slight  scar.  A  constitutional 
element  is  probably  at  work,  but  the  mechanism  of  the  destruction  is  largely 
cellular. 

In  another  group  the  implanted  nodules  maintain  a  low  grade  of  nutrition 
or  gradually  extend  over  much  of  the  peritoneum,  causing  adhesions  and  as- 
cites  and  persisting  until  the  death  of  the  patient  from  cachexia  or  inter- 
current  disease.  These  cases  survive  in  poor  health  until  the  peritoneum 
becomes  so  badly  altered  that  the  intestinal  functions  are  gravely  disturbed. 
The  ascites  appears  to  be  a  less  important  factor  in  the  cachexia. 

In  a  third  group  the  tumor  recurs  after  extirpation  in  the  form  of  pap- 
illary nodules  at  the  stump,  in  the  wound,  or  on  the  peritoneum.  Pfannen- 
stiel  finds  that  77  per  cent,  of  the  papillary  serous  adenomas  can  be  pro- 
nounced cured  by  operation  after  5  years,  most  of  the  recurrences  following 
intraligamentary  growths.  An  unusually  long  period  of  observation  is  re- 
quired, since  recurrences  have  been  observed  at  the  site  of  the  tumor  or  in 
the  peritoneum  after  13,  15,  20,  and  21  years  (Malcolm,  Opitz,  Pozzi,  Hol- 
zapfel),  and  in  the  line  of  incision  after  21  years  (Olshausen).  Even  after 
recurrence  the  patient  may  survive  many  years  in  fair  health  (Schroeder). 

Finally,  the  implantations  may  rapidly  or  gradually  change  their  type 
and  become  malignant,  spreading  over  the  peritoneum,  producing  more 
bulky  infiltrating  local  tumors  and  causing  increasing  cachexia.  Definite 
metastases  of  papillary  cystic  type  in  diaphragmatic  and  retroperitoneal 
nodes,  and  in  subcutaneous  tissue  are  recorded. 

The  serous  cystadenomas  show  with  other  cystic  ovarian  tumors  a  series 
of  anatomical  peculiarities  and  accidental  complications. "  The  pedicle  of 
these  tumors  may  become  elongated  or  divided,  or  it  may  remain  short  and 
thick.  The  movable  tumors  even  when  benign  often  form  adhesions  to 
omentum,  intestine,  appendix,  opposite  ovary  or  bladder,  and  much  of  their 
nutrition  may  eventually  come  from  such  channels.  Intraligamentary 
tumors,  on  trie  other  hand,  extend  through  the  pelvic  fascias  about  uterus, 
bladder,  and  rectum,  which  are  displaced,  compressed,  or  elongated.  The 
Fallopian  tube  is  usually  stretched  over  the  tumor,  but  in  some  instances  the 
tube  is  quite  movable.  Elevation  out  of  the  pelvis  is  regularly  accompanied 
by  rotation  on  the  pedicle,  and  in  the  further  wandering  of  tumors  with  long 
pedicles  various  grades  of  torsion  occur.  Martin  estimates  that  6  per  cent, 
of  all  ovarian  tumors  exhibit  this  condition.  It  occurs  chiefly  in  relaxed 
abdomens  and  is  especially  frequent  in  pregnancy.  The  results  are  edema, 
hemorrhage  into  the  tumor,  peritoneum  or  uterus,  sometimes  fatal,  or  com- 
plete infarction  leading  to  peritonitis  or  rupture.  The  symptoms  vary  with 
the  intensity  of  the  process,  but  in  slow  cases  they  take  the  form  of  cachexia. 
Suppuration  in  ovarian  cysts  is  not  infrequent.  The  microorganisms  re- 
covered include  Bacillus  coli,  streptococcus,  Bacillus  typhosus,  and  the  tubercle 
bacillus. 

Papillary  Serous  Adenocarcinoma. — The  clinical  malignancy  of  many 
simple  papillary  adenomas  becomes  more  pronounced  in  those  tumors  in 
which  the  structure  reveals  the  histological  signs  of  malignancy  and  which 
must,  therefore,  be  classed  as  adenocarcinoma.  A  considerable  proportion 
(50  per  cent.,  Pfannenstiel)  of  papillary  cystic  tumors  reveal  adenocarcino- 


590  NEOPLASTIC  DISEASES 

matous  structure  in  at  least  some  portions  of  the  growth,  but  most  of  such 
tumors  being  encapsulated,  are  successfully  removed.  The  typical  malig- 
nant tumor  is  adenocarcinomatous  throughout  and  its  variations  extend 
toward  alveolar  and  diffuse  carcinoma.  There  is  little  doubt  that  many  of 
the  former  group  represent  malignant  transformations  of  more  typical  adeno- 
mas. A  similar  transformation  has  repeatedly  been  observed  in  the  recur- 
rences of  serous  adenomas  and  in  their  peritoneal  implantations.  Yet  the 
majority  of  adenomas  long  retain  their  benign  type  and  there  is  some  ground 
for  the  view  that  the  malignant  tumors  are  usually  carcinomatous  from  the 
first.  Gebhard  takes  exactly  the  opposite  view,  interpreting  every  papillary 
adenocarcinoma  as  a  degenerated  adenoma.  He  holds  that  it  is  never  pos- 
sible to  determine  even  approximately  their  duration.  Yet  unless  these 
tumors  are  exceptions  to  the  rule,  the  transformation  often  occurs  so  early  as 
to  constitute  a  primary  adenocarcinoma.  The  tendency  of  papillary  adeno- 
mas in  other  regions  to  become  carcinomatous,  the  occasional  occurrence 
of  adenoma  in  malignant  form,  the  frequent  mingling  of  benign  and  malig- 
nant areas  in  the  same  tumor,  and  the  association  of  adenocarcinoma  in  one 
ovary  with  adenoma  in  the  other,  all  indicate  that  ovarian  adenomas  are  to 
some  extent  specially  prone  to  malignant  change. 

The  papillary  adenocarcinoma  is  usually  cystic,  but  the  cysts  are  smaller 
and  less  numerous  than  in  adenoma,  the  inverted  tumor  masses  are  larger, 
and  much  of  the  tumor  is  solid.  The  finely  honeycombed  texture  of  pseudo- 
mucinous  adenocarcinoma  is  missing.  Some  malignant  tumors  are  pedun- 
culated  and  movable,  like  the  adenomas,  but  a  larger  porportion  are  intra- 
ligamentary  or  bound  by  adhesions.  The  cyst  contents  are  seldom  clear, 
since  degenerating  epithelium  is  thrown  off  in  large  numbers,  and  small  hem- 
orrhages discolor  the  fluid  brownish.  The  capsule  is  commonly  perforated 
and  papillary  growths  cover  portions  of  the  surface  and  invade  the  perito- 
neum. The  tumors  are  frequently  bilateral  (66  per  cent.),  and  the  malignant 
structure  may  be  more  advanced  on  one  side.  Only  a  small  proportion  of 
these  bilateral  tumors  can  be  referred  to  implantation. 

In  advanced  stages  metastases  appear  in  the  pelvic  region  and  extend  over 
the  peritoneum  and  even  through  the  diaphragm  to  the  pleura,  accompanied 
by  serous  effusions.  These  secondary  carcinomatous  growths  are  more  ag- 
gressive than  the  adenomatous,  they  do  not  regress,  but  invade  the  serosa, 
intestinal  wall,  diaphragm  and  liver,  and  produce  firm  adhesions  or  fistulous 
tracts.  From  the  surface  the  peritoneal  lymphatics  may  be  extensively 
invaded.  The  intestinal  functions  are  severely  disturbed. 

Intraligamentary  growths  less  frequently  produce  ascites,  but  they  invade 
the  ligaments,  pelvic  tissues,  uterus,  vagina,  rectum,  and  retroperitoneal  and 
inguinal  nodes,  but  distant  metastases  in  the  organs  rarely  occur.  Virchow's 
observation  of  the  excessive  rarity  of  distant  organ  metastases  in  ovarian 
carcinoma  applies  especially  to  the  adenocarcinomas. 

The  structure  varies  with  the  malignancy,  but  regularly  presents  a  pro- 
nounced papillary  form  or  at  least  its  traces.  A  uniform  alveolar,  medullary, 
or  tubular  structure  has  not  been  traced  to  this  origin,  although  in  some 
solid  portions  the  growth  may  be  nearly  diffuse.  Multiplication  of  cell  layers, 
cohesion  of  adjoining  papillae,  filling  of  intermediate  spaces  and  of  pseudo- 
alveoli,  are  the  usual  features  of  malignancy,  but  the  adenocarcinomatous 
type  is  commonly  preserved.  Pfannenstiel,  however,  finds  mixed  forms 
in  which  there  is  solid  medullary  carcinoma  without  evidence  of  glandular 
structure.  The  cells  may  vary  little  from  those  of  adenoma,  but  tend  to 
increase  in  size,  and  to  become  irregular  in  form,  while  nuclear  hyperchroma- 
tism  is  pronounced.  Giant-cells  are  prominent  in  some  tumors.  Calcific 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY 


591 


granules  forming  about  capillaries  in  the  stroma  or  in  epithelial  masses  may 
be  a  very  prominent  feature  (psammocarcinoma).  The  formation  of  these 
granules  is  preceded  by  colloid  degeneration. 

The  stroma  forms  branching  vascular  papillary  strands;  it  may  be  invaded 
and  split  up  by  tumor  alveoli,  and  in  solid  alveolar  areas  it  may  be  reduced 
to  a  trace.  Very  cellular  types  of  stroma  occur,  suggesting  a  neoplastic  proc- 
ess in  the  connective  tissue.  These  tumors  grow  with  unusual  rapidity,  but 
the  stroma  always  appears  to  be  in  a  certain  relation  to  the  epithelium;  it 
does  not  follow  the  metastases  and  its  designation  as  sarcoma  is  hardly 
justified.  Loeb,  however,  secured  a  pure  sarcomatous  tumor  by  successive 
transplants  of  such  a  growth  in  the  rat.  Ovarian  remnants  are  rarely  pre- 
served in  the  stroma,  but  in  one  case  I  found  the  abundant  septa  containing 
many  groups  of  large  polyhedral  cells  resembling  lutein-cells. 

The  course  of  ovarian  papillary  carcinoma,  while  slower  than  that  of 
other  varieties,  is  unfavorable,  because  of  local  recurrence  after  apparently 


FlG.  268. — Adenocarcinoma  of  ovary  with  abundant  calcific  concretions.     Psammoma. 

complete  extirpation,  intraligamentary  position,  early  peritoneal  implanta- 
tions, and  later  appearance  of  new  tumors  in  the  opposite  ovary.  Pfannen- 
stiel  estimates  the  recurrence  of  papillary  carcinoma  at  83.3  per  cent.,  of 
other  types  of  carcinoma  at  66  per  cent.  These  data  are  contrasted  with 
those  of  papillary  adenoma  of  which  16  per  cent,  recur.  The  glandular 
type  recurs  later,  but  more  frequently  than  the  papillary  (95  per  cent.).  Ob- 
servations on  bilateral  tumors  vary  greatly.  Glockner's  cases  all  recurred, 
while  Hoffmeier  found  only  50  per  cent,  of  recurrences;  and  there  are  not  a 
few  bilateral  carcinomas  of  miscellaneous  types,  which  permanently  recovered 
(Pfannenstiel,  Lit.).  The  removal  of  both  ovaries  is  probably  indicated, 
but  permanent  recovery  without  this  more  radical  procedure  is  recorded  by 
Hoffmeier,  Glockner,  and  Tauffer. 

Pseudomucinous  Cystadenoma. — Typical  pseudomucinous  cystadenomas 
are  distinctly  different  in  gross  appearance  from  the  serous  tumors.  They 
are  usually  of  larger  dimensions,  the  walls  are  thin,  a  multilocular  structure  is 
pronounced  and  persistent,  they  are  more  frequently  unilateral  and  pedun- 


592 


N EOF LA  STIC  DISEASES 


culated  and  the  contents  are  firm  or  soft  gelatinous  material  or  highly  mucin- 
ous  fluid.  They  form  the  majority  of  ovarian  cystadenomas.  Bilateral 
growths  occur  in  17.7  per  cent.,  and  intraligamentary  in  9.65  per  cent.  (Pfan- 
nenstiel).  The  size  of  some  of  these  tumors  has  been  remarkable.  Zacharias 
reports  a  case  in  which  the  tumor  contents  weighed  132  kg.  He  has  col- 
lected a  series  of  these  cases,  some  of  which  occurred  in  young  subjects  and 
most  of  which  were  fatal. 

On  section  the  cyst  presents  several  roomy  compartments  with  broad, 
thin  partitions.  As  the  cyst  enlarges  the  partitions  rupture,  atrophic  frag- 
ments and  strands  fall  into  the  fluid,  and  the  cyst  is  occupied  by  one  large 
central  and  several  peripheral  cavities.  The  walls  are  usually  thin,  but  cer- 
tain areas  may  be  rather  compact  with  many  small  cysts,  or  solid  portions 
may  appear,  Scanty  low  papillary  nodules  may  usually  be  found  on  the 


FIG.  269. — Adenocarcinoma  of  ovary  with  hyperplasia  of  interstitial  cells. 

inner  surface,  and  in  one  group  of  cases  these  papillary  projections  are  highly 
developed  (papillary  pseudomucinous  cystadenoma).  In  most  tumors  the 
papillary  tendency  is  not  highly  developed  and  the  growths  belong  in  the 
group  of  glandular  cystadenoma.  The  pseudomucinous  adenoma  may  show 
a  very  large  number  of  small  cysts,  honeycombed  areas,  and  exactly  resemble 
stroma  ovarii.  In  fact,  Bauer  holds  that  all  cases  of  struma  ovarii  are  pseudo- 
mucinous adenomas  derived  from  superficial  ovarian  epithelium.  Yet  some 
are  associated  with  other  teratoid  elements,  and  the  colloid  contains  iodin 
(Pick,  R.  Meyer).  The  contents  are  first  clear,  thin  gelatinous  material, 
which  may  become  condensed  and  firmer,  or  thinner  and  fluid.  The  addi- 
tion of  much  cell  detritus,  fatty  matter,  cholesterin,  serum,  or  blood  alters 
the  color. 

The  main  ingredient  is  pseudomucin  (Hammersten).     This  substance  is  soluble  in 
water,  precipitable  by  alcohol  but  not  by  acetic  acid,  and  when  treated  with  dilute 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  593 

mineral  acid  it  yields  a  substance  which  reduces  copper  sulphate  in  alkaline  solution. 
It  is,  therefore,  a  glycoproteid  and  on  chemical  analysis  yields  small  proportions  of 
hydrogen,  nitrogen,  and  sulphur.  lodin  is  absent  (Kretschmar,  Bauer).  The  mucinous 
substance  does  not  always  occur  in  the  form  of  typical  pseudomucin.  In  certain  cases, 
sometimes  called  pseudomyxoma  ovarii,  the  material  is  much  firmer,  strongly  alkaline, 
insoluble  in  water,  but  dissolved  by  strong  alkali.  This  substance,  Pfannenstiel's 
pseudomucin  B,  has  a  very  low  nitrogen  content.  A  thin  mucin,  very  soluble  in  water 
and  with  high  nitrogen  content,  is  designated  by  Pfannenstiel  as  pseudomucin  G. 
Pafamucin  is  a  substance  obtained  from  ovarian  cysts  by  Mitjukoff,  which  reduces 
copper  without  boiling  in  acid.  The  pure  pseudomucin  occurs  only  in  small  cysts  con- 
taining clear  gelatinous  material.  It  is  usually  mixed  with  albumin,  producing  the 
paralbumin  which  Eichardt  wrongly  supposed  to  be  a  single  substance.  In  the  demon- 
stration of  pseudomucin  in  albuminous  mixture  the  fluid  may  be  precipitated  and  washed 
in  alcohol,  treated  on  a  water-bath  for  half  an  hour  with  10  per  cent.  HC1,  and  after 
cooling,  the  albumin  precipitated  by  phosphotungstic  acid.  The  filtrate  gives  Fehling's 
reaction.  True  mucin  may  be  separated  by  chemical  means,  but  does  not  occur  in 
ovarian  tumors.  To  separate  pseudomucin,  a  part  of  the  material  is  extracted  in  water 
and  another  part  in  I  per  cent.  NaOH  for  2  days.  The  filtrates  are  then  treated  with 
increasing  amounts  of  acetic  acid.  If  no  precipitate  falls,  mucin  is  absent.  If  present, 
the  precipitated  mucin  is  filtered  off,  and  filtrate,  heated  with  acid,  is  tested  for  pseudo- 
mucin by  Fehling's  test.  Mucin  appears  not  to  occur  in  ovarian  tumors.  Pseudo- 
mucin, on  the  other  hand,  is  not  limited  to  ovarian  cysts,  but  occurs  under  many  other 
conditions  (E.  Herter,  Lit.). 

The  structure  presents  narrow  and  slightly  vascular  septa  or  partitions, 
lined  by  one  layer  of  high  cylindrical  cells,  in  which  all  stages  of  secretion 
are  observed.  The  nuclei  lie  at  the  bases  of  the  cells,  the  cell  bodies  are  low, 
granular  and  opaque  in  the  resting  stage,  high  and  clear  in  active  secretion. 
Goblet  cells  may  be  abundant  and  occasionally  the  cells  are  ciliated.  Pres- 
sure of  firm  secretion  may  cause  flattening  or  complete  atrophy  of  cells  and 
septa.  The  production  of  mucus  is  a  secretory  function  and  does  not  usually 
entail  the  degeneration  of  the  cell.  In  well-preserved  areas  of -typical  ade- 
nomas there  is  little  desquamation  of  cells,  but  in  more  actively  growing 
tumors  the  secretion  is  less  abundant,  many  cells  are  exfoliated,  the  cells 
become  atypical  and  granular,  and  the  nuclei  hyper  chromatic.  In  such 
areas  the  cysts  are  small  and  epithelial  papillae  become  very  numerous.  By 
exaggeration  of  this  process  adenocarcinoma  develops.  A  false  appearance 
of  malignancy  may  be  produced  by  compression  of  many  thin  septa  with 
low  papillary  outgrowths,  and  this  appearance  may  be  exaggerated  by  the 
collapse  of  any  cystic  tumor  after  aspiration. 

The  two  main  structural  types,  glandular  and  papillary,  are  designated 
by  Gebhard  as  "cystadenoma  evertens"  and  "cystadenoma  invertens."  No 
satisfactory  explanation  of  their  different  growth  tendencies  is  available. 
In  the  papillary  type  Waldeyer  assumed  a  primary  proliferation  of  the  con- 
nective tissue.  Gebhard  and  Pfannenstiel  consider  that  the  primary  factor 
always  resides  in  the  epithelium.  Gebhard  thinks  that  the  presence  of  secre- 
tion prevents  the  growth  of  papillae  in  tensely  filled  cysts,  while  in  other 
portions  of  the  same  tumor  a  papillary  growth  may  be  observed.  It  is  pos- 
sible that  the  conditions  under  which  the  tumor  originates  determine  the 
structures.  Thus  in  the  alveolar  strictly  glandular  tumor,  described  by 
Bauer,  the  tumor  originated  by  downward  growth  of  surface  epithelium 
which  early  formed  alveoli.  The  papillary  tumors  appear  to  develop  by 
growth  into  preexisting  cysts  or  cavities. 

The  course  of  the  pseudomucinous  tumors  is  slow,  and  most  of  them  being 
unilateral  and  pedunculated  are  successfully  removed  by  operation  (98  per 
cent.,  Pfannenstiel).  When  a  papillary  structure  is  pronounced  the  tumors 
are  most  often  bilateral,  more  difficult  to  eradicate,  implantation  metastases 
may  develop,  and  recovery  follows  extirpation  in  a  smaller  proportion,  esti- 
mated by  Frommel  at  85  per  cent.  Strassmann,  however,  estimated  the 
38 


594 


NEOPLASTIC  DISEASES 


recoveries  as  low  as  44  per  cent.  Fatalities  result  from  recurrence  of  incom- 
pletely extirpated  tumors,  from  later  development  of  a  tumor  in  the  remaining 
ovary,  from  implantations  in  the  peritoneum  or  abdominal  incision,  and 
from  progressive  pseudomyxomatous  changes  in  the  peritoneum.  Ascites 
is  relatively  infrequent.  The  elongated  pedicle  of  many  of  these  tumors 
renders  them  especially  susceptible  to  torsion,  which  occurred  in  14.5  per 
cent,  of  Martin's  cases.  The  recurrence  usually  reproduces  the  structure 
and  follows  the  slow  course  of  the  original  tumor.  A  period  of  many  years 
(14,  17,  Olshausen)  may  intervene  before  the  recurrent  tumor  appears.  Rarely 


FIG.  270. — A  type  of  malignant  cystic  adenocarcinoma  of  ovary. 

the  implantation  or  recurrence  assumes  a  malignant  carcinomatous  form 
(Frank,  Olshausen,  Pfannenstiel).  Recurrence  in  the  opposite  ovary  several 
years  after  extirpation  of  the  first  tumor  has  been  observed  by  Martin,  Hof- 
meier,  and  others,  and  must  be  interpreted  as  a  new  primary  tumor. 

Owing  to  the  thin  walls  of  the  cysts  spontaneous  or  traumatic  rupture 
not  infrequently  occurs,  and  the  contents  and  cells  are  discharged  into  the 
peritoneum.  When  this  event  occurs  at  operation  and  the  material  is  re- 
moved no  ill  effects  follow.  Spontaneous  rupture  is  followed  by  prostration, 
fever,  and  a  marked  swelling  of  the  abdomen.  The  further  results  depend 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  595 

much  on  the  character  of  the  tumor  and  its  contents,  but  a  condition  regu- 
larly follows  known  as  pseudomyxoma  peritonei.  The  first  effect  is  the  pas- 
sage of  the  pseudomucinous  material  into  the  peritoneal  lymphatics.  These 
spaces  become  distended  and  ruptured,  the  material  infiltrates  the  meshes 
of  the  peritoneum,  round-cell  infiltration,  growth  of  granulation  tissue  and 
proliferation  of  endothelium  result,  and  the  peritoneum  is  everywhere  thick- 
ened by  a  painless  form  of  chronic  peritonitis  (Werth,  Gunzberger,  West- 
phalen).  When  many  fragments  from  papillary  tumors  are  carried  along 
these  may  become  implanted  and  produce  small  papillary  outgrowths  or 
small  subserous  cysts,  but  as  a  rule  the  organs  are  found  embedded  in  gelat- 
inous material  without  any  sign  of  cellular  invasion.  The  large  amount 
of  material  produced  in  some  cases  has  led  to  the  assumption  that  a  true 
myxomatous  process  becomes  established  in  the  peritoneum  (Mennig, 
Wendeler),  but  this  conception  is  negated  by  the  complete  recovery  which 
sometimes  follows.  When  the  condition  progresses  steadily  and  spontaneous 
rupture  has  not  occurred  the  chief  factor  must  be  found  in  a  dissemination 
of  tumor-cells  throughout  the  peritoneum  and  this  process  has  been  fully 
described,  especially  with  papillary  tumors,  by  Olshausen,  Ackermann,  and 
Pfannenstiel.  The  passage  of  mucus  apparently  without  tumor-cells  in  the 
diaphragm,  along  the  portal  canals,  into  the  liver  and  into  the  appendix  has 
been  reported  by  Werth  and  Polano.  The  prognosis  in  this  condition  is  un- 
favorable. Of  40  cases  collected  by  Gunzberger,  17  were  said  to  have 
recovered.  Early  cleansing  of  the  peritoneum  greatly  favors  recovery  and 
the  final  absorption  of  mucus  and  tumor-cells.  When  firm  adhesions  form 
the  material  cannot  be  removed  and  a  slowly  fatal  course  is  the  rule.  The 
peritoneum  becomes  thickened,  adhesions  and  fistulous  tracts  form,  and 
intestinal  paralysis  eventually  follows.  Occasionally  a  rapid  course  is  ob- 
served with  all  the  signs  of  a  carcinomatous  process. 

Pseudomucinous  Adenocarcinoma. — Malignant  changes  in  previously  be- 
nign pseudomucinous  cystadenoma  occur,  as  previously  mentioned,  under 
several  conditions,  (a)  Implantations  from  a  benign  tumor  develop  in  the 
stump,  peritoneum,  abdominal  wall,  or  navel,  and  pursue  a  malignant  course. 
(b)  Pseudomyxoma  peritonei  may  develop  malignant  neoplastic  tendencies 
and  structure,  (c)  In  portions  of  benign  cystadenomas  the  structure  is  ma- 
lignant, but  being  encapsulated  the  tumor  is  completely  extirpated.  All  of 
these  events  are  comparatively  rare. 

In  addition,  there  is  a  group  (d)  of  ovarian  adenocarcinomas  which  repre- 
sent malignant  forms  of  the  cystadenoma.  Some  of  these  evidently  represent 
a  malignant  change  in  an  originally  benign  cystadenoma.  The  history 
reveals  the  long  existence  of  an  ovarian  tumor  which  on  examination  proves 
to  be  in  whole  or  in  part  carcinomatous.  Gebhard  points  out  that  the  long 
duration  of  these  tumors  eliminates  the  probability  that  they  were  malignant 
from  the  first.  Others  develop  more  rapidly,  present  a  uniform  adenocarcino- 
matous  structure,  and  are  probably  malignant  from  their  inception. 

The  adenocarcinomas  of  these  types  still  contain  cysts,  but  large  portions 
of  the  tumor  are  solid  and  present  the  opaque  cellular  texture  of  carcinoma. 
The  cysts  represent  natural  cavities  produced  in  the  growth  of  the  tumor 
and  spaces  of  more  ragged  outline  formed  by  degeneration  and  necrosis  of 
central  areas.  Small  hemorrhages  frequently  occur.  The  mucus  is  greatly 
reduced  in  amount,  but  still  persists  in  the  small  alveoli  and  spaces  of  the 
tumor.  It  is  seldom  clear,  but  more  often  discolored  by  cell  detritus  and 
blood.  The  capsule  is  often  perforated,  adhesions  form,  implantations  de- 
velop and  metastases  occur  in  pelvic,  retroperitoneal,  or  inguinal  nodes. 

The  structure  is  usually  of  the  glandular  type  with  large  and  small  alveoli 


596 


NEOPLASTIC  DISEASES 


lined  by  convoluted  multiple  rows  of  cells  and  filled  with  mucus  or  occupied 
by  numerous  secondary  alveoli.  A  diffuse  growth  of  cells  is  unusual,  the  most 
active  areas  retaining  the  structure  of  malignant  adenoma.  The  cells  vary 
widely  from  the  clear  columnar  type  of  simple  adenoma.  They  increase  in 
number  and  height,  lose  most  of  the  features  of  mucus  secretion,  and  become 
granular  and  opaque,  while  the  nuclei  are  very  large  and  hyperchromatic. 

Solid  Ovarian  Adenoma. — Many  cystic  pseudomucinous  adenomas  present 
solid  areas  and  when  such  areas  predominate  over  the  cysts  the  commonest 
form  of  solid  adenoma  is  produced.  Stratz  estimates  that  3  per  cent,  of  all 
epithelial  ovarian  tumors  are  solid  adenomas.  Usually  the  solid  tumor 


FIG.  271. — A  type  of  adenocarcinoma  of  ovary. 

presents  on  close  inspection  a  finely  honeycombed  texture  and  this  tumor 
may  be  designated  as  the  parvilocular  ovarian  adenoma.  It  is  a  pseudo- 
mucinous tumor,  the  small  spaces  being  filled  with  firm  mucus  or  with  mucus 
and  cell  detritus.  In  accordance  with  its  solid  character  it  is  far  more 
cellular  than  the  cystic  growth  and  the  epithelium  is  usually  atypical, 
granular,  and  overnourished.  Many  transitional  cases  connect  this  adenoma 
with  solid  and  with  cystic  adenocarcinoma.  Yet  the  typical  solid  adenoma 
reaches  a  large  size  without  exhibiting  malignant  characters.  Ascites  is 
common.  Pfannenstiel  described  3  cases  in  which  large  partly  cystic  tumors 
of  the  above  type  were  successfully  removed  and  the  patient  remained  well. 


597 

In  a  case  studied  in  this  laboratory  the  structure  approached  adenocarcinoma. 
Glockner  describes  a  large,  solid  pure  adenoma  without  cystic  tendency, 
the  convoluted  alveoli  being  lined  by  cylindrical  epithelium  and  containing 
little  mucus. 

The  superficial  or  everted  papillary  adenoma  forms  a  distinct  variety  of 
solid  tumor.  Including  the  small  and  early  forms  this  tumor  is  relatively 
frequent.  Of  the  more  advanced  and  bulky  growths  J.  W.  Williams  has 
collected  15  cases.  One  or  both  ovaries  present  numerous  bulky  compact 
papillary  outgrowths  which  spring  from  a  central  core,  the  altered  or  disin- 
tegrated ovary.  The  appearance  in  the  advanced  stages  is  extremely  char- 
acteristic. Ascites  is  common  and  implantation  metastases  occur  early,  but 
the  essentially  benign  character  is  attested  by  the  successful  extirpation 
recorded  in  most  cases.  An  origin  from  superficial  ovarian  epithelium  is 
clearly  indicated.  Gebhard  suggests  that  an  early  rupture  of  a  papillary 
cystic  tumor  permits  the  entire  growth  to  become  everted,  but  some  very 
early  papillomas  are  superficial  from  the  first.  Local  inflammatory  processes 
have  apparently  contributed  to  the  inception  of  the  tumor  process  in  many 
cases. 

A deno fibroma.- — Epithelial  alveoli  are  occasionally  observed  in  ovarian 
fibromas  and  rarely  these  epithelial  structures  increase  to  such  an  extent 
as  to  constitute  an  adenofibroma.  Orthmann  describes  carcinomatous 
changes  in  such  a  tumor.  Cystic  dilatation  of  the  alveoli  may  occur,  and 
Orthmann  describes  carcinomatous  changes  in  such  cysts. 

Adenofibjroma  colloides  designates  a  rare  form  of  this  tumor  in  which 
gelatinous  changes  are  prominent.  Amann  described  a  bulky  tumor  covered 
with  warty  iexcrescences  and  containing  some  small  cysts  and  many  alveoli 
lined  by  high  cylindrical  cells  and  filled  with  mucus.  Orthmann  found 
a  small  tubal  metastasis  from  a  bilateral  tumor  of  this  same  structure. 
Another  form  of  superficial  fibroma  with  carcinomatous  infiltration  by  cubical 
or  flat  cells  is  interpreted  by  Orthmann  as  an  invasion  from  the  superficial 
ovarian  epithelium.  In  all  these  tumors  the  stroma  greatly  exceeds  the  cel- 
lular portions. 

Carcinoma. — Waldeyer  classified  ovarian  carcinomas  according  to  the 
proportions  of  cells  arid  stroma  as  simple  (alveolar),  medullary,  and  scirrhous. 
Gebhard  found  it  more  serviceable  to  distinguish  between  the  malignant 
forms  of  cystadenoma  and  genuine  solid  carcinomas  of  other  types,  thus 
introducing  the  histogenetic  principle.  Due  consideration  of  the  histology, 
histogenesis,  and  specific  anatomical  and  clinical  characters  requires  the 
recognition  of  several  distinct  groups  of  these  tumors  as  follows:  Cystic 
adenocarcinoma;  solid  carcinoma;  carcinoma  mucocellulare,  Krukenberg; 
carcinoma  folliculoides;  ovulogenic  carcinoma. 

There  are  also  rare  forms  of  carcinoma  which  cannot  be  grouped  with 
any  of  the  above  classes,  as  squamous-cell  carcinoma,  malignant  forms  of 
adenofibroma  and  melanoma.  There  is  also  considerable-  support  for 
Rokitansky's  belief  that  certain  carcinomas  develop  from  lutein  cells. 

1.  Cystic  adenocarcinoma  has  been  discussed  with  the  cystic  adenomas 
with  which  it  is  identical  in  origin  and  very  similar  in  course. 

2.  Solid  Carcinoma. — In  this  class  may  be  conveniently  grouped  all  the 
tumors  of  large  or  small  alveolar  or  medullary  structure  which  are  not  con- 
nected with  the  cystic  adenocarcinomas,  and  which  do  not  exhibit  the  specific 
structure  of  Krukenberg's  tumor  nor  of  carcinoma  folliculoides.    That  some 
of  the  small  alveolar  carcinomas  are  atypical  examples  of  cystic  adenocar- 
cinoma is  possible,  since  the  alveoli  may  contain  cylindrical  cells,  as  in  Glock- 
ner's  cases.    Nevertheless  their  gross  appearance  and  microscopical  structure 


NEOPLASTIC  DISEASES 


are  very  different  from  malignant  cystic  adenocarcinoma,  of  which  even  the 
solid  forms  regularly  maintain  an  adenocarcinomatous  structure.  The  medul- 
lary carcinomas  with  ova-like  cells  present  a  somewhat  distinctive  subvariety, 
but  until  their  histogenesis  is  much  clearer  than  can  now  be  claimed  a  separate 
classification  seems  hardly  warranted.  Until  a  more  thorough  understanding 
of  the  many  forms  of  ovarian  carcinoma  is  attained  no  classification  can  hope 
to  escape  revision. 

The  alveolar  and  medullary  carcinomas  produce  as  a  rule  solid  tumors 
maintaining  the  form  of  the  ovary  in  the  early  stages,  but  eventually  becoming 


FIG.  272. — Solid  adenocarcinoma  of  ovary. 


irregular  and  lobulated.  On  section  many  are  cystic,  but  the  cysts  are  chiefly 
the  result  of  necrosis  and  liquefaction  and  not  of  dilatation  of  alveoli.  The 
tumors  reach  considerable  and  even  large  dimensions,  but  rarely  beyond 
15  to  20  cm.  in  diameter.  They  are  at  first  usually  unilateral,  but  metastasis 
and  recurrence  in  the  other  ovary  are  very  frequent.  If  pedunculated  they 
become  bound  to  the  pelvic  tissues  by  adhesions  and  are  held  by  a  broad 
short  pedicle  composed  of  the  ovarian  and  broad  ligaments.  Many  occupy 
the  pelvis  in  a  retroligamentary  position  (Winter).  The  consistence  is  firm 
or  soft  in  accordance  with  the  cellular  character.  On  section  they  exhibit 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY 


599 


an  opaque  uniform  texture  broken  by  many  lobules,  small  cysts,  areas  of 
necrosis  and  hemorrhage,  and  foci  of  gelatinous  degeneration. 

The  structure  presents  a  confusion  variety  of  types.    Small  alveolar  car- 
cinoma presents  many  small  groups  of  granular  polyhedral  cells  without 


FIG.  273. — Structure  of  a  widely  metastasizing  small  alveolar  bilateral  carcinoma  of 

ovary. 


FIG.  274. — Carcinoma  of  ovary  with  ova-like  cells. 


definite  lumen,  supported  by  scanty  cellular  stroma.  It  is  characteristic 
of  this  group  of  tumors  that  the  outlines  of  alveoli  may  be  lost  and  the  cells 
not  only  grow  diffusely,  but  become  more  difficult  to  distinguish  from  stroma- 
cells,  suggesting  myxoma,  sarcoma,  or  a  mixed  tumor.  This  tendency  toward 


600  N  EOF  LAST  1C  DISEASES 

diffuse  growth  and  mucoid  degeneration  of  cells  and  stroma  is  observed  in 
many  ovarian  carcinomas  and  appears  to  reach  its  height  in  Krukenberg's 
tumor.  Careful  study  of  such  growths  usually  reveals  definite  alveolar  areas 
and  supports  Heinrich's  conclusion  that  no  true  mixed  carcinoma  and  sarcoma 
of  the  ovary  exists  outside  the  ovulogenic  group.  Glockner,  however,  de- 
scribes a  rapidly  growing  mixed  tumor  in  a  girl  of  19  years,  which  resembled 
the  parotid  cylindroma  and  for  which  he  suggested  an  origin  from  the  Wolffian 
body.  I  have  studied  tumors  of  this  general  type  and  concluded  that  some 
belong  with  the  medullary  carcinomas  with  ova-like  cells.  Others  may  very 
well  be  true  mixed  tumors  originating  from  the  complex  alien  tissue  masses 
described  by  Walthard. 

The  typical  small  alveolar  carcinoma  presents  well-defined  alveoli.  The 
early  stages  are  probably  represented  by  v.  Kahlden's  case,  and  charac- 
teristic examples  are  described  by  Glockner,  Orthmann,  Heinrichs,  and  others. 

In  the  medullary  type  the  cell  columns  are  large,  broad,  and  freely  anasto- 
mosing. The  cells  are  large  or  small,  polyhedral  or  rounded,  opaque,  and 
granular.  Scattered  at  notably  regular  intervals  may  appear  large  clear 
ova-like  cells,  the  significance  of  which  has  been  much  discussed.  These 
cells  are  large,  spheroidal,  with  clear  cytoplasm,  well-marked  membrane, 
and  one  or  more  vesicular  nuclei.  They  may  be  surrounded  by  a  radiating 
circle  of  tumor-cells  (Schroeder).  They  may  resemble  ova  in  every  detail 
(Gebhard)  and  they  have  been  so  interpreted  by  Emanuel,  Kworostansky, 
Schroeder,  and  others.  Acconci  found  them  in  a  cystadenoma.  Somewhat 
similar  structures  may  be  produced  by  cross-sections  of  strands  of  mucinous 
stroma,  but  the  cells  in  question  are  spheroidal.  Very  similar  cells  may  un- 
doubtedly result  from  mucous  degeneration  and  this  origin  of  all  of  them  is 
accepted  by  the  majority  of  observers.  Gebhard,  however,  will  not  deny 
the  possibility  that  they  represent  primordial  ova,  but  the  more  recent  em- 
bryological  data  do  not  favor  such  a  possibility  (cf.  Ingier).  Ova-like  cells 
appear  in  the  epithelial  layer  of  primordial  follicles,  although  these  cells  are 
not  derived  from  germ  epithelium  (W.  Nagel). 

In  a  very  cellular  tumor  which  probably  belongs  in  this  group  I  found 
numerous  small  pearls  composed  of  flattened  cells.  Since  most  of  the  tumor 
was  composed  of  granular  polyhedral  cells,  the  squamous  characters  were 
metaplastic.  Hansemann  has  described  a  squamous  epithelial  tumor  which 
he  referred  to  metaplasia  of  ovarian  epithelium. 

In  a  well-defined  group  the  cells  are  usually  small,  and  grow  in  indistinct 
alveoli  or  groups  which  vary  greatly  in  size.  Such  tumors  may  present  areas 
of  diffuse  growth  and  when  the  cells  become  intimately  mingled  with  the 
stroma  or  appear  in  rows  between  stroma  fibrils  or  arranged  about  blood- 
vessels they  suggest  an  endothelial  origin.  Not  a  few  so-called  endotheliomas 
of  the  ovary  are  probably  of  this  nature  (cf.  Pfannenstiel,  Figs.  161,  163). 

In  another  group  the  cell  masses  are  large,  circular  on  section,  and  com- 
posed of  large  polyhedral,  clear,  or  slightly  granular  cells.  These  tumors 
have  often  been  described  as  endothelioma.  Yet  this  structure  is  occasion- 
ally seen  in  distinctly  alveolar  and  epithelial  tumors  and  there  is  no  necessity 
of  assuming  an  endothelial  origin.  Polano  divides  the  pseudo-endotheliomas 
among  (i)  alveolar  carcinoma,  (2)  adenocarcinoma,  and  (3)  sarcoma.  To 
these  may  be  added  the  peritheliomatous  structure  which  is  often  assumed  by 
epithelial  tumors. 

In  young  subjects  there  occurs  a  form  of  solid  ovarian  carcinoma  which  is 
bilateral,  of  rapid  growth,  producing  wide-spread  local  invasions,  and  numer- 
ous bulky  metastases,  while  presenting  a  structure  of  diffuse  growth  of  small 
rounded  cells  resembling  lymphosarcoma.  Stone  has  described  such  a  case 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY 


601 


in  which  a  large  metastasis  in  the  breast  first  attracted  attention,  and  the 
ovarian  tumors  were  overlooked.     In  the  ovary  the  supposed  sarcomatous 


FlG.  275. — Structure  of  a  peculiar  carcinoma  of  ovary,  presenting  anastomosing  cords 

of  small  polyhedral  cells. 


FIG.  276. — Structure  of  a  highly  malignant  small  cell  carcinoma  of  both  ovaries  in  a 
young  subject.  There  were  metastases  in  breast  and  other  organs,  in  which  the  struc- 
ture suggested  lymphosarcoma. 

growth  revealed  its  primary  alveolar  structure.    I  have  seen  other  very  similar 
cases. 

A  distinctly  scirrhous  carcinoma  of  the  ovary  is  rare  and  is  observed  chiefly 
in  elderly  subjects. 


602 


NEOPLASTIC  DISEASES 


Carcinoma  develops  in  fibromas  either  from  the  downward  growth  of 
surface  epithelium  (Orthmann),  or  from  the  proliferation  of  glands  in  a  fibro- 
adenoma.  In  either  case  the  connective-tissue  areas  are  predominant  and 
the  tumor  usually  presents  the  gross  appearance  of  the  original  fibroma. 

Folliculoma  malignum  ovarii  is  a  term  employed  by  S.  Gottschalk  in  de- 
scribing a  peculiar  small  alveolar  carcinoma  of  the  ovary.  Several  apparently 
related  but  structurally  somewhat  different  tumors  have  been  grouped 
under  this  term,  and  while  their  origin  and  significance  are  not  clear,  the 
tumors  are  peculiar  in  many  respects  and  deserve  separate  consideration. 
Their  chief  characters  are  a  comparatively  small  size,  honeycombed  texture, 
small  alveolar  structure,  embryonal  cell  character,  and  slight  malignancy. 
Metastases  are  absent.  In  Ingier's  cases  the  tumors  were  bilateral.  Ascites 
may  occur.  In  Gottschalk's  case  the  tumor,  10  X  8  X  3!  cm.,  maintained 
the  form  of  the  ovary,  presented  numerous  small  and  minute  cysts,  inter- 
stitial hemorrhages,  and  a  tumor  process  affecting  chiefly  the  ovarian  cortex. 
The  structure  resembled  struma  ovarii  and  presented  many  small  alveoli 


;  •  -  r*>% ;•:• 


^^::m>^m^i^m 

£.'  vjtmFt  *:  **&•"*  "*  -i»  w»»  -  «.•*    ?• "  "*S5*f?*«*<*^%!fl 

?«? -Si^i  -"' 4f    *       H  ? ;  *:*  ^V^^siKw 
^*^Slfe"-ir  *:;^rr^*%ig^^ffl 


py? 

FIG.  277. — Structure  of  granulosa  cell  carcinoma  of  ovary.     (After  Werdt,  Z.  B.,  59.) 

lined  by  small  cubical  epithelium  with  prominent  nuclei  and  surrounded  by 
many  small  groups  of  cells.  The  small  cysts  contained  mucinous  material. 
Very  similar  tumors  have  been  described  by  M.  Voight,  Lonnberg,  and  Ingier. 
Other  cases  sometimes  included  in  this  group  seem  to  belong  rather  with  the 
medullary  carcinomas  with  ova-like  cells  (Mengershausen,  Schroeder).  The 
presence  of  ova-like  cells  led  some  to  assume  an  origin  from  primary  follicles. 
Voight  derived  his  tumor  from  downgrowth  of  superficial  ovarian  epithe- 
lium. L.  Pick  regarded  Gottschalk's  case  as  struma  ovarii.  Ingier  attacks 
the  whole  group  because  the  follicular  origin  is  not  demonstrable.  Yet  Bauer 
has  shown  that  a  form  of  struma  ovarii  may  develop  from  the  superficial 
ovarial  epithelium,  and  since  the  early  stages  of  his  tumor  were  practically 
identical  with  Gottschalk's,  one  is  led  to  believe  that  folliculoma  malignum 
is  a  form  of  ovarian  tumor  in  which  the  alveoli  resemble  thyroid  structures, 
while  the  secretion  of  mucus  is  scanty.  These  tumors  must,  therefore,  be 
distinguished  from  very  similar  growths  of  teratoid  origin.  In  the  latter 
group  other  teratoid  elements  are  usually  demonstrable  and  iodin  may  be 
present  in  traces.  Among  the  tumors  which  produce  multiple  small  cysts 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  603 

in  an  enlarged  ovary  are  the  granulosa  cell  carcinoma  of  Werdt,  and  the 
oophoroma  folliculare  of  Brenner. 

The  term  folliculoma  malignum  seems  applicable  also  to  a  group  of  tumors 
resembling  in  many  respects  those  described  by  Voight  and  Ingier,  of  which 
I  have  studied  four  examples.  In  the  gross  these  tumors  are  of  moderate 
size,  preserve  the  form  of  the  ovary,  and  present  a  finely  honeycomb  or  solid 
texture.  In  structure  they  are  glandular  adenocarcinomas  and  carcinomas. 
The  alveoli  are  small  and  compact,  or  larger  with  a  free  lumen.  The  cells 
are  unusually  large  and  polygonal.  The  cytoplasm  is  clear  and  the  borders 
very  distinct.  The  stroma  is  abundant  and  consists  of  hyperplastic  ovarian 
tissue.  An  origin  from  undeveloped  follicles  is  indicated  by  a  diffuse  neo- 
plastic  overgrowth  of  the  lining  cells  of  the  small  cortical  follicles. 

Carcinomatous  tumors  of  this  class  present  an  alveolar,  diffuse,  or  scirrhous 
structure.  The  cells  are  very  large,  giant-cells  are  abundant,  and  the  cyto- 


FlG.  278. — Oophoroma  folliculare.    A  rare  ovarian  tumor  arising  from  multiple  Graaffian 

follicles.     (Brenner.} 

plasm  is  clear  or  granular.    The  structure  differs  in  these  particulars  from 
other  forms  of  ovarian  carcinoma. 

Fibrosarcoma  Mucocellulare  Carcinomatodes  (Krunkenberg). — Under  this 
term  Krunkenberg  in  1896  described  a  peculiar  malignant  tumor  of  the  ovary, 
usually  bilateral,  of  considerable  dimensions,  maintaining  the  form  of  the 
ovary,  of  myxomatous  appearance,  occurring  in  young  or  old  subjects,  grow- 
ing slowly,  usually  with  ascites.  sometimes  chylous,  and  eventually  fatal  by 
extension  and  recurrence.  The  structure  presented  small  groups  or  a 
diffuse  growth  of  large  polyhedral  or  rounded  cells  with  mucoid  contents 
compressing  the  nucleus  into  a  signet  ring  form.  In  the  diffuse  areas  the 
cells  were  intimately  mingled  with  the  stroma  so  as  to  suggest  an  origin  from 
stroma  cells  or  endothelium.  Krunkenberg's  first  case  presented  a  large 
cyst  with  carcinomatous  wall  in  one  side,  a  solid  tumor  on  the  other,  while 
there  was  extensive  invasion  of  lymphatics  of  abdomen,  stomach,  pleura, 
and  bronchial  and  axillary  nodes,  a  condition  not  commonly  observed  in 
other  ovarian  carcinomas.  Krunkenberg  failed  to  point  out  the  close  resem- 


604 


NEOPLASTIC  DISEASES 


blance  of  his  tumors  to  secondary  carcinoma  of  the  ovary  and  he  was  unable 
to  determine  from  which  ovarian  element  the  tumors  arose.  These  deficien- 
cies were  soon  supplied  by  Wagner,  Romer,  Schlagenhaufer,  and  Glockner, 
with  the  demonstration  that  this  peculiar  tumor  may  be  exactly  reproduced 
by  secondary  carcinoma  from  stomach  and  other  abdominal  organs,  and  that 
the  great  majority  of  such  growths  are  secondary  to  tumors  in  other  organs. 
It  is  still  generally  admitted  that  there  are  primary  tumors  of  the  ovary 
of  the  Krunkenberg  type,  and  cases  reported  by  Glockner,  Schenk,  and  Rost- 
horn  are  regarded  as  examples.  It  is  obvious  that  cases  without  autopsy, 
as  that  of  Outerbridge,  are  unavailable  in  the  discussion.  In  Glockner's 
case  both  ovaries  were  much  enlarged  and  extensions  from  one  had  eroded 
the  spinal  column.  The  entire  tumor  had  a  myxomatous  texture  and  there 
were  liquefaction  cysts.  One  portion  presented  diffuse  myxomatous  tissue, 
while  in  another  the  structure  was  distinctly  alveolar.  Schenk  described 


FIG.  279. — Follicular  carcinoma  of  ovary. 

bilateral  tumors  in  a  subject  27  years  of  age,  one  weighing  2300  gm.  and 
presenting  the  typical  structure. 

Although  Marchand  and  Chiari  were  unable  to  find  any  primary  tumors 
in  the  cases  of  Krunkenberg  and  Schenk,  and  doubtless  no  such  tumors  were 
demonstrable,  it  still  seems  uncertain  that  the  typical  structure  of  secondary 
mucoid  carcinomas  can  be  exactly  duplicated  by  primary  carcinoma  of  the 
ovary.  It  is  not  always  possible  to  demonstrate  the  primary  focus  in  cases 
of  wide-spread  carcinoma  of  the  abdomen  with  involvement  of  the  ovary, 
although  the  structure  is  not  always  that  of  Krunkenberg's  tumor. 

Glockner  states  that  the  typical  structure  may  be  seen  in  portions  of 
alveolar  carcinoma  of  the  ovary,  but  the  typical  cases  show  little  or  no  alveo- 
lar structure.  I  have  studied  5  secondary  ovarian  tumors  of  this  type  and 
i  primary  carcinoma  with  myxomatoid  areas.  The  structures  while  similar 
were  far  from  identical,  the  primary  tumor  containing  distinctly  alveolar 
areas.  None  of  these  tumors  gave  evidence  that  the  stroma  reaction  was 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  605 

neoplastic  or  sarcomatous,  or  that  the  large  cells  were  derived  from  the  stroma. 
I  am  inclined  to  believe,  therefore,  that  the  pure  Krunkenberg  tumor  is  al- 
ways secondary,  and  that  primary  carcinomas  presenting  this  structure 
regularly  yield  areas  of  a  different  type. 

The  clinical  course  of  ovarian  carcinoma  varies  greatly.  The  clinical 
features  of  the  adenocarcinomas  have  been  considered  under  the  cystic  tumors. 
The  alveolar  and  medullary  carcinomas  are  uniformly  malignant,  but  statis- 
tical reports  of  this  group  are  wanting.  The  majority  of  these  tumors  are 
originally  bilateral  or  soon  become  so.  When  pedunculated  they  may  remain 
movable  for  some  time,  even  after  general  metastases  have  occurred.  After 
extirpation  local  recurrence  in  the  stump  or  in  the  opposite  ovary  is  common. 
Peritoneal  metastases  are  less  common  than  with  cystic  adenocarcinoma, 
but  through  the  lymph-  and  blood-vessels  there  may  be  general  dissemina- 


FIG.  280. — Structure  of  a  Krunkenberg  tumor  of  ovary,  secondary  to  gastric  carcinoma. 

tion  in  the  early  stages  of  growth.  In  such  cases  the  general  condition  of  the 
patient  may  long  remain  remarkably  good,  but  cachexia  eventually  super- 
venes. That  the  prognosis  in  this  group  of  tumors  is  not  wholly  unfavorable 
is  shown  by  Glockner's  report  of  5  survivals  out  of  18  cases  after  3  years. 
Yet  some  of  his  tumors  were  adenocarcinomas. 

In  Martin's  table  of  41  cases  of  various  types  only  one  solid  carcinoma 
failed  to  prove  fatal. 

The  Krunkenberg  tumors,  both  primary  and  secondary,  are  uniformly 
fatal.  Tumors  of  the  type  of  carcinoma  folliculoides  are  of  slow  growth  and 
offer  a  better  prognosis,  a  fact  which  commends  the  retention  of  this  tumor 
as  a  special  form  of  ovarian  carcinoma.  The  so-called  endotheliomas  of  the 


606  NEOPLASTIC  DISEASES 

ovary  are  not  distinguished  from  carcinomas  by  any  clinical  peculiarities,  but 
are  usually  malignant  (Apelt,  Pfannenstiel). 

General  Etiology. — In  view  of  the  remarkable  embryological  history,  the 
complex  structure,  and  the  series  of  functional  changes  which  the  organ  suf- 
fers, tumors  of  the  ovary  are  not  notably  frequent.  Dippert  refers  to  58,787 
female  clinic  patients  of  all  types  among  whom  were  941  ovarian  tumors, 
1.6  per  cent.  Gurlt  collected  947  ovarian  tumors,  8.5  per  cent.,  among  11,140 
women  with  tumors  of  all  types. 

Hereditary  influence  is  suggested  only  in  isolated  instances  such  as  are 
mentioned  by  J.  Simpson,  Lohlein,  and  others.  Trauma  is  a  negligible  factor, 
owing  to  the  protected  position  of  the  organs.  Inflammatory  changes  are 
held  to  influence  the  development  only  of  the  fibromas  and  simple  cysts 
(Pfannenstiel). 

Single  women,  furnishing  18  per  cent,  of  ovarian  tumors,  are  relatively 
more  susceptible  than  the  married,  especially  for  dermoids  (32  per  cent.) 
and  parovarian  cysts  (26.19  Per  cent.)  (Olshausen,  J.  Williams,  Lippert, 
Wedekind).  Childbirth  seemed  to  entail  less  liability  in  Martin's  1005  cases, 
of  which  554  were  nulliparae.  Yet  Lippert  found  that  73.6  per  cent,  of  his 
638  cases  had  borne  children. 

Age. — All  ages  are  susceptible,  from  birth  to  senility,  but  the  period  of 
sexual  activity,  25  to  35  years,  is  most  prominent.  A  fetal  cystadenoma  and 
sarcoma  are  described  by  Doran,  and  a  bilateral  sarcoma  by  Lonnberg.  Wiel 
collected  24  cases  under  5  years  and  60  under  10  years  of  age,  and  Hubert 
175  cases  in  children.  The  predominance  of  cysts,  dermoids  and  sarcomas, 
and  of  malignant  tumors  in  early  life  is  notable.  Kelly  emphasizes  the  high 
operative  mortality  in  children  in  a  collection  of  55  cystic,  47  dermoid,  and 
24  solid  tumors.  Many  cases,  chiefly  cystic,  occur  also  after  70  years.  Most 
of  the  carcinomas  occur  between  40  and  50  years  (Martin). 

The  relative  frequency  of  the  different  forms  of  tumors  I  have  calculated 
from  the  reports  of  Martin  and  Libbert,  over  200  cases,  as  follows:  Cystade- 
noma, 55  per  cent.;  carcinoma,  22  per  cent.;  embryoma,  9.2  per  cent.;  paro- 
varial,  8.4  per  cent.;  sarcoma,  2.9  per  cent.;  fibroma,  2.5  per  cent.  Pick  em- 
phasizes the  relative  frequency  of  ovarian  tumors  in  pseudohermaphrodites. 

From  the  above  data  it  appears  that  the  effective  causes  of  ovarian  tumors 
are  quite  as  obscure  as  with  other  organs.  Neither  predisposing  nor  exciting . 
factors  can  be  accurately  defined,  but  it  may  be  assumed  that  chronic  hy- 
peremia  exaggerating  the  natural  regenerative  processes  in  the  organ  figures 
in  most  cases.  The  studies  of  histogenesis,  on  the  other  hand,  indicate  that 
developmental  anomalies  are  essential  conditions  in  the  growth  of  the  great 
majority  of  ovarian  tumors. 

Histogenesis. — Virchow  and  the  older  pathologists  held  that  the  Graafian 
follicle  produces  only  simple  cysts  and  that  some  other  source  must  be  sought 
for  the  cystic  tumors.  Waldeyer  (Eierstock  u.,  Ei,  1870)  traced  the  origin 
of  the  tumors  to  Pfliiger's  tubes,  which  he  held  were  either  fetal  remnants 
or  newly  formed  in  later  life  by  the  ingrowth  of  superficial  ovarial  epithe- 
lium. Olshausen  contrasted  the  papillary  serous  tumors  with  the  pseudo- 
mucinous  and  chiefly  because  of  the  prominence  of  ciliated  cells  in  the  former 
he  derived  them  from  the  Wolffian  medullary  cords  of  Kolliker.  This  view 
he  later  abandoned,  but  it  long  received  support  from  Fischel,  Coblentz, 
Doran,  and  others.  Marchand  (1878)  studied  an  ovary  the  cortex  of  which 
was  filled  with  minute  cysts  containing  papillae  of  ciliated  epithelium,  and 
he  thus  showed  that  the  presence  of  ciliated  cells  did  not  require  an  origin 
from  medullary  Wolffian  tubes.  He  was  inclined  to  refer  them  to  included 
portions  of  tubal  epithelium  or  to  Graafian  follicles. 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  607 

In  a  similar  cystic  ovary  Malassez  and  Sinety  traced  the  origin  of  these 
small  cysts  to  the  superficial  ovarian  epithelium,  finding  the  cysts  often  con- 
nected by  cords  of  cells  with  the  surface.  Ciliated  columnar  epithelium  they 
found  on  the  surface  in  the  closed  tubes  (Pfliiger's)  and  in  the  cysts.  Flaisch- 
len  also  traced  the  downward  growth  of  surface  epithelium  forming  tubes 
which  developed  into  cysts  with  ciliated  cells,  in  the  intact  portions  of  a 
cystomatous  ovary. 

Elaborate  confirmation  of  these  observations  has  been  furnished  by  Wal- 
thard  who  in  serial  sections  of  many  ovaries  of  all  ages  demonstrated  the 
downward  growth  of  surface  epithelium  forming  cords,  tubes,  and  cysts 
lined  by  cubical,  columnar,  ciliated,  and  even  flat  epithelium.  He  describes 
the  formation  of  granulosa  cells  of  the  primitive  follicles  by  downgrowths 
of  surface  epithelium,  chiefly  in  the  fetus  and  during  the  first  year  of  life.  A 
somewhat  similar  downgrowth  occurs  up  to  old  age,  but  without  relation  to 
follicles,  and  these  cell  groups  may  produce  small  cysts.  Several  varieties 
of  ciliated  cell  groups  are  found  in  the  cortex  and  connected  with  surface 
epithelium.  Most  of  these  undergo  atrophy,  but  others,  in  which  there  is  a 
row  of  supporting  cells  and  the  stroma  is  very  cellular,  go  on  to  develop 
cystomas  of  various  types.  Larger  areas  of  this  type  with  cellular  stroma 
he  regarded  as  misplaced  tubal  mucosa.  All  the  tumor-bearing  areas  give 
the  impression  of  alien  tissue.  Mesonephric  (Wolffian)  rests  are  commonly 
found  in  the  hilus  and  penetrate  the  zona  vasculosa,  rarely  the  zona  paren- 
chymatosa  (v.  Franque),  in  the  form  of  compact  groups  of  cubical  cylindrical 
or  ciliated  cells  surrounded  by  connective  tissue  and  smooth  muscle.  They 
appear  not  to  develop  beyond  small  cysts  or  minute  cystic  adenomas. 

Many  of  the  structures  observed  by  Walthard  had  been  described  by 
Pfliiger  and  Kolliker,  both  of  whom  demonstrated  a  postembryonal  and 
periodically  recurring  formation  of  ovarial  tubes.  It  appears  from  Wal- 
thard's  study  that  the  probable  sources  of  tumors  are  not  to  be  identified 
with  Pfluger's  tubes,  which  are  connected  with  the  formation  of  granulosa 
cells,  but  with  congenitally  misplaced  groups  of  goblet,  ciliated,  or  squamous 
cells  with  which  a  portion  of  cellular  stroma  is  associated.  It  should  be  noted 
that  while  these  alien  tissue  masses  exhibit  many  of  the  elements  regarded 
as  essential  to  tumor  growth,  the  actual  development  of  the  tumors  from 
these  sources,  although  highly  probable,  is  still  unproved. 

The  superficial  ovarian  epithelium  has  been  clearly  shown  to  give  origin 
to  the  superficial  papillomas  of  the  ovary  (Malassez,  de  Sinety,  Flaischlen, 
Pick).  Recently  Bauer  has  shown  that  pseudostruma  ovarii  is  derived  by 
downward  growth  of  surface  epithelium.  Since  the  papillary  serous  cystoma 
is  identical  in  structure  with  the  papilloma,  and  since  downward  growth  of 
this  epithelium  is  commonly  seen  at  various  ages  there  is  considerable  ground 
for  assuming  that  this  form  of  cystoma  is  derived  from  embryonal  or  adult 
surface  epithelium.  When  one  considers  that  these  same  cells  may  secrete 
much  mucus  and  assume  the  goblet  form  (Walthard),  the  same  origin  is 
indicated  for  the  pseudomucinous  tumors.  The  direct  transformation  of 
these  cells  into  alveolar  or  solid  carcinoma  is  described  by  Glockner,  Linnell, 
and  Bauer. 

The  follicular  origin  of  ovarian  cystomas  has  long  been  a  popular  theory, 
but  still  lacks  definite  proof.  Wendeler  erroneously  assumes  the  embryonic 
origin  of  the  granulosa  cells  from  the  connective  tissue  of  the  Wolffian  body, 
which  might  eliminate  them  as  sources  of  epithelial  tumors.  That  the  super- 
ficial ovarian  epithelium  as  well  as  that  of  the  follicles  may  be  ciliated  has 
been  shown  by  v.  Velits,  who  also  found  an  ill-defined  ovum  in  such  a  follicle. 
Lateral  sprouts  from  primitive  follicles  have  also  been  observed  by  Steffeck, 


608 


NEOPLASTIC  DISEASES 


Hoffmeier,  and  v.  Franque,  but  these  may  represent  the  granulosa  cords  of 
Walthard,  which  tend  to  atrophy.  Low  and  even  branching  papillary  out- 
growths into  follicles  have  been  described  by  W.  Williams,  but  it  is  not  clear 
that  these  slight  grades  of  proliferation  go  on  to  produce  definite  tumors. 
They  are  seen  in  simple  follicular  cysts,  v.  Miiller  and  Pozzi  traced  ovarian 
carcinomas  to  altered  follicles  in  which  they  identified  ova.  Yet  it  is  doubt- 
ful if  the  identity  of  these  structures  was  established. 

The  presence  of  ova-like  cells  in  early  cystoma  does  not  prove  their  fol- 
licular origin,  since  these  cells  are  probably  not  true  ova  and  the  granulosa 
cells  are  not  sex  cells  or  capable  of  producing  such.  Pfannenstiel  holds  the 
frequent  association  of  cystoma  with  dermoids  as  an  argument  in  favor  of 
the  follicular  origin  of  the  cystoma. 

It  is  commonly  assumed  that  ovarian  tumors  arise  from  a  narrowly  defined 
tissue  segment  or  single  follicle.  Yet  the  early  stages  of  many  tumors 

suggest  that  considerable  areas  of 
superficial  epithelium  or  many 
follicles  are  successively  involved 
in  the  origin  of  the  growth.  This 
mode  of  origin  has  been  proved, 
for  the  pseudostruma  of  Bauer 
is  strongly  indicated  by  those 
tumors  which  preserve  the  form 
of  the  ovary,  and  by  those  which 
present  multiple  cysts  throughout 
the  cortex,  and  is  suggested  by  the 
hyperplasia  in  remaining  follicles 
.observed  in  many  cases  of  cyst- 
adenoma. 

The  Wolfiian  remnants  in  hilus 
and  body  have  been  urged  as  the 
source  of  pseudomucinous  and 
serous  tumors  by  Rokitansky, 
Kossmann,  Nagel,  and  others. 
The  intraligamentary  position  ac- 
cords with  this  origin,  and  Wal- 
thard found  one  small  adenoma  in 
a  mesonephric  tubule. 

The     occasional     presence     of 

FIG.  281.— Development  of  pseudostruma  smooth  muscle-cells,  the  associa- 
ovarii  from  superficial  epithelium.  (After  tion  with  struma  ovarii  or  der- 
Bauer,  Z.  G.  G.,  75.)  molds,  and  the  striking  resem- 

blance of  the  columnar  and  mucous 

cells  to  intestinal  epithelium  led  Ribbert  to  propose  a  teratoid  origin  for 
pseudomucinous  cystoma.  Misplaced  portions  of  tubal  mucosa  or  of  ac- 
cessory Fallopian  tubes  have  been  held  by  Marchard  and  by  Kossmann 
as  sources  of  papillary  tumors  with  ciliated  cells.  Walthard  identified  some 
of  his  alien  tissue  masses  as  tubal  remnants. 

It  thus  appears  that  moderate  proliferation  of  epithelium  has  been  ob- 
served in  primitive  and  adult  follicles,  in  the  superficial  epithelium  and  its 
various  invaginations  in  embryonal  and  adult  life,  and  in  the  Wolfnan  tubules 
of  the  hilus,  but  that  only  the  surface  epithelium  has  been  fully  traced  into 
tumor  growth.  That  the  proliferating  cells  are  not  the  normal  surface  epi- 
thelium, but  are  misplaced  and  embryonal  is  strongly  suggested  by  many 
features  of  ovarian  tumors.  Wendeler  would  combine  the  views  of  March- 


*/ 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  609 

and,  Walthard,  Kossmann,  and  others  by  assuming  that  the  originating  cells 
are  misplaced  Mullerian  epithelium,  which  in  its  upper  segments  goes  to 
form  the  Fallopian  tube.  This  theory  would  seem  consistent  with  most  of 
the  observed  facts  and  may  for  the  present  be  accepted.  That  ovarian 
tumors  may  also  arise  from  other  structures  is  not  thereby  excluded.  It  is 
highly  probable  that  tumors  of  adult  type  are  derived  from  adult  epithelium. 
The  ovulogenic  origin  of  certain  atypical  adult  and  embryonal  carcinomas, 
sarcomas,  and  mixed  tumors  should  be  entertained  for  the  ovary  as  for  the 
testis.  The  search  for  elements  demonstrating  the  tridermal  composition 
has  not  been  pursued  as  actively  in  ovarian  tumors  as  in  testicular  growths, 
but  there  appears  to  be  no  reason  why  the  one-sided  development  of  tera- 
tomas  should  be  less  frequent  in  one  organ  than  in  the  other.  It  is  especially 
in  tumors  of  bizarre  and  varying  structure,  which  do  not  fall  distinctly  in  the 
recognized  classes  of  intrinsic  ovarian  neoplasms,  that  the  ovulogenic  origin 
should  be  considered. 

Tumors  of  the  Parovarium  (Epoophoron). — The  parovarium  is  the  rem- 
nant of  the  sexual  portion  of  the  Wolffian  body.  It  lies  in  the  membrane 
connecting  ovary  and  tube  and  consists  of  a  main  channel  running  close  to 
the  tube,  and  of  10  to  18  lateral  branches  arranged  like  the  teeth  of  a  comb. 
The  main  channel  ends  in  a  blind  pouch  which  may  be  dilated  into  a  small 
cyst,  the  hydatid  of  Morgagni.  Portions  of  these  tubules  may  be  found  in 
the  wall  of  the  tube,  where  they  may  be  confused  with  secondary  Fallopian 
canals,  and  in  the  hilus  of  the  ovary.  The  tubules  are  small,  lined  by  low 
cylindrical  cells,  and  walled  by  circular  and  longitudinal  muscle-fibers. 
Slight  dilatation  of  the  tubules  is  common  and  has  been  interpreted  as  an 
evidence  of  functional  activity  (Bucura). 

Cysts  of  the  parovarium  are  observed  in  about  n  per  cent,  of  ovariot- 
omies (Olshausen).  They  commonly  reach  the  size  of  the  fist,  but  very  large 
cysts  weighing  42  pounds,  or  containing  33  liters  of  fluid,  are  recorded  by 
Kummel  and  Nagel.  Kossmann  holds  that  only  the  small  multiple  or  multi- 
locular  cysts  rise  from  the  parovarium.  The  large  cysts  he  refers  to  dilata- 
tion of  accessory  Fallopian  tubes,  hydroparasalpinx.  Favoring  this  view  are 
the  presence  of  muscle-tissue  in  the  wall,  the  preservation  of  parovarian  tissue 
noted  in  some  cases,  the  unilocular  character,  the  difficulty  of  deriving  a 
single  large  cyst  from  the  tubules  of  the  parovarium,  and  the  close  contact 
of  the  cyst  with  the  tube  wall.  Orth  states  that  the  cysts  which  show  par- 
ovarian  tubules  in  their  walls  are  derived  from  the  par-epoophoron. 

Parovarian  cysts  are  characterized  by  their  elliptical  form,  thin  walls, 
close  contact  with  an  elongated  tube,  a  movable  serous  covering,  and  the 
presence  of  an  intact  ovary.  The  parovarian  cysts  are  subserous,  so  that  the 
peritoneal  coat  is  movable  over  the  tumor.  The  tube  is  intimately  adherent 
and  stretches  over  the  cyst  wall  in  greatly  elongated  form,  measuring  in 
Payer's  case  76  cm.,  the  fimbrise  n  cm.  The  ovary  may  be  stretched  to  a 
flat  plate.  The  chamber  is  usually  single.  While  commonly  pedunculated 
and  subject  to  torsion,  these  cysts  may  be  extraperitoneal  and  displace  the 
elongated  uterus  out  of  the  pelvis.  The  thin  wall  easily  ruptures.  The  cyst 
wall  is  composed  of  connective  tissue  and  blood-vessels,  and  muscle-fibers 
are  occasionally  seen.  Elastic  fibers  may  be  abundant  and  to  their  contrac- 
tion or  that  of  the  muscle-fibers  is  attributed  the  numerous  foldings  of  the 
inner  surface.  The  lining  is  of  low  cylindrical  and  ciliated  epithelium  which 
is  often  degenerated  and  desquamated.  The  contents  when  clear  are  of 
thin,  opalescent  alkaline  fluid  of  low  gravity,  1005.  Mucin  and  pseudo- 
mucin  are  absent  or  present  in  traces  only,  and  albumin  is  scanty.  Urea 
may  occur  in  considerable  traces,  and  a  reducing  substance  is  usually  demon- 
39 


610  NEOPLASTIC  DISEASES 

strable.  The  salts  are  chiefly  chlorids  and  sulphates.  Hemorrhage  and 
fatty  degeneration  often  alter  the  character  of  the  fluid.  Papillary  fibro- 
epithelial  growths  from  the  cyst  wall  occur  in  a  considerable  proportion  of 
cases  and  Pfannenstlel  refers  to  an  extensive  cauliflower  growth  with  invasion 
of  the  wall. 

A  variety  of  other  forms  of  tumors  has  also  been  referred  to  the  par- 
ovarium  on  account  of  their  structure  and  location.  These  include  adeno- 
myomas  (Pick),  multilocular  hydatidiform  cystoma,  adenosarcoma  (Werth), 
fibre-adenoma,  fibrosarcoma,  and  carcinoma  (Pick,  R.  Meyer). 

Mesonephric  Tumors.— While  most  observers  find  that  the  Wolfnan 
tubules  (epoophoron)  often  found  in  the  hilus  of  the  ovary  show  little  tend- 
ency to  develop  tumor  growth,  a  small  group  of  cystic  tumors  have  been 
referred  to  this  origin.  Usually  they  produce  harmless  cysts  of  small  size 
lying  in  the  hilus  or  medulla  (v.  Franque,  Walthard).  Other  tumors  are 
solid  and  composed  of  tubules  presenting  the  comb-like  arrangement  of  the 
epoophoron  (Schickele,  Lit.).  The  cells  are  high  and  cylindrical  and  they 
may  show  moderate  proliferation. 

A  peculiar  malignant  tumor  of  mixed  structure,  containing  myxosarco- 
matous  and  gland-like  structures,  somewhat  resembling  the  embryonal  ade- 
nomyosarcoma  of  the  kidney,  is  described  by  Glockner  and  referred  to  a 
mesonephric  origin. 

Adenomyoma  of  Ovary. — A  rare  form  of  ovarian  tumor  reproduces  exactly 
the  structure  of  Recklinghausen's  adenomyoma.  They  are  small,  multi- 
cystic,  and  benign.  They  present  tubules  with  dichotomous  branching  and 
ampullary  sacs  lying  in  a  very  cellular  stroma.  Such  cases  have  been  de- 
scribed by  Babo,  Aschoff,  Neumann,  and  Vassmer,  and  referred  to  a  meso- 
nephric origin,  but  since  they  are  usually  associated  with  adenomyoma  of 
uterus  or  tubes  it  is  probable  that  Russell's  interpretation  of  his  case  as  of 
Miillerian  origin  is  correct.  The  mesonephric  tubules  are  free  from  a  very 
cellular  stroma  (Schickele,  Lit.). 

Adrenal  tumors  of  the  ovary  occur  in  typical  form  and  present  the  usual 
variations  in  structure  of  adenoma,  adenocarcinoma,  and  perithelioma.  They 
commonly  reach  a  large  size,  are  of  yellowish  "color,  and  prove  malignant. 
They  arise  from  the  broad  ligament,  hilus,  or  body  of  the  ovary,  where  adrenal 
tissue  is  often  present.  Typical  tumors  of  the  hilus  or  broad  ligament  are 
described  by  Weiss,  L.  Pick,  and  Peham,  and  in  the  body  of  the  ovary  by 
Peham,  Sternberg,  and  Pfannenstiel.  It  would  seem  difficult  to  distinguish 
between  such  tumors  in  the  body  of  the  ovary  and  tumors  of  the  corpus 
luteum. 

Testicular  Adenoma  of  Ovary. — L.  Pick  has  described  a  peculiar  adenoma 
of  the  ovary  and  brought  forward  satisfactory  evidence  to  show  that  it  is 
derived  from  a  testicular  element  in  the  ovary  of  the  hermaphrodite  subject. 
The  tumor  is  a  well  circumscribed,  yellowish,  solid  growth  of  moderate  dimen- 
sions and  lobular  conformation.  The  structure  presents  regular  elongated 
tubules  about  35  m.  in  diameter,  lined  and  filled  by  uniform  cuboidal  epithe- 
lium. The  stroma  is  slightly  developed  and  may  contain  cells  resembling 
the  interstitial  cells  of  the  testis.  The  tubules  resemble  those  of  the  sweat- 
glands  and  are  exactly  similar  to  the  tubular  adenomas  of  undescended  testes. 

CARCINOMA  OF  THE  FALLOPIAN  TUBE 

Since  Orthmann's  first  description  of  primary  carcinoma  of  the  tube 
(1886)  about  120  cases  have  been  reported  (Doran,  Fromme,  Heynemann, 
Lit.).  It  occurs  chiefly  between  43  to  50  years,  but  cases  have  been  observed 


CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY  611 

as  early  as  the  ayth  year  (Norris).  In  its  etiology  the  influence  of  chronic 
inflammation  is  of  first  importance.  Many  cases  begin  as  multiple  papillary 
outgrowths  of  the  mucosa  such  as  arise  on  inflamed  mucous  membranes. 
Sterility,  which  may  also  be  referred  to  inflammation,  was  noted  by  Kerhrer 
in  14  and  a  single  birth  in  20,  of  52  cases.  Association  with  tubo-ovarian 
cysts  and  uterine  myoma  is  often  observed  (Orthmann),  and  various  abnor- 
malities in  the  position  and  structure  of  the  tube  may  serve  as  predisposing 
factors  to  tumor  growth. 

In  gross  appearance  the  tumors  are  solid  and  nodular,  or  more  diffuse 
and  papillary.  They  arise  from  the  middle  and  outer  portions  of  the  tube, 
the  uterine  end  usually  being  free.  Very  early  tumors  have  been  found  in 
the  form  of  small  superficial  excrescences,  while  the  advanced  carcinomas 
may  reach  the  size  of  a  child's  head.  Distention  of  the  tube  with  fluid  may 
add  to  the  bulk  and  lead  to  perforation  with  peritonitis  (Kiwisch). 

The  tumors  were  bilateral  in  about  one-third  of  the  cases.  Stolz  collected 
10  such  cases  which  had  the  structure  of  malignant  adenoma  and  I  have 
recorded  one  other.  In  a  recent  case  studied  by  L'Esperance  in  this  labora- 
tory the  mucosa  of  uterus  and  both  tubes  was  the  seat  of  diffuse  adenocar- 
cinoma  and  co-extensive  tuberculosis. 


FIG.  282. — Double  primary  adenocarcinoma  of  Fallopian  tubes. 

The  papillary  forms  of  the  tumor  long  remain  benign,  but  others  invade 
the  wall,  cause  adhesions,  perforate  the  peritoneum,  and  cause  local  and 
distant  metastases.  Extensions  have  often  been  observed  in  the  ovary, 
uterus,  opposite  tube,  and  pelvic  nodes  (Stolz),  in  omentum,  stomach  and, 
intestine  (Amann),  rectum  (Cullen),  and  inguinal  nodes  (Rosthorn).  Tubo- 
ovarian  carcinoma  is  difficult  to  trace  to  its  exact  origin  on  account  of  the 
resemblance  of  the  epithelial  tumors  of  these  organs.  In  3  reported  cases 
this  condition  was  bilateral  (Dittrich,  Edebohls,  Sanger).  Ascites  and  ovarian 
abscess  are  occasional  complications  of  tubal  carcinoma. 

Structure. — The  earliest  cases  observed  have  appeared  as  numerous  low 
papillary  outgrowths  of  the  tubal  folds,  covered  with  a  single  layer  of  cuboidal 
cells,  and  resembling  ovarian  papilloma.  Some  tumors  retain  this  distinctly 
papillary  structure  with  increase  in  the  cell  layers.  Others  exhibit  an  al- 
veolar structure,  probably  from  fusion  of  adjacent  papillae,  and  resemble 
uterine  adenocarcinoma.  Sanger  and  Earth  believe  that  the  latter  develop 
from  the  former  by  a  gradual  change  in  structure  and  malignancy. 

Orthmann  describes  a  diffuse  acanthoma  of  the  tube  with  hornification 


6l2  NEOPLASTIC  DISEASES 

and  pearl  formation,  and  the  transformation  of  cylindrical  cells  into  squa- 
mous. 

For  some  tumors  apparently  originating  in  the  wall  an  origin  from  an 
accessory  tube  or  from  Gartner's  duct  has  been  suggested  (Friedenheim, 
Doran). 

Secondary  carcinoma  of  the  tube  is  relatively  frequent,  especially  from 
the  uterus  and  ovary  (Sanger).  Direct  extension  of  corpus  carcinoma  into 
both  tubes  was  described  by  Lancereaux  and  3  cases  of  tubal  metastases 
from  corpus  carcinoma  were  collected  by  Kundrat.  Primary  carcinomas  of 
both  tube  and  uterus  are  recorded  by  Hofbauer  and  by  Novy.  The  prognosis 
of  tubal  carcinoma  is  no  better  than  that  of  cervical  carcinoma  and  after 
infiltration  of  the  wall  it  is  distinctly  unfavorable  (Doran,  Stotz). 

Miscellaneous  Tumors  of  the  Fallopian  Tube. — Extensive  proliferation 
of  peritoneal  and  vascular  endothelium  of  inflammatory  origin  is  described 
by  Kworostansky.  A  peculiar  tumor  composed  of  carcinoma  arising  from 
the  mucosa,  sarcoma  of  the  wall,  and  endothelioma  of  the  blood-vessels  is 
described  by  v.  Franque.  A  teratoid  chondrosarcocarcinoma  is  reported 
by  Amann. 

Primary  sarcomas  and  myxosarcomas  are  described  by  Janvrin,  Jacobs, 
Sanger,  and  v.  Kahlden.  They  were  of  variable  and  uncertain  structure  and 
origin. 


CHAPTER  XXX 
THE  OVARIAN  TERATOMA 

The  commonly  recognized  varieties  of  this  tumor,  the  cystic  dermoid 
and  the  solid  teratoma,  represent  adult  and  embryonal  types  of  the  same 
growth.  Although  varying  greatly  in  gross  anatomy  and  clinical  course 
they  are  probably  identical  in  origin  and  many  intermediate  forms  connect 
the  extremes  of  either  type  in  one  nearly  continuous  series.  The  chief  dis- 
tinction is  the  clinical  malignancy  of  the  solid  teratoma,  the  simple  dermoid 
being  relatively  benign. 

Clinical  Course. — Dermoids  constitute  about  10  per  cent,  of  all  ovarian 
tumors,  while  solid  teratomas  are  much  less  frequent  in  occurrence  (Kroemer, 
Lit.)-  They  appear  at  all  ages,  often  in  childhood,  most  frequently  between 
30  and  40  years,  the  malignant  growths  occurring  rather  earlier  than  the 
dermoids.  The  early  growth  of  both  varieties  is  rapid,  but  after  attaining  a 
certain  development  the  dermoid  reaches  its  limit  and  may  remain  stationary 
for  many  years,  its  later  course  being  determined  by  accumulating  secretion 
in  the  accompanying  cystoma,  or  by  malignant  changes,  or  other  complica- 
tions. The  dermoid  may  migrate  from  the  ovary  and  become  implanted 
elsewhere  or  perforate  the  hollow  viscera.  Extensive  calcification  may  lead 
to  complete  arrest  of  growth.  Rupture  of  the  cyst  and  discharge  of  its  con- 
tents if  sterile  lead  to  a  low  grade  of  peritonitis,  with  encapsulation  of  dis- 
charged detritus  or  to  multiple  implantation  cysts.  Purulent  peritonitis 
results  if  the  cyst  is  infected.  Malignant  processes  develop  in  about  3  per 
cent,  of  dermoids  and  commonly  lead  to  invasion  of  the  peritoneum.  These 
secondary  processes  take  the  form  of  pseudomyxoma  peritonei,  or  numerous 
cellular  nodules,  or  more  diffuse  pelvic  growths  of  sarcomatous  type. 

The  solid  embryonal  tumors  develop  rapidly  and  are  malignant  from  the 
first.  They  soon  reach  considerable  dimensions,  become  adherent  to  sur- 
rounding structures,  perforate  the  capsule  and  become  implanted  in  the 
pelvis,  on  opposite  ovary,  abdominal  wall,  or  over  the  diaphragm  and  omen- 
turn,  with  ascites  and  peritonitis.  Later,  distant  metastases  occur  in  retro- 
peritoneal  nodes,  lungs,  and  liver. 

The  prognosis  of  simple  ovarian  dermoids  is  favorable,  as  the  tumors 
are  well  circumscribed,  often  pedunculated,  and  readily  extirpated.  The 
various  complications  alter  this  prognosis  and  with  malignant  changes  the 
operative  mortality  is  considerable  and  recurrence  is  the  rule.  With  bilateral 
dermoids  malignant  processes  appear  to  be  comparatively  frequent  (Hohne). 

The  solid  malignant  tumors  are  usually  fatal,  directly,  or  from  operation, 
or  recurrence.  Yet  when  the  tumor  is  circumscribed  or  pedunculated  and 
early,  it  may  be  successfully  removed.  Neuhauser  estimates  the  cured  cases 
at  27  per  cent.  Struma  ovarii  is  usually  benign,  but  many  give  recurrence 
and  metastases.  Chorioma  ovarii  is  uniformly  fatal. 

Gross  Anatomy. — The  ovarian  dermoid  is  a  cystic  tumor  of  globular 
outline  and  smooth  surface  and  varies  in  size  from  a  small  nodule  to  a  bulky 
cyst.  It  arises  within  the  ovary,  destroying  the  organ,  or  leaving  a  small 
nodule  lying  upon  the  cyst.  It  may  be  attached  to  the  ovary  by  a  pedicle 
which  may  break  from  torsion,  leaving  the  tumor  attached  to  surrounding 
tissues.  The  polypoid  form  has  been  referred  to  a  superficial  position  of  the 

613 


614 


NEOPLASTIC  DISEASES 


follicle  supposed  to  give  origin  to  the  dermoid.  They  may  develop  in  the 
broad  ligament  or  in  the  retroperitoneal  space,  and  both  ovaries  may  be 
normal  when  the  tumor  arises  from  a  supernumerary  organ,  traces  of  which 
are  found  in  these  extra-ovarian  growths.  The  solid  embryonal  and  malig- 
nant teratomas  exhibit  the  same  variations  in  position,  they  often  contain 
many  small  cysts  and  they  may  reach  very  large  dimensions,  Falk's  tumor 
weighing  25  kg. 

Both  dermoids  and  solid  teratomas  are  frequently  (14  per  cent.  Arnsper- 
ger)  combined  with  ovarian  cystomas,  either  serous  or  pseudomucinous  or 


FIG.  283. — Dermatocystoma  of  ovary.    Simple  cystoma  above.     Dermoid  with  hair  in 
center.     Thyroid-like  tissue  below. 

lined  by  ciliated  epithelium.  A  corpus  luteum  cyst  may  also  be  associated 
with  the  dermoid,  and  Schottlander  believes  such  cysts  are  often  overlooked. 
In  these  cases  the  dermoid  portion  is  limited  to  a  segment  of  the  wall  of  a 
large  cyst,  or  the  dermoid  projects  as  a  finger-like  protrusion  at  one  point 
of  the  cyst  (Rokitansky's  protuberance),  or  two  partly  or  completely  separate 
cysts,  dermoid  and  adenoid,  are  in  apposition  or  show  various  stages  of  fusion. 
The  dermoid  portion  may  be  represented  also  by  an  embryonal  teratoma. 
In  not  a  few  cases  the  dermoid  is  found  in  one  ovary,  a  cystadenoma  in  the 
other. 


THE  OVARIAN  TERATOMA  615 

Dermoid  cysts  usually  contain  hair  and  teeth.  The  hair  is  very  long 
like  that  of  the  head,  or  short  and  fine  as  lanugo,  or  curled  and  stiff  as  of  the 
pubes,  and  it  is  often  silvery  in  tumors  in  young  subjects.  Sebaceous  or 
oily  material  is  mingled  with  the  hair.  It  may  be  condensed  in  the  form  of 
firm  globules,  or  in  a  large  mass  consisting  of  fatty  crystals  forming  about 
hair,  or  in  epidermal  concretions.  The  occurrence  of  these  masses  has  been 
referred  to  albuminous  bloody  exudate  following  torsion,  to  mixture  with 
secretion  from  sweat-glands,  or  to  a  sort  of  butter  formation.  Bonney  counted 
4000  small  globules  in  one  case  and  Opitz  reports  their  appearance  in  the 
stool  through  an  intestinal  fistula. 

In  the  combined  cystomas  the  mucinous  material  mingles  with  the  fatty, 
and  when  blood  is  added,  the  dermoid  element  may  be  obscured  and  require 
careful  identification  on  the  cleansed  interior.  A  small  tuft  of  hair  or  a  pig- 
mented  spot,  or  a  bony  plate,  often  mark  the  dermoid  area.  Calcification 
transformed  the  entire  mass  into  a  stone  in  Pfannenstiel's  case.  Teeth  occur 
in  about  half  the  dermoids  and  in  many  solid  tumors.  They  lie  loosely  on 
the  surface  or  firmly  fixed  in  a  rudimentary  maxilla,  or  deeply  embedded 
in  dental  follicles.  The  teeth  are  well  formed  and  may  be  identified  as  in- 
cisors or  molars,  etc.  The  embryonal  tumors  usually  contain  only  small 
milk  teeth,  while  those  of  the  dermoid  are  more  adult.  Rokitansky  observed 
the  eruption  of  permanent  after  the  discharge  of  milk  teeth  which  fall  into 
the  cyst  contents  and  become  absorbed.  Saxer's  dermoid  consisted  of  a 
single  well-formed  tooth,  while  Schnabel  and  Plouquet  counted  from  100  to 
300  or  more. 

The  maxillae  have  resembled  the  lower  jaw  with  coronoid  process  or  the 
upper  with  antrum  Highmori.  Other  bony  masses  have  been  interpreted 
as  sternum  (Wilms),  skull  (Grechen),  ribs  (Schramm),  or  pelvis  (Kuster). 
Portions  of  long  bones  connected  by  joints  are  described  by  Kappeler.  Well- 
formed  extremities  have  occasionally  been  observed,  as  a  finger  with  three 
phalanges  and  nail  (Amor),  several  fingers  (Reverdin),  short  extremity  with 
long  nails  (Thornton).  Axel  Key  identified  two  lower  limbs  with  toes,  skull, 
brain,  and  jaw.  Even  more  complete  rudimentary  fetuses  are  described 
by  Repin,  Askanazy,  Shattock,  and  Goffe,  who  identified  such  structures 
as  skull,  cystic  brain  vesicles,  pigmented  optic  cups,  complete  extremities, 
pelvis  with  hairy  pubes,  vulva,  clitoris,  spinal  cord,  and  blind  coil  of  intestine. 
The  development  of  these  structures,  however,  falls  considerably  below  that 
of  the  epignathi.  In  the  embryonal  tumors  the  complex  structure  usually 
renders  the  gross  identification  of  organ  rudiments  impossible. 

Glandular  organs  may  occasionally  be  detected.  Areas  of  thyroid  tissue 
are  rather  frequently  present,  as  small  colloid  foci,  or  large  masses  of  typical 
gland  tissue,  or  the  entire  tumor  may  be  composed  of  thyroid  tissue,  constitut- 
ing the  well-known  "struma  ovarii."  Salivary  glands  lying  near  a  maxillary 
bone  are  described  by  Axel  Key  and  Flaischlen. 

Brain  tissue  appears  in  the  form  of  convolutions  of  soft  gray  tissue  (Baum- 
garten).  It  is  often  the  seat  of  hemorrhage.  A  portion  of  cerebellum  was 
observed  by  Askanazy.  Pigmented  optic  cups  have  been  found  embedded 
within  or  lying  near  the  brain  tissue.  Baumgarten  described  double  rudi- 
mentary eyes,  one  of  which  exhibited  a  cornea-like  structure.  Kordi  recog- 
nized a  lens  and  eyelid,  and  Graves  found  eyelid  with  lashes. 

The  embryonal  teratomas  may  usually  be  distinguished  from  the  more 
adult  dermoids  by  the  absence  of  any  large  cystic  cavities  with  hair  or  seba- 
ceous material,  or  definite  limbs,  or  organs.  The  solid  tumors  usually  con- 
tain many  small  cysts  and  close  inspection  may  reveal  islands  of  bone  or 
cartilage,  rudimentary  teeth,  minute  dermoids  with  fine  hair,  pigmented 


616 


NEOPLASTIC  DISEASES 


retinal  structures,  and  in  general  the  cellular  structure  of  an  embryonal 
tumor.  Transitional  cases  between  the  main  types  occur,  and  overgrowth 
of  one  element,  as  in  struma  ovarii,  gives  rise  to  peculiar  forms  requiring 
special  consideration. 

Microscopical  study  reveals  the  extensive  details  of  the  structure  of 
ovarian  teratomas,  strengthens  the  interpretation  of  the  various  forms  of 
fetal  mimicry,  and  reveals  the  essential  tridermal  nature  of  these  growths. 

The  hairy  dermal  papilla  is  covered  with  a  thin  epidermis  and  a  corium 
of  normal  structure  which  contains  many  sebaceous,  sweat,  and  hair  glands 
and  presents  an  almost  exact  duplicate  of  the  scalp.  Retention  in  the  glands 
often  produces  comedones  and  small  sebaceous  cysts.  The  epidermis  may 
be  traced  into  the  mucous  membrane  which  covers  the  maxillae  and  the  tis- 
sues in  which  teeth  are  found.  This  point  may  be  indicated  by  a  shallow 
depression  or  deep  pocket  suggesting  a  buccal  cavity.  All  stages  of  the 


land  alveoli  in  a  small  ovarian  dermoid. 


development  of  teeth  have  been  traced,  from  a  simple  enamel  organ  to  a 
perfectly  formed  adult  tooth.  Here  have  been  found  the  rudiments  of  buccal 
and  salivary  glands.  The  subcutaneous  tissue  contains  embryonal  fat, 
connective  tissue,  and  blood-vessels.  Beneath  this  layer  one  commonly  finds 
plates  of  bone  or  cartilage  which  may  be  interpreted  as  fragments  of  skull, 
since  brain  tissue,  medullary  canal,  spinal  cord,  and  ganglia  may  sometimes 
be  identified  in  this  region  (Kroemer).  Here  also  small  cysts  may  present 
an  ependymal  lining.  Cerebral  elements  may  be  reduced  to  pigment  streaks, 
ependymal  tufts,  or  concretions  (brain  sand).  Askanazy  points  out  that 
the  nerve  tissues  of  ovarian  dermoids  include  the  central,  peripheral,  and 
sympathetic,  as  well  as  special  sense  organs,  as  of  eye  and  ear.  The  dominant 
system  is  the  sympathetic.  The  adult  forms  of  these  tissues  are  represented 
by  brain  cortex,  ganglia,  and  nerve  trunks,  the  embryonal  by  neuro-epithelial 
cell  groups.  The  chromatophores  of  the  central  nervous  system  are  often 


THE  OVARIAN  TERATOMA 


617 


abundant.  The  respiratory  tract  is  represented  by  canals  lined  by  columnar 
or  ciliated  epithelium  in  a  cellular  lymphoid  mucosa  walled  by  cartilaginous 
rings  and  strands  of  smooth  muscle.  Mucous  glands,  islands  of  thyroid 
tissue,  and  occasionally  striated  muscle  bundles  complete  the  resemblance 
to  the  fetal  trachea.  Kroemer  interprets  certain  sharp  infoldings  of  this 
mucosa,  with  change  to  squamous  lining,  as  vocal  cords,  and  he  identifies 
the  nares  by  ciliated  epithelium  lying  on  curved  cartilaginous  plates.  Wilms 
describes  a  rudiment  of  lung  connected  with  trachea  by  a  bronchus.  Mam- 
mary gland  tissue  is  described  by  Button  and  Reverdin.  Gastro-intestinal 
tract  appears  in  segments  which  resemble  stomach,  ileum,  or  colon.  A  single 
layer  of  low  columnar  epithelium,  lining  a  flat  mucosa  with  many  glands 
without  lymphoid  tissue  or  valvulae,  but  backed  by  layers  of  smooth  muscle, 
recalls  more  or  less  definitely  the  stomach.  In  the  portions  of  small  intestine 
valvulae,  villi,  crypts,  and  simple  or  agminated  lymphoid  follicles  are  found, 
the  lymphoid  tissue  being  frequently  present  in  abundance.  Segments  of 


FIG.  285. — Ependymal  structure  in  brain  tissue  in  a  small  ovarian  dermoid. 

colon  are  often  observed.  Pommer  described  cecum  and  appendix.  Colon 
with  meconium  has  been  described  by  Perls,  Repin,  and  others.  Arnsperger 
identified  a  portion  of  esophagus,  but  Askanazy  finds  that  the  esophageal 
remnant  is  commonly  missing,  and  that  the  intestinal  tract  opens  directly 
into  the  respiratory,  constituting  a  condition  which  is  characteristic  of  tera- 
tomas.  Kroemer  identified  a  Mullerian  duct  with  cervical  and  uterine  glands, 
myometrium,  and  vaginal  mucosa.  Tn  the  embryonal  tumors  the  respiratory 
and  intestinal  structures  are  reduced  to  short  canals  or  small  cysts  in  which 
one  type  of  epithelium  often  changes  sharply  into  another. 

The  ocular  structures  vary  from  rudimentary  eyes  with  retina,  choroid, 
lens,  and  cornea,  which  have  appeared  separately,  although  not  all  in  the  same 
case,  down  to  isolated  groups  of  pigmented  choroid  or  retinal  cells.  The 
most  frequent  structure  is  a  layer  of  pigmented  cells  lying  upon  a  vascular 
membrane  which  incloses  an  optic  vesicle.  The  pigmented  cells  resemble 
those  of  the  choroid,  or  they  are  hexagonal  plates  reproducing  the  mosaic 


618  NEOPLASTIC  DISEASES 

of  the  retinal  epithelium.  These  structures  may  be  bilateral  and  lie  near 
or  within  areas  of  brain  tissue  with  which  no  definite  connection  by  an  optic 
nerve-trunk  has  yet  been  observed. 

Mesodermal  elements,  besides  those  recognized  in  the  gross,  appear  in 
many  forms.  Islands  of  hyaline  or  elastic  cartilage  occur  in  both  adult  and 
embryonal  tumors,  and  in  the  latter  they  may  grade  into  myxomatous  or 
sarcomatous  tissue.  Spongy  bone  masses  may  contain  lymphoid  marrow,  but 
without  giant-cells  (Coe,  Kroemer).  Muscle-fibers  are  usually  smooth,  but 
scanty  striated  cells  have  been  observed,  as  well  as  heart-muscle  cells  (Wilms, 
Askanazy,  Katsurada). 

The  outer  wall  of  a  dermoid  cyst  varies  greatly  in  structure  and  probably 
passes  through  certain  transformations.  Any  ovarian  tissue  remaining 
is  confined  to  a  small,  often  cystic,  mass  of  tissue  located  at  one  point  or 
distributed  along  the  wall.  When  the  original  dermoid  sac  is  preserved  the 
lining  is  of  cuboidal  or  columnar  epithelium  and  is  derived  by  many  from 
the  cells  of  the  Graafian  follicle.  This  membrane  with  low  epithelial  lining 
has  been  interpreted  as  a  form  of  amnion.  An  extension  of  squamous 
epithelium  from  the  dermoid  papilla  over  much  of  this  sac  is  regarded  by 
Kroemer  as  a  late  and  secondary  change.  Erosion  of  this  lining  epithelium 
is  accompanied  by  formation  of  giant-cells  lying  on  granulation  tissue.  Fat 
crystals  and  fragments  of  hair  may  be  embedded  in  this  tissue  and  consider- 
able calcification  of  the  wall  may  occur,  especially  after  separation.  The 
gradual  absorption  of  the  oily  contents  of  the  cyst  may  result  in  honeycomb- 
ing of  the  wall,  the  fat  passing  into  dilated  lymphatics  lined  by  proliferating 
endothelium. 

Schottlander  traces  the  large  serous  cysts  accompanying  some  dermoids 
to  dilated  lymphatics.  The  gradual  absorption  of  the  thin  wall  of  the 
original  dermoid  chamber  leads  to  communication  with  surrounding  cavities 
which  include  corpora  lutea,  serous  cysts,  and  adenomatous  cysts.  As  these 
communications  widen,  the  wall  of  the  cyst  changes  and  its  lining  varies 
in  different  portions  and  at  different  periods. 

Metastases  develop  from  dermoids  in  which  malignant  changes  have 
become  established  and  more  frequently  from  the  solid  and  embryonal  tera- 
tomas. 

Local  dissemination  of  the  tumor  elements  over  the  peritoneum  follows 
rupture  of  the  cyst  wall  or  tumor  capsule.  These  implantation  metastases 
are  of  very  variable  structure.  Lazarus  found  nodules  on  diaphragm  and 
in  Douglas'  pouch,  the  latter  containing  cartilage  and  cysts  with  cylindrical 
cells.  In  several  cases  multiple  epidermoid  and  dermoid  cysts  have  resulted. 
Neuhauser  described  multiple  miliary  nodules  of  glia-tissue  along  the  ves- 
sels of  a  portion  of  omentum  removed  at  operation  on  a  patient  who  recovered. 
Falk  demonstrated  at  autopsy  complete  regression  of  peritoneal  metastases 
3  years  after  laparotomy  in  an  inoperable  tumor. 

Through  the  lymph-vessels  the  retroperitoneal  nodes  are  involved  by 
metastases  which  are  of  simple  or  complex  type.  Many  of  these  are  of  ecto- 
dermal  and  neuro-epithelial  nature.  Ewald  found  ectodermal  and  ento- 
dermal  cysts  and  cartilage  in  a  large  recurrent  retroperitoneal  tumor.  Pick 
demonstrated  a  long  bone  with  marrow  cavity,  lying  in  a  retroperitoneal 
node.  Falk  described  a  complex  metastasis  in  the  abdominal  wall  contain- 
ing brain  tissue,  and  intestinal  canal  with  musculature.  All  of  the  complex 
secondary  tumors  are  probably  the  result  of  direct  extensions  or  implantations. 

Through  the  blood-vessels  metastases  have  appeared  in  lungs,  liver,  and 
kidney,  and  are  usually  of  sarcomatous  or  indifferent  embryonal  type.  It 
is  evident  from  these  observations  that  several  types  of  differentiated  cells 


THE  OVARIAN  TERATOMA  619 

may  be  detached  from  ovarian  teratomas  and  give  rise  to  metastatic  tumors. 
That  undifferentiated  cells  capable  of  developing  tridermal  structures  may 
be  dislodged  from  the  ovarian  tumors  is  as  yet  unproved.  All  the  tridermal 
secondary  growths  appear  to  be  local  recurrences  or  implantations  in  or 
about  the  peritoneum.  The  various  cells  of  the  original  tumor  appear  to 
become  separated  by  the  embolic  process  and  to  develop  only  their  particular 
kind  in  metastatic  tumors.  Yet  it  must  be  admitted  that  the  embolic  cells 
or  cell  groups  are  capable  of  developing  organoid  structures,  such  as  brain 
tissue  and  dermoid  cysts  (cf.  Saxer). 

Atypical  Forms  of  Ovarian  Dermoids. — Not  all  ovarian  dermoids  exhibit 
the  tridermal  and  complex  structures  of  the  fully  developed  tumor.  Sup- 
pression of  one  germ  layer,  overgrowth  of  single  elements,  and  secondary 
changes  give  rise  to  several  well-defined  subvarieties. 

(1)  Bidermal   Atrophic   Teratomas. — Simple   dermoid   cysts  without   de- 
monstrable elements  of  a  third  germ  layer  constitute  about  5  per  cent,  of  all 
ovarian  teratomas  (Wilms).    The  ectodermal  lining  presents  the  usual  fea- 
tures of  a  typical  dermoid  and  the  wall  contains  dermal  glands,  teeth,  connec- 
tive, fat,  smooth  muscle  and  bone  or  cartilage,  but  entodermal  structures 
are  missing.    While  only  a  very  thorough  study  can  determine  the  absence 
of  entoderm,  there  is  little  doubt  that  this  layer  is  the  least  vigorous  of  the 
three  in  this  as  in  other  teratomas.    Askanazy  saw  complete  loss  of  ento- 
dermal structures  in  a  petrified  dermoid  containing  teeth.     Kroemer  ob- 
served partial  separation  and  beginning  atrophy  of  the  entire  dermoidal  area, 
which  hung  by  a  narrow  pedicle  to  the  cyst  wall.    It  seems  possible  that  the 
entire  dermoid  might  be  destroyed  in  this  way,  especially  when  associated 
with  a  large  adenocystoma.    Kroemer  pictures  a  very  large  multilocular  cys- 
toma  in  which  the  dermoid  was  reduced  to  a  diminutive  hairy  nodule.    These 
observations,  as  well  as  the  occurrence  of  a  dermoid  in  one  ovary  and  a  sepa- 
rate adenocystoma  in  the  same  or  the  other  ovary,  led  Hanan,  Ribbert,  Lan- 
dau, Pick,  and  others  to  conclude  that  the  pseudomucinous  cystadenoma  is  a 
one-sided  entodermal  development  of  a  teratoma.    Askanazy  includes  among 
typical   dermoids   some   which   seem   to   consist   exclusively   of   epidermis. 
Saxer's  dermoid  consisting  of  a  single  tooth  must  have  resulted  from  early 
suppression  of  other  elements.     Portions  of  the  main  dermoid,   including 
epidermis  and  hair  or  even  bone  (Wilms),  may  be  transplanted  into  adjoining 
cysts,  giving  a  false  impression  of  multiplicity  of  dermoids.    After  rupture  of 
ovarian   dermoids   multiple   implantation   dermoids   may   appear   over   the 
peritoneum. 

(2)  Multiple   dermoids   in   one   or   both   ovaries   have   repeatedly   been 
observed    (Novak,   Lit.).     Schroeder  reported  seven  isolated  dermoids  in 
one  tumor  and  Pfannenstiel  saw  five,  all  of  uniform  size.     Wulkow  found 
two  dermoids  in  one  cystoma  and  four  in  a  similar  tumor  of  the  other  ovary. 
Some  of  these  may  have  been  the  result  of  transplantation,  but  Heinsius 
described  five  complete  dermoids  in  four  separate  compartments.    Hoffmeier 
found  four  in  one  ovary  and  seven  in  the  other.    The  largest  number  observed 
was  by  Novak,  who  found  ten  in  one  ovary  and  eleven  in  the  other.    Keitler 
observed  in  one  ovary  a  dermoid  cyst  with  hair  and  teeth,  in  the  other  two 
dermoids  and  a  cyst  enclosing  a  solid  teratoma.     The  genesis  of  the  true 
multiple  dermoids  may  be  referred  either  to  the  simultaneous  growth  of 
separate  ova  (oocytes),  or  to  the  separation  of  blastomeres  of  one  original 
ovum. 

Retroperitoneal  and  intraligamentary  dermoids  containing  portions  of 
ovarian  tissue  have  been  reported  by  Coen,  Dunnwald,  and  others.  Rarely 
this  location  may  be  referred  to  the  separation  from  the  ovary  and  secondary 


620 


N  EOF  LAST  1C  DISEASES 


implantation  elsewhere  (Reinprecht) .  More  often  a  supernumerary  ovary 
is  the  probable  source  (Hermann,  Wilms). 

An  elongated  pedicle  may  permit  unusual  migration  and  attachments  of 
the  dermoid.  I  have  examined  a  complex  dermoid,  showing  epithelioma  of 
the  skin,  hanging  in  the  cecum.  Perforations  of  bladder,  rectum,  or  ileum 
are  recorded. 

(3)  Secondary  changes  may  greatly  alter  the  appearance  and  structure 
of  dermoids.  Torsion  leads  to  hemorrhagic  infiltration  and  necrosis,  and 
this  may  be  followed  by  extensive  calcification  or  by  suppuration.  All 
traces  of  the  original  dermoid  structure  may  thus  be  lost  and  the  tumor  be- 
comes a  solid  calculus  (Busse,  Askanazy). 


FIG.  286. — Atypical  epidermal  growth  in  an  ovarian  dermoid. 

(4)  Malignant  characters  in  the  dermoid  itself  or  in  the  associated  cys- 
toma  are  important,  features  of  many  cases. 

The  epidermis  may  develop  epithelioma  invading  the  other  tissues  of 
the  dermoid,  of  which  Bab  has  collected  37  cases.  A  mammary  carcinoma 
in  a  dermoid  is  reported  by  Yamagiva,  and  adenoma  of  the  sweat-glands  by 
Friedlander.  Seeger  observed  bilateral  carcinomatous  dermoids.  Sarcoma- 
tous  changes  occur  in  dermoids,  while  in  many  teratomas  much  of  the  tissue 
may  be  of  embryonal  and  sarcomatous  character  (Ludwig,  Lit.).  Pigmented 
sarcoma  arising  in  the  cyst  wall  is  recorded  by  Amann  and  by  Lor  rain.  Round- 
cell  sarcoma  in  the  wall  and  in  hepatic  metastases  is  recorded  by  Litten. 


THE  OVARIAN  TERATOMA  621 

Bierman  described  a  large  spindle-cell  sarcoma  and  Neumann  a  perithelial 
alveolar  tumor,  arising  from  the  corium  of  dermoids.  The  wall  of  the  asso- 
ciated cystoma  appeared  to  be  the  source  of  spindle-cell  sarcomas  in  the 
cases  of  Flaischlen  and  Ludwig.  A  typical  perivascular  and  alveolar  sarcoma 
is  described  and  pictured  by  Schwertassek.  Kroemer  traced  an  alveolar 
sarcoma  of  the  cyst  wall  to  the  vascular  endothelium,  and  the  endothelial 
origin  of  many  of  these  tumors  is  also  maintained  by  Mirabeau  and  Schott- 
lander.  The  ovarian  tissue  is  believed  to  furnish  some  of  the  dermoid  sar- 
comas, as  in  the  cases  of  Geyer  and  Thornton.  It  would  appear  that  the 
tumor  process  is  incited  in  some  way  by  the  dermoid,  according  to  Kroemer 
in  some  cases  by  the  absorption  of  oily  material. 

The  malignant  processes  extend  beyond  the  dermoid  with  rupture  of 
the  cyst  and  produce  metastases  in  peritoneum  and  liver.  The  rupture  of 
the  cyst  may  also  be  followed  by  multiple  dermoidal  implantations  or  by 
encapsulation  of  fatty  material  which  lodges  on  the  peritoneum. 

(5)  Struma  Ovarii. — The  occurrence  of  thyroid  tissue  in  ovarian  tumors 
has  long  been  recognized  and  variously  interpreted  (Bell).  It  is  relatively 
frequent  in  ovarian,  while  very  rare  in  testicular,  teratomas.  An  origin  from 
metastatic  thyroid  cells  or  from  mucous  degeneration  of  a  carcinoma  (Kretsch- 
mar,  Voight)  has  now  fully  yielded  to  the  view  that  these  tumors  represent 
one-sided  growths  of  a  teratoma.  This  view  was  strongly  supported  by 
Walthard  and  others,  who  found  in  several  such  growths  islands  of  cartilage, 
bone,  epidermis,  and  acinous  glands.  Moreover,  Pick  in  21  dermoids  found 
islands  of  thyroid  tissue.  Both  these  observations  are  frequently  verified 
(Trapl,  Lit.). 

The  tumors  occur  in  both  benign  and  malignant  forms.  The  benign 
tumors  may  reproduce  almost  exactly  the  structure  of  the  normal  adult 
thyroid  gland.  Meyer  demonstrated  iodin  in  the  tissues.  They  produce 
rather  bulky  tumors  resembling  a  colloid  goiter  in  the  gross  and  they  are 
subject  to  hemorrhage,  cyst  formation,  and  regressive  changes.  Trapl  brings 
evidence  to  show  that  the  ovarian  struma  may  functionate  vicariously  for 
the  thyroid  gland. 

The  malignant  tumors  are  more  cellular,  invade  the  surrounding  tissues, 
and  produce  metastases  (Polano,  Katsurada).  To  what  extent  the  malignant 
cellular  tumors  may  lose  their  structural  resemblance  to  thyroid  tissue  is 
not  yet  clear,  but  it  appears  not  unlikely  that  some  solid  carcinomas  of  the 
ovary  are  derivatives  of  teratoid  thyroid  tissue. 

That  the  typical  structure  of  struma  ovarii  may  be  produced  by  a  tumor 
originating  from  downgrowth  of  superficial  epithelium  is  clearly  shown  by 
Bauer,  but  his  claim  that  all  ovarian  strumas  originate  in  this  manner  cannot 
be  entertained. 

(6)  Chorioma  Ovarii. — While  chorioma  testis  is  comparatively  frequent, 
the  ovary  has  furnished  only  rare  or  uncertain  examples  of  this  type  of 
atypical  teratomas. 

A  notable  example  is  described  by  L.  Pick  in  which  both  microscopical 
and  gross  features  were  complete  reproductions  of  the  primary  uterine 
chorioma.  Small  polyhedral  Langhans'  cells  rich  in  glycogen  and  with  many 
mitoses  were  combined  with  large  vacuolated  syncytial  masses.  The 
syncytium  appeared  to  spring  from  neuro-epithelial  cell  groups,  invaded  the 
vessels,  and  added  a  hemorrhagic  character  to  the  tumor.  In  addition,  there 
was  a  sarcomatous  framework  holding  epidermis  and  glands  lined  by  mucous 
cells. 

The  occurrence  of  choriomatous  tumors  of  the  pelvis  and  liver  without 
demonstrated  involvement  of  the  ovary  leaves  a  well-founded  suspicion 


622  NEOPLASTIC  DISEASES 

that  an  ovarian  teratoma  may  have  been  suppressed  or  overlooked.  Kroe- 
mer  described  a  pure  chorioma  of  the  ovary  in  a  woman  of  51  years, 
without  other  teratoid  elements.  A  typical  malignant  chorioma  ovarii  was 
also  described  by  Glinski  and  Rosner.  Lubarsch  examined  a  large  tumor 
mass  in  the  pelvis  of  a  i.3-year  virgin,  which  consisted  of  polyhedral  vacuolated 
cells  and  syncytium.  He  concluded  that  this  structure  might  be  duplicated 
by  tumors  arising  from  various  epithelial  structures  of  the  genito-urinary 
tract. 

In  several  instances  it  has  been  shown  that  epithelial  tumors  of  ordinary 
type  may  in  metastases  yield  a  structure  much  resembling  chorioma.  Hence 
Risel  discards  many  of  the  reported  choriomas  of  tubes,  ovary,  and  other 
organs  as  spurious  imitations  derived  from  other  than  teratomatous  sources 
or  gestation  products.  Monckberg  considers  many  of  these  growths  to  be 
derived  from  endothelium.  Not  a  few  of  the  so-called  choriomas  of  the  liver 
appear  to  me  to  be  derived  from  primary  carcinomas  of  the  liver-cells. 
L'Esperance,  in  this  laboratory,  has  described  such  a  spurious  hepatic  chori- 
oma and  pointed  out  its  notable  distinctions  from  true  chorioma. 

Nevertheless  the  gross  and  microscopical  features  of  a  group  of  heterotopic 
choriomas  in  both  sexes  exactly  reproduce  those  of  uterine  chorioma.  On 
the  other  hand,  the  secondary  chorioma-like  structure  occurring  with  carci- 
noma and  other  tumors  fails  to  yield  such  complete  reproductions  of  the  true 
chorioma.  Hence  I  am  disposed  to  think  that  many  of  the  above  tumors 
are  true  teratomas  derived  originally  from  ovary  or  testis  and  that  the  original 
tumor  is  suppressed  or  overlooked,  or  that  such  tumors  arise  from  deported 
chorionic  structures  from  uterine  gestation.  For  the  diagnosis  of  such  true 
heterotopic  choriomas  it  is  necessary  to  insist  on  complete  identity  in  gross 
characters  including  pulmonary  metastases  and  not  to  rely  merely  on  occa- 
sional microscopical  resemblances. 

(7)  The  Relation  of  Simple  Ovarian  Tumors  to  Teratoma. — The  demonstra- 
tion that  one  element  of  an  ovarian  teratoma  may  suppress  the  others  raises 
the  question  how  far  the  apparently  simple  tumors  of  the  ovary  may  prove 
to  be  of  teratomatous  origin. 

Under  the  term  "epithelioma  chorio-ectodermale"  L.  Pick  would  include 
certain  embryonal  ovarian  tumors  resembling  adenoma,  carcinoma,  and 
endothelioma.  He  describes  5  cases  of  cystic  or  solid  growths  in  which  the 
cells  were  rich  in  glycogen,  and  were  arranged  in  cystic  adenomatous  or  solid 
carcinomatous  structure.  The  main  tumor-cell  he  identifies  as  the  Lang- 
hans'  cell,  while  syncytium-like  masses  were  often  present. 

Pick's  interpretations  of  these  tumors  has  not  been  supported.  Kroemer 
did  not  find  a  convincing  resemblance  of  the  tumor-cells  to  chorionic  epithe- 
lium, and  Risel  notes  the  absence  of  a  vasodestructive  property  in  the  tumor- 
cells.  It  seems  probable  that  the  tumors  described  by  Pick  were  embryonal 
growths  in  which  the  syncytial  masses  were  developed  from  the  main  tumor- 
cells  of  ordinary  ectodermal  or  entodermal  origin  and  that  they  were  not  of 
chorionic  nature.  This  conclusion,  however,  does  not  dispose  of  the  possible 
teratomatous  origin  of  many  apparently  simple  embryonal  tumors  of  the 
ovary.  Especially  for  the  extensive  group  of  sarcomas  of  the  ovary,  round- 
and  spindle-cell,  perivascular,  alveolar,  and  "endothelial,"  the  observations 
by  many  authors  of  identical  structures  arising  from  dermoids  and  teratomas, 
strongly  suggest  a  teratomatous  relation.  This  question  must,  however, 
await  further  observations. 

Chondroma  of  the  ovary  is  described  by  Reiss  and  Jung  as  a  mesodermal 
teratoma,  and  Meyer  accepts  this  interpretation.  The  chondrosarcomas 
being  embryonal  tumors  should  from  this  point  of  view  be  regarded  as 


THE  OVARIAN  TERATOMA  623 

teratomatous.  Ovarian  melanoma  may  also  be  interpreted  as  of  terato- 
matous  origin. 

In  all  of  these  cases  further  observations  are  necessary  before  a  teratoma- 
tous element  can  be  accepted.  While  the  observations  on  tumors  of  the 
testis  point  by  analogy  to  the  simple  origin  of  many  ovarian  tumors,  the 
conditions  in  the  ovary  are  much  more  complex  than  in  the  testis. 

Etiology. — The  origin  of  ovarian  dermoids  and  teratomas  is  now  referred 
by  the  great  majority  of  observers  to  the  sex  cell  or  ovum.  The  essentially 
tridermal  character  of  these  tumors  requires  that  the  originating  material 
be  totipotent.  Only  two  possible  sources  of  such  material  have  been  seri- 
ously considered,  the  isolated  blastomere  of  Marchand-Bonnet,  and  the 
primitive  unfertilized  ovum.  Bandler  constructed  an  elaborate  argument  for 
the  Wolffian  origin  of  ovarian  dermoids,  but  this  view  has  not  met  with  favor. 
Several  considerations  speak  against  the  theory  of  an  isolated  blastomere. 
Chief  among  these  is  the  frequency  of  such  tumors  in  the  sex  glands,  both 
ovary  and  testis.  While  it  is  not  necessary  to  regard  all  tridermal  tumors 
from  the  same  viewpoint,  those  of  the  sex  glands  find  a  direct  and  obvious 
explanation  in  the  autonomous  growth  of  a  totipotent  cell  which  is  constantly 
present  in  these  organs  in  considerable  numbers.  On  the  other  hand,  it  is 
almost  impossible  to  conceive  how  isolated  blastomeres  can  gather  in  suffi- 
cient numbers  to  explain  the  incidence  of  dermoids.  The  occurrence  of  as 
many  as  seven  dermoids  in  one  ovary  and  eleven  in  both  organs  practically 
eliminates  the  blastomere  or  polar  body  as  a  possible  source.  The  field  of  the 
isolated  blastomere  lies  with  the  parasitic  implantations,  and  its  extension  to 
the  teratomas  of  the  sex  glands  is  unwarranted. 

The  direct  evidence  in  favor  of  the  origin  from  sex  cells  is  considerable. 
Ovarian  dermoids  occur  during  the  period  of  functional  activity  of  the  ovary. 
They  are  excessively  rare  in  the  fetus  and  they  are  practically  unknown  as 
a  tumor  arising  after  the  climacteric.  The  multiplicity  is  readily  explained 
by  the  abundance  of  ova  in  the  organ.  The  spontaneous  growth  of  the  un- 
fertilized ovum  is  a  reasonable  hypothesis,  in  view  of  the  very  numerous 
factors  which  are  known  to  incite  the  growth  of  ova  in  lower  animals.  It 
is  a  matter  of  little  consequence  whether  this  growth  be  designated  as  par- 
thenogenetic  or  otherwise.  No  one  has  traced  the  dermoid  to  an  ovum,  but 
the  frequent  association  of  cystoma  with  dermoids  suggests,  as  Kroemer 
holds,  that  the  cystoma  arises  from  the  epithelium  of  the  Graafian  follicle 
and  the  dermoid  from  the  contained  ovum.  The  occasional  combination 
with  a  corpus  luteum  cyst  finds  a  parallel  explanation.  Malformation  of 
the  genitals  has  been  observed  with  ovarian  dermoids,  but  not  with  sufficient 
frequency  to  indicate  a  definite  relation  of  such  gross  anomalies  with  the 
tendency  to  teratomatous  growths  (Freund).  These  anomalies  have  in- 
cluded pseudohermaphroditism,  infantilism,  supernumerary  ovaries,  elon- 
gated cervix  with  cysts  of  Wolffian  duct  (Amann),  and  myomas  in  many  cases. 

That  the  dermoid  and  the  teratoma  have  an  identical  origin  is  indicated 
by  the  occurrence  of  intermediate  types  of  tumors,  and  by  the  association 
of  both  embryonal  and  adult  tissues  in  the  same  tumor.  Yet  the  difference 
in  the  structure  of  the  dermoid  and  the  teratoma  has  not  been  satisfactorily 
explained.  Askanazy  assumes  that  the  adult  tissues  of  the  dermoid  are  of 
equal  age  with  those  of  the  host  and  the  tumors  are  congenital,  while  the 
teratoma  arises  later  in  life  and  yields  embryonal  tissues.  Yet  congenital 
dermoids  are  excessively  rare,  and  since  their  initial  stages  are  never  seen  the 
early  growth  must  be  rather  rapid.  After  attaining  a  certain  size  they  may 
remain  stationary,  so  that  the  age  of  a  dermoid  extirpated  after  the  climac- 
teric is  difficult  to  determine.  Hence  it  is  probable  that  both  dermoids  and 


624  NEOPLASTIC  DISEASES 

teratomas  arise  chiefly  in  young  adults,  especially  about  the  2oth  year 
(Kroemer).  It  is  possible  that  the  varying  structure  depends  upon  the  de- 
gree of  differentiation  of  the  originating  sex  cell.  Back  of  the  mature  ovum 
are  the  docytes,  the  oogonia,  and  the  primary  sex  blastomere,  each  of  which 
may  be  assumed  to  give  origin  to  tumors.  From  this  point  of  view  the  two 
theories  of  origin,  from  sex  cell  and  from  isolated  blastomere,  approximate 
each  other.  The  embryonal  tumors  may  thus  be  assumed  to  develop  from 
early  members  of  the  sex  cell  series,  the  dermoids  from  late  members.  Yet 
the  localization  in  the  ovary  requires  that  all  the  tumors  must  arise  from 
cells  included  within  this  organ,  a  condition  which  the  isolated  blastomere 
does  not  readily  meet.  It  seems  probable,  therefore,  that  the  varying  struc- 
ture is  determined  by  local  factors,  still  undefined,  acting  upon  cells  of  a  uni- 
form character. 


CHAPTER  XXXI 
CARCINOMA  OF  STOMACH 

Statistical. — The  stomach  is  probably  the  most  frequent  seat  of  cancer  in 
males  as  is  the  uterus  in  females.  The  exact  proportions  of  these  two  forms 
of  cancer  are  matters  awaiting  expert  statistical  study.  Welch  (1885),  from  an 
analysis  of  31,482  cases  of  cancer  in  cities,  found  the  proportions:  stomach, 
21.4  per  cent.;  uterus,  29.5  per  cent.  These  figures  include  Gurlt's  Vienna 
statistics,  which  are  much  too  low  for  the  stomach,  10  per  cent,  in  4131  cases. 
I  should  be  inclined  to  balance  Gurlt's  data  with  Haberlin's  figures  for 
Switzerland,  which  are  much  too  high  for  most  localities,  41.5  per  cent,  in 
27,511  cancers.  Intermediate  but  high  ratios  are  recorded  by  Reiche  (Ham- 
burg), 35.5  per  cent.;  Virchow  (Wurzburg,  1855),  34.9  per  cent.;  Martin  (com- 
piled from  70,000  cases),  33  per  cent.  The  U.  S.  Census,  1912,  reports  46,534 
deaths  from  cancer,  18,517  of  stomach  and  liver,  39.75  per  cent.,  7089  of 
female  genital  organs,  4431  of  breast,  indicating  a  distinct  predominance  of 
gastric  cancer.  This  census  also  shows  a  more  rapid  increase  of  reported 
gastric  cases  than  of  uterus  or  breast  cancer  during  the  past  decade.  Marked 
variations  in  different  countries  and  cities  and  slight  relative  immunity  of 
negroes  and  in  the  tropics,  appear  in  various  studies. 

Males  are  slightly  more  often  affected  than  females  (5  to  4  Welch,  3  to  2 
Haberlin,  65  to  35  Kaufmann,  588  to  412  Friedenwald).  Of  deaths  from  all 
causes  gastric  cancer  gives  i  per  cent.  (Brinton) ;  i|  per  cent.  (Gussenbauer, 
v.  Winniwarter,  Vienna);  3!  per  cent.  (Welch,  Prague);  2  per  cent.  (U.  S. 
Census,  1911,  stomach  and  liver). 

Etiology. — Age. — The  average  age  of  incidence  is  61.2  years  (U.  S.  Census, 
1911).  The  distribution  is  indicated  in  the  following  table: 


Decade 

Total 
Welch,  1885  2,038 

0 
10 

IO 
20 

20 
30 

30 
40 

40 
50 

50 
60 

60 
70 

70 
80 

80 

IOO 

— 

.1 
04 

2.7 

13-3 

24-5 

30-4 

21 

6.85 

1-15 

Reiche,  1900  2,000 

.87 

5-85 

H-I5 

25-9 

32.1 

18.1 

2.76 

Martin,  1908  7,000 

12 

.08 
.26 

i-5 

8.8 

18.0 

28 

28 

H 

2.0 

U.  S.  Census,  1911: 
Stomach  and  liver  !7>365 

I-I5 

4 

13.2 

25-5 

30 

20.8 

5-5 

U.  S.  Census,  1914: 
Stomach  alone  1  1,733 

6 

92 

457 

1345 

2857 

3587 

2647 

725 

The  average  age  for  carcinoma  of  liver  is  47.2  years  (Rolleston). 

While  the  disease  is  distinctly  one  of  advanced  age  its  rather  frequent 
occurrence  between  30  and  40  years,  and  even  between  20  and  30,  is  note- 
worthy. A  high  proportion  of  the  early  cases  appear  to  be  adenocarcinomas. 
A  congenital  adenoma  of  the  pylorus  in  an  infant  5  weeks  old  was  reported 
40  625 


626  NEOPLASTIC  DISEASES 

by  Cullingvvorth.  Of  several  other  cases  under  10  years,  collected  by  R. 
Williams,  none  appeared  to  be  true  carcinoma  of  the  stomach.  In  the  second 
decade  Osier  and  McCrae  collected  13  cases,  illustrating  ulcerating  and  fun- 
gating  carcinomas  of  cardia  and  pylorus  (Moore,  Dock,  Glynn,  Wilde),  scir- 
rhus  of  the  pylorus  (Kostei,  Dittrick,  Landouzy),  and  encephaloid  cancer 
(Scheffer).  Carcinoma  developing  on  an  ulcer  in  a  girl  of  18  years  is  described 
by  Bernoulli.  In  the  third  decade  the  usual  forms  of  the  disease  are  not 
infrequently  represented,  and  they  tend  to  run  a  rapid  course  (Osier,  McCrae, 
Matthieu). 

Heredity. — From  a  study  of  1744  gastric  cases  from  various  authors  Welch 
found  that  in  about  14  per  cent,  other  members  of  the  family  suffered  from 
cancer.  Napoleon  I,  his  father,  brother,  and  two  sisters  died  of  gastric  can- 
cer. Twenty-three  families  known  to  Manishon  included  69  cancerous  mem- 
bers, of  which  in  57  the  disease  was  in  the  stomach.  In  these  and  other  cases 
collected  by  R.  Williams  it  is  possible  to  assume  a  tissue  predisposition.  The 
rarity  of  these  observations  emphasizes  the  usual  absence  of  any  element 
of  heredity  in  gastric  cancer.  Yet  this  group  of  cases  seems  to  be  a  particu- 
larly favorable  field  for  the  clinical  study  of  heredity  in  cancer. 

Trauma. — Many  observers  have  endeavored  to  establish  a  definite  re- 
lation between  trauma  and  gastric  cancer.  Menne  cites  a  series  of  cases 
designed  to  illustrate  a  direct  or  indirect  relation  to  trauma,  and  concludes 
that  the  trauma  may  be  the  effective  etiological  factor,  or  may  excite  malig- 
nant growth  in  a  latent  and  quiescent  focus,  or  may  accelerate  the  growth 
of  an  existing  carcinoma.  He  also  describes  various  traumatic  lesions  of  the 
stomach  of  benign  course  which  might  serve  as  sources  of  carcinoma.  The 
legal  verdict  in  these  casvs  strongly  favored  the  victim,  on  the  ground  that 
the  evidence  created  a  probability  approaching  certainty  that  the  carcinoma 
resulted  from  the  trauma.  Although  the  violence  was  sufficient  to  injure 
the  stomach  and  gastric  symptoms  began  within  a  reasonable  time,  there 
was  in  the  history  and  anatomical  findings  in  these  cases  insufficient  data 
from  the  pathological  standpoint  to  prove  the  traumatic  origin.  Boas  reported 
a  traumatic  history  in  six  gastric  carcinomas,  but  holds  that  trauma  never 
produces  carcinoma  in  a  healthy  stomach.  Most  observers  fail  to  find  any 
traumatic  history  in  their  experience  with  gastric  cancer.  With  the  excep- 
tion of  rare  cases  following  ulcer,  the  known  beginning  of  the  disease  is  in- 
consistent with  a  traumatic  origin. 

Idiosyncrasy. — R.  Schmidt  describes  two  types  of  subjects  who  develop 
gastric  carcinoma,  the  dynamic  and  the  adynamic.  The  former  are  well- 
nourished  individuals  whose  parents  were  long  lived  and  whose  digestion 
has  always  been  so  good  that  they  may  be  designated  as  "gastric  athletes." 
They  develop  the  disease  in  adult  or  later  life.  The  latter  are  poorly  nour- 
ished, present  a  phthisical  habit,  a  low  pilosity,  and  suffer  from  epistaxis, 
gastric  ulcer,  or  achylia.  They  develop  the  disease  early. 

Alcoholism  was  noted  in  the  majority  of  cases  of  gastric  carcinoma  in 
adults  by  Martin  and  R.  Schmidt,  but  Friedenwald  found  it  in  only  15 
per  cent. 

Location. — Three-fifths  of  all  gastric  cancers  originate  in  the  pyloric 
region,  another  20  per  cent,  arise  along  the  lesser  curvature  and  cardia,  and 
the  remainder  from  the  walls  of  the  greater  curvature.  The  fundus  is 
rarely  involved.  Welch's  table  from  1300  cases  exhibits  this  distribution- — 
pyloric  region,  60.8  per  cent.;  lesser  curvature,  11.4  per  cent.;  cardia,  8  per 
cent.;  posterior  wall,  5.2  per  cent.;  diffuse,  4.7  per  cent.;  multiple  tumors,  3.5 
per  cent.;  greater  curvature,  2.6  per  cent.;  anterior  wall,  2.3  per  cent.;  fundus, 
1.5  per  cent. 


CARCINOMA  OF  STOMACH  627 

By  more  minute  distinction  between  the  pylorus  proper  and  the  vicinity 
of  the  pylorus,  Boas  in  125  cases  located  27.2  per  cent,  in  the  pylorus,  and 
26.4  per  cent,  in  the  lesser  curvature,  and  in  40  later  cases  he  found  25  of 
the  lesser  curvature  and  6  in  the  pylorus.  Mathieu  in  234  cases  locates  56 
per  cent,  at  pylorus,  12  per  cent,  at  cardia,  4  per  cent,  on  lesser  curvature, 
1.2  per  cent,  on  greater  curvature,  23.5  per  cent,  on  the  lateral  walls. 

Tabora  connects  the  occurrence  of  cancer  at  the  pylorus  and  on  the  lesser 
curvature  with  varying  physiological  conditions  in  the  stomach.  Cancer 
of  the  lesser  curvature  is  usually  associated  with  achylia,  pyloric  cancer 
with  hypersecretion.  In  achylia  the  pyloric  region  is  relaxed,  the  stomach 
is  promptly  emptied  in  \  to  f  hour  after  a  test  meal,  and  motor  insufficiency 
develops  late.  Hence  the  pyloric  region  escapes  irritation,  while  the  fixed 
and  vascular  lesser  curvature  is  chiefly  exposed.  With  hypersecretion  the 
lesser  curvature  is  equally  exposed,  but  the  long  closure  of  the  pyloric  ring 
(Pawlow)  exposes  unduly  the  prepyloric  mucosa  where  primary  cancer  chiefly 
develops. 

Gross  Anatomy. — Gastric  carcinoma  appears  in  several  characteristic 
anatomical  forms.  A  classification  of  these  forms  may  be  reached  on  strictly 
histological  data  as  done  by  Kaufmann.  Yet  the  location  and  gross  form 
of  the  tumor  determine  very  marked  differences  in  the  symptoms  and  course 
of  the  disease,  which  it  seems  desirable  to  emphasize  by  a  classification  accord- 
ing to  etiology,  gross  anatomy,  and  structure.  From  this  point  of  view  one 
may  recognize  the  following  types : 

(1)  Bulky  adenocarcinoma. 

(2)  Gelatinous  carcinoma. 

(3)  Carcinoma  following  peptic  ulcer.    Ulcerocancer. 

(4)  Carcinoma  simplex.    Diffuse  carcinoma. 

(5)  Diffuse  scirrhous  carcinoma. 

(6)  Sclerosing  fibrocarcinoma.    Linitis  plastica. 

Of  1 22 1  cases  reviewed  by  Welch,  791  (64.8  per  cent.)  were  medullary, 
399  (32.7  per  cent.)  scirrhus;  31  (2.5  per  cent.)  colloid.  Adenocarcinoma  is 
the  most  frequent  variety  in  my  material. 

(i)  Bulky  Adenocarcinoma. — The  distinguishing  features  of  this  group  de- 
pend upon  a  relatively  benign  adenocarcinomatous  structure,  which  presents  a 
circumscribed  polypoid  or  fungating  and  eventually  ulcerating  growth.  This 
tumor  is  the  gastric  counterpart  of  adenoma  destruens  of  the  colon  and 
uterus.  As  in  other  situations  it  may  reach  large  dimensions  before  invad- 
ing the  lymph-nodes,  but  it  is  rather  more  malignant  in  the  stomach  than 
elsewhere. 

The  location  is  chiefly  near  the  pylorus,  less  frequently  at  the  cardia, 
in  both  of  which  situations  it  soon  ulcerates.  Or  it  may  develop  from  the 
lesser  or  greater  curvatures  where  it  tends  to  reach  large  dimensions.  This 
type  of  carcinoma  may  be  multiple  in  the  stomach  and  similar  tumors  may 
appear  in  the  colon  (Hauser).  In  the  early  stages,  as  described  by  Verse, 
it  appears  as  a  flat,  warty  thickening  of  the  mucosa,  which  may  develop 
into  a  polypoid  outgrowth,  but  more  frequently,  especially  at  the  pylorus, 
it  early  ulcerates,  infiltrates  the  wall,  and  runs  the  course  of  an  ulcerating 
carcinoma.  These  cases  are  sometimes  difficult  to  distinguish  from  second- 
ary carcinoma  developing  on  a  peptic  ulcer.  Their  broad  base,  markedly 
overhanging  edges,  and  histological  structure  usually  serve  to  separate  them 
from  the  secondary  carcinomas  arising  from  ulcers. 

A  second  mode  of  origin  is  through  the  carcinomatous  transformation 
of  an  adenomatous  polyp,  all  stages  of  which  are  described  by  Hauser  and 
Verse.  It  appears  probable  that  most  of  the  bulky,  polypoid,  and  fungating 


628  NEOPLASTIC  DISEASES 

adenocarcinomas  develop  from  such  preliminary  lesions.  It  is  characteristic 
of  these  bulky  tumors  that  they  grow  to  large  size  without  prominent  gastric 
symptoms  or  invasion  of  lymph-nodes.  Ulceration  becoming  established 
rapidly  transforms  the  clinical  picture,  adding  hemorrhage,  pain,  vomiting, 
and  cachexia.  The  excavation  of  such  tumors  may  be  extensive  and  deep 
and  lead  to  fatal  hemorrhage  or  perforation. 

All  of  these  growths  are  comparatively  solid  on  section,  resembling  medul- 
lary carcinoma,  but  some  show  accumulation  of  mucus,  and  areas  of  fatty 
degeneration,  hemorrhage,  and  necrosis.  In  a  small  subgroup  the  gross 
structure  is  distinctly  villous,  resembling  the  coarser  tumors  of  the  bladder. 


FIG.  287. — Bulky  ulcerating  adenocarcinoma  of  stomach. 

Their  structure  shows  well -developed  branching,  vascular  papillae  covered 
with  multiple  layers  of  atypical  cylindrical  cells  which  may  infiltrate  the 
wall  and  have  been  known  to  produce  hepatic  metastases  (Matsuoka,  Matti). 
In  a  case  of  empyema  Verse  found  six  carcinomas  in  the  stomach,  some  of 
which  were  of  elongated  papillary  or  villous  type. 

The  adenocarcinomas  are  regularly  embedded  in  the  submucosa  which 
may  be  widely  infiltrated  and  in  the  muscularis  which  is  usually  perforated, 
but  extensions  to  the  lymph-nodes  may  be  long  delayed.  Yet  the  nodes, 
liver,  and  other  organs  are  eventually  invaded  by  growths  which  reach  con- 
siderable dimensions,  and  precocious  metastases  in  distant  localities  have 
been  observed.  Finlay  found  multiple  subcutaneous  metastases,  the  struc- 


CARCINOMA  OF  STOMACH  629 

ture  of  which  led  to  the  diagnosis  of  a  latent  cancer  of  stomach,  verified  at 
autopsy.  I  have  seen  a  similar  case  in  which  a  single  nodule  excised  from 
the  midscapular  region  presented  the  typical  structure  of  malignant 
adenoma  of  the  stomach,  which  was  later  found  at  autopsy.  Roseler's 
multiple  ulcerating  carcinomas  of  the  skin,  although  not  examined  micro- 
scopically, were  probably  of  this  type.  A  metastatic  growth  in  the  humerus 
was  the  first  sign  of  gastric  cancer  in  a  case  of  Tilling's. 

The  structure  of  gastric  adenocarcinoma  presents  somewhat  orderly  imi- 
tations of  the  gastric  tubule.  The  originating  tubes  become  much  elongated, 
bifurcated  and  sacculated,  and  the  tumors  are  composed  of  such  alveoli  com- 
pactly grouped  with  little  stroma.  The  cells  are  cylindrical  or  cubical,  the 
cytoplasm  clear,  and  the  nuclei  hyperchromatic.  It  is  notable  that  in  many 
gastric  tumors  the  infiltrating  and  metastasizing  alveoli  are  lined  by  single 
rows  of  cells,  and  that  multiple  layers  of  very  large  cells  are  less  common  than 
in  tumors  of  the  colon.  Hence  the  structure  often  suggests  a  benign  adenoma. 
The  lumina  of  the  alveoli  are  usually  small,  or  they  may  be  distended  with 
mucus  and  exudate,  or  secondary  alveoli  may  form  within  the  acinus. 

Carcinoma  cylindrocellulare  micro scysticum  is  a  type  described  by  Hauser 
and  presenting  many  large  or  cystic  alveoli  distended  with  thin  mucus  and 
serum. 

The  gastric  mucosa  is  often  the  seat  of  glandular  and  polypoid  over- 
growths and  in  the  neighborhood  of  the  tumor  the  hyperplastic  glands  may 
gradually  pass  into  carcinomatous  structures  (Hauser,  Verse).  Kulbs  de- 
scribed an  infiltrating  adenocarcinoma  with  ciliated  cells  in  original  tumor 
and  in  metastases  in  adrenals  and  lung. 

Adenocarcinomas  of  the  pylorus,  with  scanty  groups  of  squamous  cells  more 
abundant  in  metastases,  are  described  by  Herxheimer  and  Lubarsch.  The 
squamous  cells  were  probably  of  metaplastic  origin.  Primary  squamous-cell 
carcinoma  of  the  cardiac  region,  probably  derived  from  esophageal  epithelium, 
is  described  by  Kaufmann,  Ziegler,  and  Borst. 

Simple  adenoma  of  the  stomach  occurs  in  single  or  multiple  polypoid  form. 
Rarely  this  tumor  is  submucous.  The  single  tumors  usually  remain  of  small 
size  and  give  no  symptoms  unless  located  near  the  orifices.  Others  become 
the  seat  of  adenocarcinoma.  Rarely  they  reach  large  dimensions  while  re- 
taining an  adenomatous  structure.  Chaput  described  a  pedunculated  tumor 
of  the  fundus  as  large  as  a  child's  head,  which  was  free  from  ulceration  and 
presented  a  pure  adenomatous  structure.  Multiple  adenomas  usually  form 
a  part  of  the  lesions  of  gastritis  polyposa. 

(2)  Gelatinous  Carcinoma. — Mucous  changes  are  a  frequent  microscopic 
feature  of  most  forms  of  gastric  cancer,  but  when  this  change  becomes  very 
pronounced  it  greatly  alters  the  gross  appearance  and  course  of  the  tumor, 
which  in  structure  is  usually  an  adenocarcinoma. 

The  characteristic  gelatinous  carcinoma  usually  begins  in  the  pyloric 
region  and  infiltrates  all  coats  of  the  stomach  wall,  which  may  measure  2  to 
3  cm.  in  thickness.  The  organ  may  be  reduced  in  size,  but  not  so  markedly  as 
with  true  scirrhus.  The  gelatinous  material  infiltrates  and  largely  replaces 
the  tissues  of  mucosa,  submucosa,  and  muscularis,  and  appears  in  translucent 
nodules  on  the  serosa.  Advanced  cases  of  this  type  are  described  by  Storer, 
Amidon,  Verse,  and  others.  In  Amidon's  case  the  stomach  measured  7  inches 
in  length,  the  wall  •£  inch  in  thickness.  The  pylorus  was  but  slightly  thick- 
ened. The  mucosa  was  everywhere  replaced  by  nodules  of  gelatinous  car- 
cinoma, and  the  peritoneum  was  extensively  invaded.  Verse's  tumor  (64) 
was  a  bulky  mass  encircling  the  pylorus  and  infiltrating  the  vicinity.  In 
Hauser's  case  (32)  the  secondary  hepatic  tumors  were  pure  adenocarcinoma 


630  NEOPLASTIC  DISEASES 

without  colloid.  Adhesions  to  neighboring  organs  are  frequent  with  this 
type  of  growth.  Invasion  of  lymph-nodes  while  frequent  is  usually  late  and 
colloid  visceral  metastases  are  rare. 

In  an  important  group  of  cases  the  gastric  wall  is  penetrated  early  and 
while  the  original  tumor  may  remain  comparatively  small  there  are  numer- 
ous and  bulky  extensions  over  a  portion  or  the  whole  of  the  peritoneum,  with 
ascites.  The  stomach  outranks  the  colon  and  gall-bladder  as  a  source  of  col- 
loid carcinoma  of  the  peritoneum  (Kaufmann). 

The  structure  of  gelatinous  carcinoma  in  the  stomach  is  very  similar  to 
that  of  simple  adenocarcinoma,  with  the  addition  of  extensive  formation  of 
thin  mucus.  This  material  fills  all  but  the  youngest  alveoli  to  distention  and 
after  rupture  it  infiltrates  the  supporting  tissues  and  invades  lymphatics  and 
the  sheaths  of  vessels  and  nerves.  The  lining  cells  of  the  alveoli  present 
all  stages  of  its  formation  and  many  cells  are  desquamated  and  dissolved 
in  the  mucus.  Complete  disappearance  of  all  traces  of  epithelium  may 
occur  in  large  areas  of  such  tumors,  which  thereby  reach  a  standstill  while 
growth  proceeds  in  other  areas.  A  partial  absorption  of  this  mucus  may 
follow. 

In  infiltrating  portions  of  mucous  carcinoma  the  diffusely  growing  cells 
become  ballooned  with  mucus  and  the  nuclei  are  compressed  into  signet-ring 
forms.  These  cells  are  commonly  present  both  in  this  and  other  anatomical 
forms  of  gastric  cancer,  either  actively  growing  or  regressing,  and  their  pres- 
ence is  an  important  aid  in  diagnosis  between  chronic  inflammation  and  can- 
cer of  the  stomach. 

(3)  Carcinoma  Following  Peptic  Ulcer. — The  relation  of  gastric  ulcer  to 
carcinoma  has  long  been  an  actively  debated  question.  Rokitansky,  1840, 
recognized  that  cancer  might  develop  from  ulcer.  Dittrich,  1848,  among  160 
cancers  found  6  developing  near  ulcers,  and  2  in  which  the  carcinoma  was 
limited  to  portions  of  ulcers.  Lebert,  1878,  calculated  that  9  per  cent,  of  can- 
cers arise  from  ulcers,  while  Zenker,  1882,  went  so  far  as  to  conclude  that  all 
gastric  cancers  are  secondary  to  some  form  of  ulceration.  He  noted  the  per- 
sistence of  free  HC1  with  cancers  following  peptic  ulcer.  In  1890  Hauser 
described  several  cases  of  cancer  of  characteristic  anatomical  form  following 
ulcer.  G.  Futterer,  1902,  concluded  that  ulcers  in  the  pyloric  region  fre- 
quently give  rise  to  cancer,  especially  in  those  portions  of  the  edges  most 
exposed  to  irritation.  The  onset  of  cancer  may  be  marked  by  increasing 
pain,  anemia,  and  emaciation.  The  free  HC1  steadily  diminishes  (Riegel). 
Mayo  Robson  finds  a  history  suggestive  of  ulcer  in  59.3  per  cent,  of  his  cases 
of  gastric  cancer,  but  reports  only  one  specific  case  with  micioscopic  evidence. 
Recently  the  Mayo  Clinic  reports  that  71  per  cent,  of  their  gastric  cancers 
were  associated  with  ulcer  and  68  per  cent,  of  ulcers  were  complicated  with 
carcinoma. 

In  determining  the  relation  of  gastric  ulcer  to  cancer,  statistical,  clinical, 
gross  anatomical,  and  microscopic  data  are  available  (Ewing,  Lit.).  Statis- 
tics show  that  ulcer  is  much  more  common  and  cancer  much  less  common  in 
women  than  in  men,  and  this  conclusion  is  not  seriously  altered  by  distin- 
guishing between  simple  and  chronic  ulcer.  The  clinical  history  of  precedent 
ulcer  and  of  persistent  free  HC1,  while  suggestive  and  important  as  corrobora- 
tive evidence,  cannot  demonstrate  a  direct  connection  between  ulcer  and 
cancer. 

The  gross  anatomy,  however,  furnishes  very  strong  evidence.  In  charac- 
teristic cases,  as  described  by  Hauser,  there  is  a  deep  crater-like  ulcer  with 
thick  and  very  dense  base  free  from  cancer,  indurated  and  undermined  or 
everted  edges,  exactly  reproducing  the  chronic  peptic  ulcer.  In  addition 


CARCINOMA  OF  STOMACH 


631 


there  are  marked  contracture  of  the  wall,  swelling  and  induration  of  lymph- 
nodes  and  occasionally  visceral  metastases.  Secondary  ulceration  of  primary 
carcinoma  may,  but  does  not  often,  produce  such  a  lesion  and  these  cases 
must  be  regarded  as  probably  carcinoma  following  ulcer.  In  most  cases  of 
this  type  microscopical  evidence  is  required  and  when  it  appears  in  unequivocal 
form  there  can  be  no  doubt  that  a  carcinoma  has  been  engrafted  upon  a  peptic 
ulcer. 

The  uncertain  territory  in  this  field  includes  (i)  certain  superficial  ulcera- 
tive  processes  which  the  microscope  shows  are  clearly  carcinomatous  and 
(2)  certain  characteristic  chronic  peptic  ulcers  which  have  been  classed  as 
carcinomatous  on  les^  definite  microscopical  structure. 


FIG.  288. — Hauser's  figure  of  peptic  ulcer  with  secondary  carcinoma  of  stomach.     Note 
isolated  polypoid  outgrowths  on  edge  of  ulcer  and  elsewhere. 


(1)  That  localized  superficial  carcinomas  of  the  stomach  may  early  be- 
come ulcerated  has  long  been  known  and  is  most  clearly  demonstrated  by 
Verse's  descriptions  of  such  early  cases.     These  lesions  are  chiefly  located 
in  the  pyloric  region  and  lesser  curvature,  they  are  comparatively  super- 
ficial and  usually  lack  the  deep  funnel  form  and  extensively  indurated  base 
and  borders  of  the  carcinomatous  peptic  ulcer.    They  may  eventually  closely 
simulate  the  latter. 

Microscopically  they  present  pronounced  adenocarcinoma,  or  alveolar 
gelatinous  carcinoma  in  both  base  and  edges  and  the  surrounding  mucosa  is 
hyperplastic.  Verse  finds  that  the  glands  on  the  edges  of  such  ulcers  may 
show  a  gradual  transformation  into  carcinomatous  structures. 

(2)  Peptic  ulcers  exhibit  many  transitional  stages  suggesting  carcinomatous 
change.    Some,  and  in  the  experience  of  most  observers  the  majority,  fail  to 


632  NEOPLASTIC  DISEASES 

show  any  evidence  whatever  of  carcinoma.  In  Vienna,  2  per  cent.,  in  Copen- 
hagen, 20  per  cent,  of  the  subjects  coming  to  autopsy  show  scars  of  old  healed 
ulcers  (Hirschfeld).  Others  show  suspicious  or  pronounced  precancerous 
changes  in  a  portion  or  the  whole  of  the  edges.  The  proportion  of  ulcers 
classed  as  carcinomatous  depends  on  the  criteria  employed  by  the  observer. 
Hirschfeld  places  the  proportion  of  ulcers  which  become  cancerous  at  5  to 
6  per  cent,  and  he  summarizes  clinical  and  statistical  data  indicating  that 
the  proportion  is  small.  Futterer,  however,  places  the  proportion  very  much 
higher  and  holds  that  the  tendency  toward  carcinomatous  change  greatly 
influences  the  prognosis  of  gastric  ulcer.  Hauser  emphasizes  the  inflam- 
matory overgrowth  of  glands  in  the  edges  of  ulcers,  but  interprets  as  carci- 
noma only  very  advanced  stages  of  the  process.  Recently  Wilson  and 
MacCarty  in  the  Mayo  Clinic  report  that  68  per  cent,  of  their  gastric  ulcers 
were  associated  with  carcinoma.  They  secure  this  high  proportion  by  inter- 


FIG.  289. — Atypical  proliferation  of  gastric  glands  on  edge  of  peptic  ulcer.    A  precan- 
cerous lesion,  not  to  be  classed  as  cancer. 

preting  as  carcinomatous  many  appearances  which  it  is  difficult  to  separate 
from  chronic  inflammatory  overgrowth  and  heterotopia  of  gland  tissue. 
They  recognize  many  cases  in  which  it  is  impossible  to  determine  whether 
the  ulcer  or  the  carcinoma  was  the  primary  lesion.  Boekelmann  collects  a 
series  of  estimates  varying  from  3  to  50  per  cent.  In  France  opinions  are 
widely  at  variance.  Moutier  in  35  cases  from  operation  and  autopsy  found 
19  simple  ulcers,  15  distinctly  cancerous,  and  one  cancerous  duodenal  ulcer. 

I  believe  that  the  higher  estimates  (above  2  or  3  per  cent.)  indicate  too 
high  an  average  for  the  carcinomatous  transformation  of  ulcers.  Where 
definite  carcinomatous  alveoli  are  present  throughout  the  base  of  an  ulcer, 
especially  if  early,  the  condition  is  probably  better  regarded  as  primary  car- 
cinoma. MacCarty  states  that  where  irregular  epithelial  structures  occur  in 
the  submucosa  one  is  surely  dealing  with  carcinoma.  Yet  heterotopia  of 
epithelium  may  be  of  inflammatory  origin  and  it  would  seem  better  to  desig- 
nate many  of  these  uncertain  lesions  as  at  most  precancerous.  In  my  own 


CARCINOMA  OF  STOMACH 


633 


material  I  find  it  very  difficult  to  trace  the  development  of  cancer  in  the 
edges  of  peptic  ulcers.  The  cases  seem  to  fall  distinctly  into  the  group  of 
ulcerating  adenocarcinomas  or  among  simple  ulcers  without  any  trace  of 
cancer.  The  structure  of  the  malignant  cases  varies  greatly,  indicating  that 
there  are  several  histological  types  of  early  ulcerating  cancers.  The  mucosa 
surrounding  simple  ulcers  is  sometimes  extensively  altered,  the  glands  hyper- 
trophied,  the  cells  enlarged,  nuclei  hyperchromatic,  and  alveoli  occasionally 
misplaced,  but  definite  precancerous  changes  in  cases  of  undoubted  simple 
ulcer  I  have  rarely  found.  It  has  appeared,  however,  that  the  digestive 
fluids  may  completely  excavate  a  superficial  carcinoma  leaving  the  base 


FIG.  290. — Hypertrophic  gastritis  in  a  stomach  the  seat  of  peptic  ulcer. 


free,  but  a  submucous  ring  of  cancer  encircling  the  ulcer.  More  often  islands 
of  carcinoma  remain  throughout  the  base.  The  complete  destruction  of  all 
traces  of  carcinoma  has  been  demonstrated  by  Thalheimer.  Therefore,  the 
presence  of  small  areas  of  carcinoma  in  the  edges  of  an  ulcer  does  not  neces- 
sarily mean  a  carcinomatous  change  in  a  simple  ulcer. 

It  is  at  least  evident  that  quite  specific  criteria  must  be  employed  in  the 
diagnosis  of  cancer  following  ulcer,  since  the  conditions  surrounding  this 
process  in  the  stomach  are  peculiar. 

Against  a  very  great  frequency  of  carcinomatous  change  of  peptic  ulcer 
stand  several  general  considerations  emphasized  by  R.  Williams.  Sixty 
per  cent,  of  gastric  cancers,  he  finds,  are  located  at  the  pylorus,  while  only 


634 


NEOPLASTIC  DISEASES 


12  per  cent,  of  ulcers  occur  in  this  situation.  The  commonest  seat  of  ulcer 
is  the  lesser  curvature  (36.3  per  cent.,  Welch),  whereas  only  12.2  per  cent,  of 
cancers  occur  in  this  situation.  Ulcer  of  the  duodenum  very  rarely  gives 
rise  to  cancer.  In  other  regions  there  are  very  few  ulcers  which  are  known 
to  be  followed  by  cancer.  One  of  these  is  lupus,  in  which  the  average  interval 
is  30  years.  A  few  varicose  ulcers  of  the  leg  develop  epithelioma,  but.  nearly 
always  after  many  years.  The  age  incidence  of  the  two  diseases  is  very  differ- 
ent. Yet  I  cannot  agree  with  Williams  that  such  evidence  is  conclusive.  It 
is  much  too  general  and  uncertain.  Thus  Boas  found  27.2  per  cent,  of  his 
cancers  at  the  pylorus,  but  a  later  series  of  40  cases  gave  only  15  per  cent,  at 


FIG.  291. — Edge  of  ulcerating  carcinoma  of  stomach.    The  carcinoma  was  limited  to  a 
narrow  ring  encircling  the  ulcer. 


this  location.  Bamberger  reports  that  after  1025  gastro-enterostomies  for 
ulcer  observed  for  some  time  cancer  developed  in  22  (2.1  per  cent.).  Among 
152  cases  in  which  ulcer  was  treated  by  excision  cancer  developed  in  1.9  per 
cent.  These  results  are  quite  incompatible  with  a  frequent  origin  of  cancer 
from  peptic  ulcer. 

Experimental  production  of  adenocarcinoma  by  irritation  of  artificial 
ulcers  in  animals  is  reported  by  Hemmeter,  Futterer  and  Maniscalio,  but 
the  supposed  malignant  process  although  interesting  in  itself,  lacked  the 
progressive  character  of  cancer.  On  the  other  hand,  Haga's  experimental 
adenoma  of  the  stomach,  which  closely  approaches  a  genuine  tufnor,  always 
showed  glandular  overgrowth  first,  and  only  later,  if  at  all,  ulceration. 


CARCINOMA  OF  STOMACH 


635 


•^TSSSft* 


Gross  Anatomy. — The  type  of  carcinoma  which  is  said  to  follow  peptic 
ulcer  presents  in  its  early  stages  the  same  appearance  as  the  uncomplicated 
peptic  ulcer  and  it  may  be  impossible  to  detect  the  malignant  process  except 
by  microscopical  study.  The  carcinoma  is  said  to  begin  on  the  pyloric  side 
of  the  ulcer  and  causes  increased  swelling  and  density  of  the  borders  and 
fixation  of  the  ulcer  to  the  muscularis  and  serosa.  No  great  change  in  the 
density  of  the  base  can  be  expected  since  this  portion  of  ulcers  is  always  very 
firm  and  carcinoma  can  invade  the  base  only  from  below.  The  shortening 
of  the  curvature,  thickening  of  serosa,  and  cicatricial  contraction  drawing 
up  the  lymph-nodes,  seen  in  old  ulcers,  are  increased  in  carcinoma,  and  the 
swollen  lymph-nodes  become  more 
dense.  These  changes  observed  in 
surgical  cases  are  usually  somewhat 
aggravated  in  subjects  coming  to 
autopsy.  The  vicinity  of  the  ulcer 
then  shows  more  extensive  thickening 
from  invasion  of  all  coats  of  the 
organ,  the  lymph-nodes  are  larger, 
and  there  may  be  extensions  to  liver, 
gall-bladder,  and  peritoneum,  but  ex- 
tensive metastases  are  rare  and  in 
many  fatal  cases  the  disease  is  local- 
ised to  stomach  and  adjacent  nodes. 
Although  pyloric  stenosis  is  frequently 
established,  the  tendency  to  dilata- 
tion of  the  stomach  is  usually  counter- 
acted by  cicatricial  contraction  of  the 
lesser  curvature.  Perforation  of  the 
ulcer  occasionally  terminates  the  prog- 
ress. 

The  structural  type  of  carcinoma 
following  ulcer  is  usually  a  small 
alveolar  or  adenocarcinoma,  and  this 
type  was  exclusively  represented  in 
Hauser's  cases.  From  the  hyper- 
plastic  glands  on  the  edges  of  the  ulcer 
there  is  a  downward  growth  of  atyp- 
ical glands  which  soon  break  up  into 
irregular  alveoli  lined  by  atypical, 
cylindrical,  or  cubical  cells.  From 
these  structures  solid  cell  groups  com- 
monly develop  and  extend  laterally  in  the  wall  and  through  the  lymphatics 
into  the  lymph-nodes. 

(4)  Carcinoma  Simplex.  Medullary  and  Diffuse  Carcinoma. — The 
more  malignant  types  of  gastric  carcinoma  are  composed  of  more  atypical 
cells  arranged  in  alveoli  or  growing  diffusely.  These  tumors  produce  two 
well-defined  gross  anatomical  forms. 

(i)  Soft,  often  ulcerating,  rounded,  more  or  less  circumscribed  tumors 
of  considerable  extent  occur  chiefly  in  the  cardia  and  fundus.  They  are  often 
vascular  (carcinoma  telangiectatica)  and  subject  to  severe  hemorrhages. 
Fatty  degeneration  and  necrosis  lead  to  ulceration  of  wide  extent,  to  erosion 
of  large  arteries  and  to  perforation.  The  neighboring  organs,  liver,  pancreas, 
colon,  duodenum,  may  be  involved  by  continuity  of  growth.  The  lymph- 
nodes  are  early  invaded  and  metastases  are  very  frequently  seen  in  liver, 


FIG.  292.  —  Ulcerating  gastric  cancer. 
Groups  of  tumor  cells  and  cellular  connec- 
tive tissue  forming  base  of  ulcer. 


636 


NEOPLASTIC  DISEASES 


lungs,  peritoneum,  and  distant  organs.     This  is  the  most  aggressive  and 
rapidly  progressive  form  of  gastric  carcinoma. 

(2)  Diffuse  carcinoma  may  arise  from  any  portion  of  the  mucosa,  usually 
near  the  pylorus,  and  maintains  an  infiltrating  tendency  from  the  first.  The 
original  tumor  may  then  be  difficult  to  locate  and  a  large  segment  of  the 
wall  may  show  diffuse  thickening  of  all  coats  with  little  ulceration  or  only 
superficial  erosion  of  the  mucosa.  Early  invasion  of  lymph-nodes  and  wide- 
spread metastases  occur  as  in  the  preceding  form.  Occasionally  there  is 
deep  ulceration  at  the  pylorus  and  diffuse  infiltration  over  a  wide  area.  Most 
of  the  perforations  in  gastric  cancer  occur  in  this  type.  Among  507  cases 
of  cancer  Brinton  found  perforation  into  the  peritoneum  in  17,  into  colon,  n. 


FIG.  293. — Section  of  mucosa  in  diffuse  superficial  carcinoma  of  stomach. 


Mislowitzer  collected  17  cases  of  perforation  of  the  abdominal  wall.    Lang 
in  210  cases  reports  peritoneal  perforation  in  12. 

The  structure  presents  small  or  large  alveoli  or  a  diffuse  growth  of  atyp- 
ical cells,  which  are  usually  small,  polyhedral  or  round,  and  with  relatively 
large  hyperchromatic  nuclei.  A  desmoplastic  quality  may  be  entirely  lack- 
ing, and  some  of  these  carcinomas  are  readily  mistaken  for  lymphosarcoma. 
The  cell  form  may  vary  considerably  and  in  different  portions  of  the  same 
tumor  one  may  find  large  alveoli,  small  alveoli,  or  diffuse  growth.  Giant- 
cells  may  occur  in  considerable  numbers  and  when  they  appear  with  round- 
cells  of  various  sizes  in  a  tumor  lacking  alveolar  structure  the  resemblance  to 
sarcoma  may  be  pronounced  (cf.  Kaufmann).  The  invasion  of  muscular 
wall,  nerve-trunks,  and  lymph- vessels  is  remarkably  free.  In  less  active 
foci  mucous  globules  appear  in  many  cells.  In  metastases  an  alveolar  struc- 


CARCINOMA  OF  STOMACH 


637 


ture  is  apt  to  reappear  or  the  structure  may  be  even  more  atypical  than  the 
original. 

(5)  Diffuse  scirrhous  carcinoma  is  a  slowly  progressive  type  of  the  disease 
which  differs  from  carcinoma  simplex  in  its  slow  course,  desmoplastic  proper- 
ties, absence  of  ulceration,  prominence  of  pyloric  stenosis,  and  in  the  peculiari- 
ties of  its  metastases.  It  differs  from  sclerosing  pyloric  fibrocarcinoma  in 
its  wider  extent,  more  cellular  character,  and  frequent  metastases. 

The  gross  appearance  is  characteristic.  A  considerable  portion  of  the 
wall  beginning  at  the  pylorus  shows  smooth  thickening  of  all  coats,  especially 


FIG.  294. — Diffuse  superficial  carcinoma  of  stomach.    The  ducts  of  the  mucous  glands 
are  intact,  the  bases  are  breaking  up  into  small  carcinomatous  alveoli. 


of  the  submucosa  and  muscularis.  The  entire  organ  may  be  involved  and 
greatly  reduced  in  size  by  cicatricial  contraction.  The  pyloric  and  other 
areas  of  mucosa  may  be  eroded  over  a  wide  extent,  but  there  is  seldom  de- 
structive ulceration.  The  serosa  is  opaque,  fibrous,  and  covered  with  small 
nodules  from  invaded  lymphatics.  There  may  be  a  remarkable  freedom  from 
adhesions,  but  usually  the  pylorus  is  fixed  to  neighboring  tissues  and  much 
contracted. 

The  lymph-nodes  are  regularly  involved  and  in  these  structures  and  in  the 
liver  and  other  organs  bulky  tumors,  often  much  larger  than  the  original, 
develop  from  a  freer  growth  of  tumor-cells.  The  peritoneal  lymphatics  may 


638  NEOPLASTIC  DISEASES 

be  extensively  involved  with  constriction  and  adhesions  of  the  intestine. 
The  omentum  may  be  drawn  up  into  a  small  cancerous  mass  attached  to 
the  lower  border  of  the  stomach. 


FIG.  295. — Diffuse  carcinoma  of  pylorus  with  three  secondary  peptic  ulcers,  one  at 
pyloric  ring,  one  3  cm.  and  another  5  cm.  from  ring. 


FIG.  296. — Cross-section  of  secondary  peptic  ulcer  arising  on  diffuse  carcinoma  of  pylorus. 

In  a  well-defined  group  of  cases  the  original  tumor  is  small  and  poorly 
defined,  but  bulky  metastatic  tumors  develop,  especially  in  the  liver  and 
ovary,  and  the  disease  runs  its  course  as  a  primary  tumor  of  these  organs; 


CARCINOMA  OF  STOMACH 


639 


24  per  cent,  of  the  secondary  carcinomas  of  the  liver  are  derived  from  the 
stomach  (Rolleston)  and  not  a  few  develop  from  relatively  small  and  usually 
fibrous  cancers  of  the  stomach.  In  the  ovary  the  metastases  are  often  bi- 
lateral. A  scirrhous  tendency  may  be  associated  with  adenocarcinoma,  and 
in  the  pyloric  region  this  tendency  is  frequent  and  pronounced,  so  much  so 
that  Hauser  describes  a  special  variety  of  scirrhous  adenocarcinoma. 

The  great  majority  of  scirrhous  tumors  present  small  or  large  solid  groups 
of  polyhedral  cells  which  are  easily  recognized  as  carcinomatous.  As  the 
fibrosis  increases  the  tumor-cells  diminish  in  number,  and  in  wide  areas  they 
may  be  reduced  to  small  groups  of  degenerating  cells  with  mucous  globules, 


FIG.  297. — Diffuse  carcinoma  of  entire  stomach.     Gastro-enterostomy. 

or  to  small  granular  opaque  cells  which  resemble  plasma-cells.  In  the  nerve- 
trunks,  lymphatics,  and  capillaries  about  such  tumors  much  larger  and  more 
typical  cells  are  usually  found,  while  in  the  lymph-nodes  and  peritoneal  nodules 
the  growth  may  be  quite  typical. 

(6)  Sclerosing  Pyloric  and  Diffuse  Fibrocarcinoma.  Linitis  Plastica.— 
The  usual  form  of  scirrhous  carcinoma  of  the  stomach  is  easily  recognized 
by  the  diffuse  thickening  of  all  the  coats,  the  contraction  of  the  organ  often 
to  a  rigid  tube,  the  frequent  presence  of  metastases,  and  especially  by  the 
microscopic  evidence  of  round-cell,  or  alveolar  or  gelatinous  carcinoma.  It 
has  long  been  known  and  is  specifically  mentioned  by  Rokitansky  and  by 


640 


NEOPLASTIC  DISEASES 


Kaufmann  that  the  epithelial  cells  in  scirrhous  cancer  of  the  stomach  may  be 
reduced  to  a  minimum  or  may  largely  disappear,  so  that  a  very  careful  micro- 
scopical examination  is. required  to  detect  the  traces  of  carcinoma.  Indeed, 
the  last  traces  of  epithelial  structures  may  completely  disappear  over  con- 
siderable areas  of  thickened  submucosa  and  muscularis,  so  that  no  suspicion 
of  malignant  process  past  or  present  may  be  suggested. 

Neglect  of  this  fact  has  led  to  the  accumu- 
lation in  the  literature  of  a  large  number  of 
cases  of  supposed  benign  cirrhosis  and  con- 
traction of  the  pyloric  region  or  the  entire 
stomach,  which  have  appeared  under  various 
terms  and  interpretations  (Lyle,  Lit.).  Cru- 
veilhier  first  described  the  condition  as  benign 
hypertrophic  pyloric  stenosis.  It  is  commonly 
known  under  Brinton's  term  "linitis  plastica." 
Brinton  was  by  no  means  certain  that  the 
process  was  not  cancerous. 

Although  the  existence  of  miscellaneous 
forms  of  purely  inflammatory  gastric  and 
pyloric  sclerosis  cannot  be  denied,  it  now 
appears,  largely  through  the  critical  analyses 
of  Bret  and  Paviot,  Meinel,  Krompecher  and 
Makai,  and  others,  that  the  great  majority  if 
not  all  the  cases  of  linitis  plastica  are  atypical 
cicatrizing  fibrocarcinoma. 

Of  130  cases  collected  by  Lyle,  60  may  be 
disposed  of  as  carcinomas  belonging  with 
scirrhous  cancer,  or  in  the  present  group  of 
atypical  -fibrocarcinoma.  The  remaining  70 
occurred  under  various  circumstances. 

A  considerable  group  appear  to  be  examples 
of  chronic  gastritis  with  marked  contracture 
and  thickening  of  the  whole  or  much  of  the 
stomach.  In  these  cases  there  appears  to  be 
hypertrophy,  chiefly  of  the  muscular  coat, 
_  FIG.  298.— Characteristic  atyp-  while  the  submucosa  lacks  the  extensive  over- 
ical  structure  of  certain  carcmo-  ,,  P  r  ...  ,  ,.  T  ,,  ( 

mas  of  pylorus.  Single  tumor  cells  growth  of  linitis  plastica.  In  the  case  of 
with  hyperchromatic  nuclei  in-  Schoch  and  Nauwerck  the  stomach  was  much 
filtrating  muscularis.  dilated  from  a  lesion  limited  to  the  pylorus. 

In  many  others  the  gross  appearance  closely 

resembled  scirrhous  carcinoma  (Schmidt,  Viti,  Rosenheim,  Deguy,  Marcy, 
and  Griffith).  In  Sheldon's  case  gastric  symptoms  antedated  operation  15 
years  and  the  patient  was  well  3^  years  later,  v.  Eiselberg's  patient  was  well 
5  years  after  gastro-enterostomy. 

In  several  cases  there  were  signs  of  old  superficial  ulcers  (Formad,  Allbutt, 
Turner,  Meinel).  Nothnagel's  case  ran  the  course  of  pernicious  anemia. 
Many  cases  would  suggest  classification  with  polyserositis  and  showed  multiple 
thickenings  throughout  the  peritoneum,  intestine,  colon,  and  rectum  (Lebert, 
Marignac,  Wilks,  Henrot,  v.  Kahlden,  Gabbi).  Yet  very  similar  cases  are 
reported  by  Bret  and  Paviot,  who  point  out  that  the  intestinal  lesion  is  chiefly 
subserous  and  that  extensions  readily  pass  from  the  stomach  to  omentum 
and  colon. 

Krompecher,  under  the  term  "gastro-intestinal  sclerostenosis,"  emphasized 
a  group  of  benign  cases  which  he  attributed  to  cardiac  disease,  chronic  con- 


CARCINOMA  OF  STOMACH 


641 


gestion,  edema,  and  fibrosis,  but  he  later  abandoned  the  idea  that  these  cases 
were  not  piobably  carcinoma tous.  Leith  describes  a  case  of  this  type  as 
non-cancerous  cirrhosis.  The  lesion  involved  stomach,  ileum,  and  colon, 
but  the  microscopic  report  is  somewhat  lacking  in  details,  although  the  author 
positively  excludes  carcinoma. 

In  dealing  with  such  an  extensive  collection  of  anomalous  conditions  it  is 
obviously  impossible  to  urge  that  any  uniform  process  is  represented.  It 
appears  quite  possible  that  rare  cases  of  chronic  gastritis,  the  scarring  of 
ulceis,  late  syphilis,  peculiar  traumas,  and  atrophying  fibrous  processes  may 
simulate  nbrocarcinoma,  but  it  may  be  claimed  that  no  well-defined  group 
of  cases  exists  apart  from  fibrocarcinoma.  As  Krompecher  points  out,  the 


FIG.  299. — Sclerosing  fibrocarcinoma  of  pylorus.    Linitis  plastica.    Erosion  of  mucosa. 
Small  groups  of  tumor  cells  with  mucous  contents  limited  to  serosa. 

microscopic  study  of  older  cases  and  even  of  the  latest  reports  is  open  to 
serious  criticism,  since  the  histology  of  regressing  fibrocarcinoma  of  the  stom- 
ach is  seldom  fully  recognized.  Thus  Tilger  wrote  an  elaborate  description, 
completely  excluding  traces  of  carcinoma,  in  a  case  which  on  subsequent 
study  Meinel  found  to  be  carcinomatous. 

In  a  series  of  17  cases  of  linitis  plastica  Krompecher  and  Makai  found  9 
which  they  recognized  as  disseminated  fibrocarcinoma,  by  the  discovery  of 
islands  of  atypical  epithelium,  or  scanty  acini  of  adenocarcinoma,  or  groups 
of  cells  with  mucous  degeneration  and  typical  signet-ring  nuclei.  In  other 
portions  of  these  same  tissues  they  find  only  cellular  granulation  tissue  or 
hyaline  areas  and  cells  of  undetermined  origin,  all  of  which  made  up  the  bulk 
41 


642 


NEOPLASTIC  DISEASES 


of  the  sclerotic  areas  in  the  remaining  8  cases  in  which  no  definite  signs  of 
carcinoma  were  present.  In  the  peritoneal  plaques  and  thickenings  of  intes- 
tinal wall  and  peritoneum  similar  structures  were  present.  They  therefore 
conclude  that  all  their  cases  are  of  identical  nature  and  belong  in  a  group  of 
atypical  disseminated  sclerosing  carcinoma.  They  also  incline  to  agree  with 
Meinel  that  a  benign  acquired  cirrhosis  of  pylorus  and  stomach  of  the  type 
of  linitis  plastica  probably  does  not  exist.  The  interpretation  of  these  cases 
as  endothelioma,  offered  by  Jungmann,  Szobolew,  v.  Hansemann,  Fick, 
Cignozzi,  Aldegarmann,  and  Donath,  they  also  discard.  Yet  of  the  cases 
reported  as  endothelioma,  only  those  of  Fick  and  Cignozzi  bore  any  gross 
resemblance  to  linitis  plastica. 

My  own  study  of  a  group  of  these  cases  has  led  to  the  same  conclusions, 
modified  as  above  stated,  because  of  the  very  miscellaneous  nature  of  the 
reported  cases. 


FIG.  300. — Diffuse  sclerosing  fibrocarcinoma  of  stomach. 

bottle  stomach. 


Linitis  plastica.     Leather- 


I  find  every  gradation  from  small-cell,  diffuse,  and  scirrhous  carcinoma, 
with  pronounced  signs  of  malignancy,  down  to  overcellular  granulation  tissue 
containing  isolated  cells  with  mucous  globules,  to  vascular  tissue  with  over- 
growing capillaries  suggesting  endothelioma,  or  hyaline  connective  tissue  with 
scanty  cells  of  undetermined  origin,  and  even  to  connective  tissue  without 
a  trace  of  atypical  cells  of  any  type.  As  a  rule  extensive  search  reveals  some 
foci  of  characteristic  mucous  cells  in  submucosa  or  muscularis.  The  nerve- 
trunks  sometimes  show  infiltration  by  polyhedral  cells  with  hyperchromatic 
nuclei,  when  the  surrounding  tissue  is  free.  The  last  traces  of  epithelial  cell 
groups  may  appear  as  foci  of  mucus  lying  in  fibrous  tissue.  Single  rows  of 
cells  in  fibrous  tissue  may  resemble  plasma-cells.  In  4  cases  regarded  as 
benign  pyloric  stenosis,  and  narrowly  limited  to  this  orifice,  I  found  none  of 
the  usual  signs  of  carcinoma,  but  only  such  atypical  regressing  cell  groups. 
It  therefore  seems  necessary  to  conclude  that  all  cases  of  hypertrophic  pyloric 


CARCINOMA  OF  STOMACH  643 

stenosis  and  diffuse  cirrhosis  of  the  stomach  in  adults  are  atypical  fibrocar- 
cinoma.  Miscellaneous  cases  of  apparently  benign  character  must  be  regarded 
with  suspicion. 

From  this  point  of  view  the  origin  and  significance  of  this  type  of  carcinoma 
becomes  of  great  interest.  The  atypical  cells  may  safely  be  traced  to  the 
disordered  glands  in  the  mucosa.  This  structure  commonly  shows  advanced 
chronic  inflammation  with  hypertrophy  or  erosion,  rarely  with  atrophy  and 
replacement  by  granulation  tissue  covered  by  flat  epithelium.  The  presence 
of  scars  of  old  superficial  ulcers  in  many  cases  suggests  that  the  cells  may^be 
derived  from  the  heterotopic  glands  in  the  edges  of  these  lesions.  Meinel 
argues  for  the  derivation  of  the  cells  from  the  endothelium  or  lymph  spaces 
and  uses  the  term  "lymph-epithelioma."  I  find  it  often  difficult  to  distinguish 
atypical  epithelium  from  the  hyperplastic  endothelium  in  these  tissues,  but 
have  not  observed  any  definite  indications  that  the  atypical  cells  are  of  endo- 


FIG.  301. — Diffuse  pyloric  carcinoma  with  erosion. 

thelial  origin.  Most  of  the  cases  described  as  endothelioma  of  the  stomach 
are  quite  different  in  gross  appearance  from  linitis  plastica.  G.  Hayem  de- 
rives the  tumor  from  the  granular  acidophile  peptic  cells.  Tn  a  case  of  linitis 
plastica  extending  from  the  cardia  to  the  prepyloric  region  he  found  an  intact 
muscularis  mucosa,  but  a  diffuse  infiltration  with  large,  irregular,  granular, 
acidophile,  vacuolated  cells  with  large  nuclei,  which  he  would  trace  to  a  diffuse 
breaking  down  of  the  peptic  glands. 

The  movements  of  the  stomach  provide  unusual  facilities  for  the  mechan- 
ical transfer  of  proliferating  epithelial  cells  which  might  otherwise  be  quite 
unable  to  disseminate  themselves  over  such  wide  areas.  It  seems  necessary 
to  assume  that  the  growth  capacity  of  these  cells  is  much  less  than  that  of 
frank  carcinoma.  Hence  the  course  of  the  disease  is  slow,  fibrosis  and  mucous 
degeneration  overtake  most  of  the  cell  colonies,  and  in  many  areas  the  carci- 
nomatous  element  disappears  entirely.  The  wide  dissemination  over  duode- 
num, peritoneum,  and  colon  suggests  that  the  process  was  at  one  time  more 


644  .       NEOPLASTIC  DISEASES 

active,  but  eventually  regressed  with  fibrosis.  A  final  standstill  of  the  entire 
process  may  thus  be  assumed  in  the  cases  which  appear  to  recover  after  gastro- 
enterostomy. 

In  linitis  plastica  there  appears  to  exist  a  peculiar  form  of  gastric  carci- 
noma probably  occurring  in  resistant  subjects  and  originating  from  cells  of 
limited  growth  capacity,  which  pursues  a  chronic  course  and  tends  to  sponta- 
neous regression  of  the  tumor  process,  but  to  the  death  of  the  patient.  The 
occurrence  only  in  adults,  20  to  80  years,  clearly  separates  the  condition 
from  congenital  stenosis.  Yet  congenital  cancer  of  the  stomach  is  reported 
by  Mathieu.  Danosky  described  in  a  10  weeks'  old  infant  a  diffuse  and  very 
dense  thickening  of  the  submucosa  with  pyloric  stenosis.  Torkel  attributes 
the  benign  congenital  stenosis  of  the  pylorus  to  a  congenital  malformation 
with  inclusion  of  islands  of  Brunner's  glands  in  the  pyloric  muscle.  It  is 
possible  that  some  later  cases  of  pyloric  stenosis  may  develop  from  this  same 
anomaly  and  that  a  malignant  process  may  originate  in  these  aberrant  glands. 

In  the  typical  condition  of  linitis  plastica  the  stomach  is  much  thickened 
and  contracted  (leather-bottle  stomach).  The  lesion  begins  in  the  pylorus 
and  may  be  confined  to  this  region  or  to  the  curvatures,  from  which  it  ex- 
tends over  a  part  or  the  whole  of  the  stomach  and  occasionally  to  the  duode- 
num. The  pyloric  orifice  projects  into  the  duodenum  as  the  cervix  uteri 
into  the  vagina.  The  stomach  wall  is  four  to  eight  times  the  normal  thick- 
ness. The  new  tissue  is  chiefly  in  the  submucosa,  while  the  muscularis  is 
also  much  thickened  and  traversed  by  opaque  bands  of  fibrous  tissue.  The 
tissue  is  very  dense,  resisting  incision  almost  like  cartilage.  The  mucosa 
is  usually  thrown  into  folds  or  nodular  elevations,  or  it  is  thin,  eroded,  or 
ulcerated.  The  pylorus  may  be  movable  when  the  disease  is  limited  to  the 
stomach,  but  is  often  fixed  by  adhesions.  The  pyloric  lymph-nodes  are  usually 
moderately  enlarged.  Extensions  to  the  peritoneum  give  rise  to  fibrous 
thickenings  constricting  the  intestine  and  causing  marked  cicatricial  con- 
traction of  the  omentum.  Fibrous  areas  may  be  seen  over  the  liver  and  spleen. 
Hanot  and  Gombault  found  the  portal  vein  converted  into  a  rigid  tube.  The 
microscopical  structure  is  indicated  in  the  preceding  discussion. 

The  Gastric  Mucosa  in  Cancer  of  the  Stomach. — The  condition  of  the 
gastric  mucosa  varies  widely,  depending  on  the  type  and  progress  of  the 
tumor  and  the  previous  condition  of  the  mucous  membrane.  There  is  a 
constant  tendency  toward  diminished  functional  capacity,  associated  with 
atrophy  of  peptic  cells  and  a  metaplastic  transformation  of  gastric  into  an 
intestinal  type  of  cell  lining,  with  marked  increase  of  goblet  cells  (J.  E. 
Schmidt,  Lit.).  An  increased  secretion  of  alkaline  mucus  tends  to  neutralize 
acid.  This  change  begins  in  the  pyloric  region  where  it  may  become  very 
marked  and  simulate  heterotopia  of  duodenal  glands.  Observing  it  in  marked 
degrees  Gosset  and  Masson  were  led  to  believe  that  all  pyloric  cancers  might 
be  derived  from  heterotopic  duodenal  glands. 

Throughout  the  altered  mucosa  many  large  eosinophile  cells  and  hyaline 
globules  often  appear,  about  the  nature  of  which  there  has  been  much  discus- 
sion. They  appear  also  in  the  stroma  of  cancers.  They  have  been  regarded 
as  capillary  red-cell  thrombi  (Saltykow),  degenerated  fibroblasts  (Marchand, 
Lubarsch),  or  epithelium  (Thorel),  altered  plasma-cells  (Schridde,  Fabian), 
or  englobed  secretion  (Verse).  Very  marked  polypoid  outgrowths  are  ob- 
served in  cases  developing  on  gastritis  polyposa.  A  relatively  intact  mucosa 
often  persists  in  cancer  following  ulcer.  Thus  in  1 5  cases  examined  by  Rosen- 
heim,  Hammerschlag,  Lenek,  and  Boekelmann  the  mucosa  was  intact  in  12 
and  showed  slight  increase  of  peptic  cells  in  3.  In  some  cases  an  adenocar- 
cinoma  is  associated  with  general  hypertrophic  gastritis.  Chronic  productive 


CARCINOMA  OF  STOMACH 


645 


interstitial  gastritis  with  atrophy  is  the  most  frequent  condition,  as  was  early 
shown  by  Fenwick.  In  all  of  14  cases  Rosenheim  found  catarrhal,  inter- 
stitial, and  atrophic  gastritis,  most  marked  near  the  tumor,  but  appearing  in 
foci  throughout  the  fundus.  Similar  results  were  obtained  by  Mathieu  and 
Cohnheim.  In  17  cases  Boekelmann  found  interstitial  gastritis  in  all,  focal 
lesions  in  7,  diffuse  advanced  changes  in  8,  and  early  complete  loss  of  glands 
in  2.  In  diffuse  carcinoma  the  mucosa  has  been  found  atrophic,  with  or  with- 
out extensive  erosion.  In  diffuse  colloid  cancer  the  gelatinous  nodules  may 
be  widely  distributed  over  the  mucosa.  The  various  changes  in  the  produc- 
tion of  HC1  and  ferments  depend  closely  upon  the  state  of  the  mucosa,  but 


FIG.  302. — Gastric  cancer  at  cardiac  orifice. 

portions  of  the  fundus  may  be  nearly  intact  in  cases  with  loss  of  HC1  (A. 
Schmidt,  Kokubo).  Hence  function  may  be  restored  after  partial  gastrectomy. 
The  relation  of  the  gastritis  to  the  carcinomatous  process  varies.  Fen- 
wick  pointed  out  that  atrophy  is  most  marked  with  scirrhous  cancer  which 
occurs  in  subjects  with  general  fibroid  changes.  Here  the  atrophy  must 
be  more  or  less  independent  of  the  carcinoma.  There  is  little  ground  for 
the  assumption  that  gastric  atrophy  itself  leads  to  carcinoma,  although  the 
disease  may  rarely  arise  in  atrophic  mucosae  (Riegel).  Gastric  atrophy  occurs 
with  carcinoma  of  other  organs,  as  observed  by  Fenwick  in  1 6  of  50  cases. 
Schneider  also  found  an  acidity  in  22  of  29  cases  of  extragastric  cancer.  It 
is,  therefore,  necessary  to  assume  that  carcinoma  affects  the  gastric  mucosa 


646 


NEOPLASTIC  DISEASES 


chiefly  through  a  deleterious  influence  on  the  organism  as  a  whole.  To  a 
considerable  extent  the  two  conditions  must  be  regarded  as  coordinate. 

Extensions  of  Gastric  Cancer. — The  carcinomatous  focus  having  become 
established,  the  mode  and  rate  of  extension  are  determined  chiefly  by  the 
growth  energies  of  the  cells.  Hence  there  are  very  wide  variations  in  the 
behavior  of  different  tumors. 

Adenocarcinomas  first  remain  localized  in  the  mucosa,  but  early  perforate 
the  muscularis  mucosae,  invade  the  lymphatics  of  submucosa  and  muscularis, 
and  thus  reach  the  lymph- nodes.  They  also  penetrate  the  blood-vessels  of 
the  stomach  wall,  as  is  indicated  by  the  distant  subcutaneous  metastases 
observed  in  some  early  cases.  A  wide  superficial  extension  in  the  mucosa 
is  less  common  than  in  the  colon,  but  occasionally  one  finds  a  large  portion 
of  the  fundus  covered  by  a  superficial  adenocarrinomatous  ulcer. 


FIG.   303. — Carcinoma  of  stomach.     x-Ray  after  injection  of  vessels  with  bismuth. 

(Schmidt.) 

The  diffuse  and  scirrhous  tumors  not  only  penetrate  the  lymph-vessels 
early,  but  extend  widely  through  all  coats  of  the  stomach.  The  entire 
pyloric  region  may  be  the  seat  of  a  diffuse  infiltration  of  the  mucosa  and 
submucosa  with  superficial  erosion,  giving  a  characteristic  form  of  pyloric 
carcinoma  with  stenosis,  but  without  ulceration  or  early  metastases.  Many 
cases  of  linitis  plastica  arise  in  this  way.  All  forms  of  diffuse  and  scirrhous 
cancer  invade  the  submucosa  by  preference  and  extend  widely  through  the 
large  and  small  lymphatics.  Submucous  invasion  is  said  to  extend  usually 
i  to  2  cm.  beyond  the  superficial  lesion,  so  that  this  amount  of  tissue  requires 
excision  (Carle,  Fontino,  Terrier,  Hartman).  Yet  no  general  rule  can  apply 
to  all  tumors.  Through  this  coat  the  pylorus  may  be  passed  and  the  duode- 
num invaded  for  i  or  2  cm.  Carle  and  Fontino  had  three  pyloric  cancers 
which  extended  i  to  3  cm.  beneath  Brunner's  glands,  while  Brinton  in  210 
cases  found  15  invasions  of  the  duodenum.  More  distant  submucous  metas- 
tases in  ileum  and  colon  mentioned  by  Welch  (Lit.),  Kaufmann,  and  others 


CARCINOMA  OF  STOMACH 


647 


suggest  that  embolic  cells  may  be  propelled  long  distances  before  finding 
lodgment.  Rectal  metastases  described  by  Bensaude  probably  travel  out- 
side the  intestinal  wall.  Passage  through  the  ventral  lymphatics  of  the  mus- 
cularis  is  readily  accomplished,  usually  with  thickening  and  fibrosis  of  this 
tissue.  In  the  subserous  lymphatics  permeation  becomes  much  freer.  As 
a  rule  the  serosa  backing  a  carcinoma  is  thickened,  contracted,  and  adherent 
to  neighboring  tissues,  with  approximation  of  the  contiguous  lymph-nodes, 
and  it  is  not  unusual  to  find  the  lymphatics  leading  from  such  a  focus  clearly 
outlined  by  infiltrating  growth  over  a  considerable  area  or  even  over  much 


FIG.  304. — Diagram  of  lymphatics  of  stomach.     (After  Cuneo.) 


of  the  serous  surface.  This  process  has  much  influence  over  the  form  and 
motility  of  the  stomach,  tends  to  limit  dilatation  of  the  organ,  and  contributes 
to  the  hour-glass  contractions.  Extension  to  the  peritoneum  occurs  directly 
from  the  serosa  or  from  secondary  foci  in  other  organs.  It  is  facilitated  espe- 
cially by  mucous  changes  in  the  tumor. 

The  Lymphatics  of  the  Stomach. — Cuneo  describes  three  main  groups  of 
perigastric  lymph-nodes:  (i)  Nodes  of  the  cardia  and  lesser  curvature.  The 
coronary  nodes  are  two  to  six  in  number  and  are  closely  applied  to  the  coro- 
nary artery.  The  nodes  of  the  lesser  curvature  form  two  groups.  One  group 


648  NEOPLASTIC  DISEASES 

lies  in  the  lesser  omentum  in  front  and  behind  the  vertical  portion  of  the 
cardiac  orifice.  These  nodes  may  be  absent.  The  other  group  is  constant 
and  lies  closely  applied  to  the  stomach  wall  in  the  course  of  the  coronary 
artery  and  contiguous  to  the  vagi.  The  upper  surface  of  the  pyloric  region 
is  free  of  nodes.  When  invaded  by  carcinoma  this  group  of  nodes  is  often 
contracted  and  bound  to  the  stomach  wall. 

(2)  The  hepatic  (pyloric}  chain  drains  the  lower  two-thirds  of  the  greater 
curvature  and  the  pyloric  region.    The  nodes  form  a  subpyloric  and  a  retro- 
pyloric  group.    The  former  lie  between  the  vessels  and  the  stomach,  but  not 
in  direct  contact  with  the  organ.     Some  may  be  distinctly  aberrant  and  lie 
5  to  6  cm.  from  the  stomach  in  the  gastrocolic  ligament.    They  receive  the 
lymph-flow  from  most  of  the  greater  curvature  and  unite  with  the  retro- 
pyloric  group  or  directly  with  nodes  along  the  hepatic  artery. 

The  retropyloric  nodes  lie  with  the  gastroduodenal  artery  and  are  in 
relation  with  the  posterior  surface  of  the  pylorus  and  behind  with  the  pan- 
creas. They  receive  lymph  from  the  posterior  surface  and  upper  border 
of  the  pylorus  and  from  the  first  portion  of  the  duodenum  and  unite  with 
the  main  hepatic  chain. 

(3)  The  splenic  group  lies  along  the  splenic  artery  from  stomach  to  hilus 
of  spleen,  in  the  pancreatic-splenic  omental  fold.    They  drain  the  fundus  of 
the  stomach. 

The  lymphatics  of  the  gastric  mucosa  are  very  rich  but  fine.  Passage  of 
lymph  to  the  submucosa  is  somewhat  restricted  by  the  muscularis  mucosa, 
through  which  small  vessels  pass  to  larger  sinuses  in  the  submucosa.  Thence 
narrow  vessels  pass  between  the  muscle  bundles  to  larger  subserous  spaces. 
The  submucous  and  subserous  plexuses  communicate  freely  with  those  of 
the  esophagus,  but  only  the  submucous  plexus  joins  freely  with  that  of  the 
duodenum.  The  subserous  vessels  encircle  the  pylorus,  but  do  not  freely 
join  with  those  of  the  duodenum.  While  the  above  descriptions  indicate 
the  general  course  of  lymphatic  flow,  yet  there  are  notable  variations  in  the 
lymphatic  vessels  and  still  further  anomalies  in  the  distribution  of  lymphatic 
metastases  (Lengeman,  Mayo). 

Lymphatic  invasion  usually  begins  as  an  embolic  process  with  secondary 
growth  which  may  fill  the  lymphatics  in  all  directions  (Lengemann,  Renner). 
Yet  in  slowly  growing  carcinoma  Borrmann's  view  of  continuous  permeation 
may  be  correct. 

General  statements  regarding  the  frequency  of  lymph-nodes  invasion  have 
little  value,  since  this  event  varies  so  greatly  in  different  forms  of  tumors. 
In  postmortem  material  it  is  rare  to  find  the  lymph-nodes  free  and  this  con- 
dition may  be  expected  only  in  slow  scirrhous  cancer  and  linitis  plastica.  In 
none  of  Verse's  12  early  carcinomas,  accidentally  found  at  autopsy,  were  the 
nodes  invaded,  although  several  were  of  considerable  dimensions  and  ulcer- 
ated and  one  was  recognized  during  life.  There  is,  therefore,  a  considerable 
period  when  the  therapeutic  problem  is  purely  local. 

Operative  material  includes  chiefly  tumors  of  pylorus  or  lesser  curvature. 
When  a  sufficient  number  of  nodes  are  carefully  searched  few  cases  will  be 
found  free  from  some  invasion.  Cuneo  in  8  autopsies  found  lymphatic 
invasion  in  all,  but  in  13  gastrectomies  the  nodes  were  invaded  in  only  2. 
Lengemann,  however,  made  a  very  thorough  study  of  gastrectomies,  finding 
all  nodes  free  in  only  one,  an  extensive  adenocarcinoma  of  pylorus  with  areas 
of  carcinoma  solidum.  In  20  cases  no  of  189  nodes  examined  (58  per  cent.) 
were  free.  The  retropyloric  nodes  and  those  of  the  lesser  curvature  were 
more  often  involved  than  the  subpyloric.  The  invasions  were  rarely  continu- 
ous and  hence  must  have  occurred  by  embolism.  The  size  of  the  nodes  gives 


CARCINOMA  OF  STOMACH  649 

uncertain  indications  of  their  condition.  Kausch  believes  that  lymphatic 
invasion  is  practically  constant  in  operative  cases.  In  resected  ulcerating 
carcinomas  I  find  invasion  of  accompanying  nodes  practically  constant,  but 
careful  search  of  the  nodes  may  be  required  to  detect  small  groups  of  embolic 
cells  in  the  sinuses.  Practically  it  must  be  assumed  that  all  accessible 
nodes  should  be  removed  in  gastric  resections  for  carcinoma.  • 

Observations  on  the  occurrence  of  extragastric  metastases  concern  autopsy 
material.  In  such  cases  Cuneo  found  invasion  of  perigastric,  diaphragmatic, 
or  retroperitoneal  nodes  in  85  per  cent.  Extensions  to  the  thoracic  nodes 
are  not  uncommon.  The  subhepatic  and  pancreatic  nodes  are  among  the 
first  involved.  Mesenteric  nodes  were  invaded  in  41  cases  and  the  lumbar 
and  aortic  in  106  of  603  cases  collected  by  Gussenbauer  and  Winiwarter. 
From  these  trunks  the  inguinal  nodes  may  be  affected  (Belin).  After  pleural 
invasion  the  axillary  nodes  may  suffer. 

The  importance  of  enlargement  of  stipraclavlcular  nodes  in  the  diagnosis 
of  abdominal  cancer  was  first  emphasized  by  Troisier,  and  of  these  cases 
gastric  cancer  furnishes  the  largest  proportion  (Tarchetti).  An  inflamma- 
tory swelling  of  these  nodes  is  quite  as  frequent  as  carcinomatous  invasion. 
Thus  Hechler  found  swelling  in  25  per  cent,  of  70  abdominal  cancers,  but  the 
clinical  observations  were  not  followed  by  microscopical.  The  left  nodes 
are  usually  the  ones  affected,  but  either  or  both  sides  may  be  involved  ac- 
cording to  the  anastomoses  of  the  thoracic  duct.  The  course  of  the  invasion 
is  through  the  thoracic  duct,  which  in  several  cases  has  been  found  completely 
infiltrated  (Hosch,  Lit.).  Chylous  ascites  may  accompany  the  thrombosis 
(Leydecker,  Hektoen).  From  the  supraclavicular  nodes  the  breast  may  be 
involved  (Moutier,  March).  Extensions  to  the  thoracic  duct  are  discussed 
at  length  by  Piat.  In  rare  cases  there  are  wide-spread  metastases  strictly 
limited  to  the  lymph-nodes  after  the  manner  of  lymphosarcoma,  and  in  these 
cases  the  cells  may  be  small  and  round  (Israel,  Hosch).  Multiple  cutaneous 
metastases  may  be  the  chief  or  even  the  sole  form  of  secondary  tumors.  The 
liver  is  invaded  in  about  33  per  cent,  of  autopsy  cases  (Kaufmann)  either  by 
direct  extension  across  the  adherent  peritoneum,  or  backward  from  the  sub- 
hepatic  nodes,  or  by  embolism  from  perforated  portal  vein  (Spaeth,  Acker). 
Very  large  tumors  may  then  form  in  the  liver  and  the  disease  may  simulate 
hepatic  carcinoma. 

Along  the  splenic  lymphatics  or  through  the  splenic  vein  the  spleen  may 
be  involved  and  drawn  toward  the  stomach. 

The  pleura  and  lungs  were  involved  in  7.3  per  cent.,  the  pancreas  in  7.6 
per  cent.,  and  the  peritoneum  and  intestines  in  27.6  per  cent,  of  2156  cases 
collected  by  Martin. 

Ovarian  metastases  occur  in  2.3  per  cent,  of  the  cases  of  gastric  carcinoma 
(Borrmann)  and  form  an  interesting  feature  of  the  disease.  Characteristic 
cases  are  described  by  Schlagenhaufer,  Glockner,  and  others.  The  original 
tumor  is  usually  scirrhus,  less  frequently  a  small,  diffuse,  or  gelatinous  car- 
cinoma. The  ovarian  growths  are  generally  bilateral  and  of  such  size  that 
they  have  often  been  regarded  as  primary  ovarian  growths.  Kaufmann 
found  two  ovarian  tumors  weighing  16  pounds.  Their  structure  varies 
greatly  and  may  reproduce  an  alveolar  or  diffuse  carcinoma  or  adenocar- 
cinoma  with  mucous  changes.  In  one  variety  the  cells  are  large,  contain 
mucous  globules,  and  are  distributed  in  small  groups  or  diffusely  in  the  hyper- 
plastic  ovarian  stroma.  This  structure  is  nearly  identical  with  that  described 
by  Krukenberg  as  fibrosarcoma  mucocellulare.  It  has  been  shown  by 
Schlagenhaufer  and  others  that  many  of  the  Krukenberg  tumors  are  secondary 
carcinomas  from  mammary,  gastric,  intestinal,  and  uterine  growths.  That 


650  NEOPLASTIC  DISEASES 

some  of  the  so-called  endotheliomas  of  the  ovary  are  secondary  growths  is 
claimed  by  Polano  and  by  Papaioannou.  Bilateral  ovarian  tumors  and  even 
unilateral  growths  of  this  type  are  so  frequently  secondary  as  to  call  for  a 
careful  search  for  a  primary  growth  and  the  removal  of  both  ovaries  if  one 
is  to  be  resected.  The  mode  of  extension  to  the  ovaries  is  by  peritoneal  im- 
plantation, permeation  through  abdominal  lymphatics,  and  probably  also 
through  the  blood-stream.  When  the  peritoneum  is  extensively  invaded 
implantation  on  the  ovary  readily  follows.  Kraus  argues  that  this  is  the 
most  frequent  method,  and  Sitzenfrey  found  cancer-cells  implanted  between 
the  germinal  epithelium.  In  several  of  the  scirrhous  cases  the  abdominal 
nodes  have  been  extensively  involved  to  the  exclusion  of  other  organs  and 
the  permeation  to  the  pelvis  and  ovary  has  been  traced.  In  some  cases  the 
original  tumor  is  small  and  metastases  are  practically  limited  to  the  ovary. 
Here  it  has  been  assumed  that  tumor-cells  have  passed  the  pulmonary  blood- 
vessels and  found  a  peculiarly  favorable  soil  in  the  ovary,  but  the  possibility 
that  the  ovarian  growth  is  primary  must  be  considered  (Stickel,  Pfannenstiel). 

Of  the  miscellaneous  locations  of  metastatic  growths  may  be  mentioned 
brain,  bones,  kidney  and  adrenal,  and  spinal  cord  or  membranes. 

Direct  extensions  may  also  pass  far  beyond  the  adjacent  organs,  pene- 
trating the  diaphragm,  the  spinal  column,  and  abdominal  wall.  In  48  cases 
of  umbilical  cancer  collected  by  Longuet  and  Quenu,  14  originated  in  the 
stomach  and  passed  along  the  umbilical  lymphatics. 

Histogenesis. — The  origin  of  gastric  cancer  has  been  traced  satisfactorily 
to  altered,  but  previously  normal,  gastric  tubules.  Only  in  certain  rare  cases 
is  there  ground  for  assuming  an  origin  from  congenitally  misplaced  or  em- 
bryonal cell  groups.  Waldeyer  described  in  detail  the  hypertrophy,  cellular 
overgrowth,  and  downward  extension  of  small  groups  of  gastric  tubules  with 
the  development  of  carcinomatous  alveoli  and  invasion  of  lymphatics. 
Hauser  describes  early  adenocarcinomatous  changes  in  small  areas  of  the 
gastric  mucosa.  These  changes  consist  in  elongation  of  a  group  of  glands 
which  become  very  narrow  or  occasionally  dilated  and  joined  to  one  another 
by  numerous  lateral  outgrowths,  so  that  they  form  a  network  of  communi- 
cating acini  in  the  thickened  mucosa.  The  epithelial  cells  become  more 
opaque  and  the  nuclei  hyper  chromatic,  but  they  long  remain  confined  to  a 
single  layer.  The  stroma  is  usually  thinned  and,  while  rich  in  nuclei  of  con- 
nective-tissue cells,  is  poorer  in  lymphocytes  than  the  normal  mucosa. 

These  changes  affect  a  small  area,  i  to  3  cm.  of  the  mucosa,  which  on 
microscopic  examination  reveals  multiple  foci  of  altered  glands  separated 
by  normal  mucosa.  From  these  early  foci  develop  flat  adenomatous  thicken- 
ings and  papillomatous  elevations  which  form  a  relatively  brief  transitional 
stage  to  adenocarcinoma. 

Verse  describes  12  cases  of  beginning  carcinoma  of  the  stomach  (/.  c.,  31 
to  42).  The  lesions  consisted  of  flat  or  papillary  or  polypoid  thickenings  of 
the  mucosa,  from  i  to  5  cm.  in  diameter.  They  occurred  in  subjects  suc- 
cumbing to  other  diseases,  and  in  several  there  were  general  hyperplastic 
or  atrophic  gastritis  and  a  history  of  alcoholism.  The  structure  presented 
elongated,  branched,  and  anastomosing  tubules,  lined  with  one  or  more  rows 
of  hypertrophic  cylindrical  or  cubical  epithelium  with  hyperchromatic 
nuclei.  Many  of  these  tubules  had  perforated  the  muscularis  mucosae. 
At  the  edges  the  gradual  transformation  of  normal  into  neoplastic  tubules 
could  often  be  followed.  In  some  areas  the  line  of  separation  was  sharp, 
or  single  tubules  of  neoplastic  type  lay  among  normal  tubules.  These  small 
lesions  were  often  the  seat  of  purulent  inflammation  and  superficial  ulceration 
sometimes  resulted.  While  the  stroma  was  at  times  overcellular,  Verse  points 


CARCINOMA  OF  STOMACH 


651 


out  that  the  initial  change  was  in  the  glands  and  often  existed  without  any 
proliferation  of  stroma. 

From  these  observations  it  seems  thoroughly  well  attested  that  carcinoma 
of  the  stomach  arises  from  the  previously  normal  glands  through  a  process 
beginning  as  localized  overgrowth  and  that  the  process  is  located  primarily 
in  the  epithelial  cells  which  usually  show-  preliminary  disturbances  of  over- 
nutrition  and  excessive  function.  There  is,  however,  a  considerable  gap 
between  the  ordinary  condition  of  inflammatory  overgrowth  and  definite 
adenocarcinoma  in  the  stomach,  and  this  gap  appears  to  be  bridged,  if  at 
all,  by  a  rather  sharp  morphological  change  which  is  established  rapidly. 
Thus  single  glands  and  minute  groups  of  glands  exhibit  a  pronounced  altera- 
tion while  surrounded  by  normal  or  slightly  altered  tubules.  The  original 
cancerous  area  may  be  single  or  composed  of  multiple  foci  which  later  fuse. 
From  this  area  of  origin  the  tumor  tends  to  grow  from  its  own  elements. 
Yet  during  the  formation  of  the  original  focus  and  to  a  variable  extent 


FIG.  305. — Gastritis  polyposa. 


thereafter  normal  glands  continue  to  be  transformed  into  neoplastic  struc- 
tures. This  lateral  extension  is  more  pronounced  in  the  colon  than  in  the 
stomach. 

G.  Hayem  describes  the  development  of  a  diffuse  scirrhous  cancer  from 
a  diffuse  parenchymatous  gastritis  in  which  the  peptic  glands  seemed  to 
break  down  and  the  granular  acidophile  peptic  cells  spread  through  the  stroma 
giving  origin  to  the  tumor.  I  have  seen  one  early  ulcerating  tumor  which 
recalls  this  description. 

While  the  majority  of  gastric  carcinomas  probably  arise  from  such  focal 
lesions  as  are  described  by  Verse,  another  group  originates  from  more  ad- 
vanced polypoid  or  adenomatous  structures.  The  progress  of  carcinoma- 
tous  changes  in  gastric  polyps  has  been  followed  in  detail  by  Verse.  In 
gastritis  polyposa  a  large  portion  of  all  of  the  mucosa  may  be  the  seat  of 
multiple  outgrowths  and  from  one  or  several  of  these  carcinoma  may  develop. 
As  shown  by  Hause  and  by  Doering  the  natural  termination  of  this  condi- 
tion is  death  from  carcinoma. 


652  NEOPLASTIC  DISEASES 

In  the  development  of  carcinoma  from  peptic  ulcer  the  usual  preliminary 
changes  may  be  traversed,  including  hypertrophy  and  hyperplasia  of  lining 
cells,  enlargement  of  alveoli,  stratification  of  cell  layers,  and  elongation  and 
lateral  sacculation  of  tubules.  Or  the  cells  of  slightly  hyperplastic  tubules 
may  at  once  break  up  into  small  groups  of  atypical  cells  which  from  the  first 
grow  more  or  less  diffusely  in  the  mucosa  (cf.  Hay  em).  The  former  method 
yields  adenocarcinomas  which  later  become  more  atypical,  the  latter  pro- 
duces small  alveolar  and  diffuse  carcinoma. 

The  importance  of  developmental  anomalies  in  the  genesis  of  gastric 
carcinoma  appears  to  be  slight.  Torkel  describes  aberrant  Brunner's  glands 
in  the  pyloric  mucosa  and  finds  a  connection  between  them  and  congenital 
stenosis,  but  they  do  not  appear  to  give  origin  to  malignant  tumors.  Islands 
of  intestinal  mucosa  are  frequently  found  in  the  pyloric  region  and  it  is  pos- 
sible that  they  give  origin  to  certain  carcinomas,  especially  those  of  the 
cylindrical  cell  type.  Such  islands  are  difficult  to  distinguish  from  the  local 
or  general  metaplasia  with  assumption  of  intestinal  characters  occurring 
in  chronic  gastritis,  ulcer,  and  cancer  (Sachs,  Lubarsch,  A.  Schmidt,  Kukobo, 
J.  E.  Schmidt). 

Symptomatology. — For  a  more  detailed  discussion  of  this  subject  consult 
Welch,  Martin,  Riegel,  and  Mathieu. 

Onset. — The  initial  symptoms  of  gastric  cancer  may  be  as  vague  and 
variable  as  their  early  recognition  is  important.  The  previous  digestive  or 
gastric  history  is  almost  wholly  unknown.  Two  groups  of  incipient  cases 
present  themselves  for  diagnosis,  one  in  which  there  has  been  a  definite  history 
of  gastric  disturbance,  and  another  in  which  the  disease  appears  to  arise  in  a 
perfectly  healthy  subject.  The  spontaneous  development  of  the  disease  in 
the  "athletic  stomach"  without  demonstrable  exciting  factors  must  be  doubted, 
yet  many  patients  date  their  illness  from  a  specific  dietetic  error  or  a  trauma, 
or  some  acute  disease  (Hammerschlag).  Long-continued  abuse  of  the  stomach 
is  commonly  overlooked  until  the  disease  reaches  a  certain  stage,  when  it 
produces  symptoms  which  when  once  established  are  usually  persistent. 

Oppression  after  eating  is  a  very  early  sign.  Its  persistence  after  an  acute 
onset  distinguishes  it  from  simple  functional  disturbance.  Pain  is  a  very 
important  early  symptom  which  is  influenced  by  diet,  appears  one  or  two 
hours  after  eating,  or  when  the  stomach  is  empty,  often  worse  at  night,  and 
aggravated  by  exertion.  Chronic  gastritis  does  not,  as  a  rule,  give  persistent 
pain.  Loss  of  flesh  is  an  early  significant  symptom  in  many  cases,  especially 
with  disturbed  motility,  but  is  often  long  delayed.  Regurgitation  appears 
early  and  may  soon  be  succeeded  by  vomiting.  When  pain  and  indigestion 
persist,  a  systematic  search  for  definite  signs  of  carcinoma  is  indicated.  The 
first  of  these  definite  signs  is  usually  the  presence  of  occult  blood  in  stomach 
washings  or  stools.  Repeated  radiographs  of  the  stomach  may  be  of  much 
value  in  early  cases,  especially  of  pyloric  tumors  (Cole).  Gastroscopy  may 
locate  very  early  lesions  of  the  cardia  and  curvature,  and  a  portion  of  a  sus- 
picious ulcer  may  be  successfully  removed  for  examination  (Janeway).  Early 
loss  of  HC1  may  be  expected  only  in  cases  preceded  by  chronic  gastritis. 
Gluzinski's  test  of  relative  deficiency  of  free  HC1  is  highly  recommended  by 
Tabora.  Detection  of  tumor  fragments  in  vomitus  or  in  wash  water  and 
especially  in  blood-clots,  is  always  worth  attempting.  Reineboth  found 
such  fragments  in  5  of  8  cases.  Zoeppitz  points  out  the  nearly  con- 
stant occurrence  of  ulceration  or  erosion  in  early  lesions  and  estimates  the 
frequency  of  early  symptoms  as  follows:  occult  blood,  94.5  per  cent.;  emacia- 
tion, 89.9  per  cent.;  anacidity,  88.9  per  cent.;  lactic  acid,  67.3  per  cent.;  long 
bacilli,  64.4  per  cent.;  palpable  tumor,  63.4  per  cent. 


653 

Complete  loss  of  free  HC1  and  pepsin,  presence  of  lactic  acid  and  Boas- 
Oppler  bacilli,  marked  vomiting,  hematemesis,  and  a  palpable  tumor  belong 
to  the  established  disease,  but  may  appear  as  early  symptoms.  In  all  cases 
accurate  determination  of  the  secretory  and  motor  powers  of  the  stomach 
should  form  a  basis  for  the  interpretation  of  symptoms. 

General  Pathogenesis. — The  relation  of  the  symptoms  and  course  to  the 
anatomical  character  of  the  tumor  is  not  always  distinct,  so  that  clinical  con- 
ceptions of  the  disease  are  not  constructed  from  the  anatomical  standpoint. 
While  it  is  desirable  to  emphasize  such  relations  wherever  they  exist,  clinical 
records  are  not  usually  available  for  such  analysis. 

Several  factors  widen  the  discrepancy  between  clinical  records  and 
anatomical  type.  Chief  of  these  is  the  necessary  period  which  is  clinically 


FIG.  306. — x-Ray  photograph  of  an  extensive  gastric  carcinoma,  involving  whole  of 
pyloric  region,  without  stenosis. 

unobserved.  It  is  extremely  difficult  to  accurately  determine  the  duration 
of  gastric  carcinoma.  Thus  Osier  and  MacCrea  classify  as  clinically  acute 
carcinoma  lesions  which  gave  observed  symptoms  for  one  month,  but  which 
must  have  existed  very  much  longer.  It  seems  probable  that  the  use  of  the 
#-ray  will  eliminate  many  uncertainties  regarding  the  duration  of  gastric 
cancer.  The  studies  of  Rieder,  Fraenkel,  Holzknecht,  Jonas,  Haudek,  v. 
Schmieden,  Cole,  and  others  show  that  it  is  possible  to  locate  and  even  to 
outline  the  lesion  in  gastric  carcinoma  and  to  follow  certain  physiological 
peculiarities  of  the  cancerous  stomach,  so  that  when  other  data  confirm  the 
diagnosis,  attention  may  be  directed  to  the  anatomical  character  of  the  tumor, 
its  operability  and  prognosis.  By  serial  radiographs  Cole  has  been  able  to 
recognize  QO  per  cent,  of  gastric  carcinomas.  The  increasing  attention  of 


654  NEOPLASTIC  DISEASES 

surgeons  to  the  operative  possibilities  on  these  cases  also  bids  fair  to  throw 
much  light  on  the  early  stages  of  carcinoma.  Hence  there  are  some  indica- 
tions that  it  will  soon  be  possible  to  construct  a  clinical  classification  of  gastric 
carcinoma  with  close  reference  to  its  anatomical  types. 

The  location  of  the  tumor  determines  to  a  large  extent  its  course  and 
symptoms.  Pyloric  cancer  is  rather  sharply  distinguishable  from  lesions 
of  the  lesser  curvature.  Ulcero-cancer  of  the  pyloric  region  is  usually 
associated  with  hypersecretion  which  tends  to  cause  spasmodic  contraction 
of  the  pylorus  and  severe  pain.  Motor  insufficiency  develops  early  and  pro- 
fuse hemorrhages  are  more  frequent  with  this  type  of  carcinoma  than  with 
any  other.  Primary  carcinoma  of  the  pylorus  is  not  associated  with  hyper- 


FIG.  307. — x-Ray  photograph  of  localized  carcinoma  causing  complete  obstruction  of 
pylorus  and  dilatation  of  stomach. 

secretion,  but  even  in  its  early  stages  there  is  relative  or  pronounced  acid 
insufficiency  (Gluzinski,  Tabora).  Pain  is  less  severe,  motor  insufficiency 
occurs  early,  and  small  bleedings  are  the  rule. 

Carcinoma  of  the  lesser  curvature  usually  arises  in  cases  with  established 
achylia.  The  pylorus  being  open,  insufficiency  is  delayed.  Pain,  hemorrhage, 
and  cachexia  are  not  prominent,  and  the  disease  may  run  the  course  of 
chronic  gastritis  for  one  or  more  years.  Periods  of  marked  improvement  with 
gain  in  weight  are  not  infrequently  observed. 

Cachexia,  in  gastric  carcinoma,  is  a  complex  condition  in  which  two  main 
factors  are  usually  combined,  (i)  General  dyscrasia  referable  to  infection, 
ulceration,  hemorrhage,  anemia,  pain,  and  loss  of  digestive  capacity,  and 


CARCINOMA  OF  STOMACH 


655 


(2)  the  more  specific  terminal  cachexia  of  carcinoma.  The  latter  is  rarely 
observed,  while  the  former  group  of  factors  dominate  the  clinical  history 
throughout.  In  the  absence  of  such  complicating  conditions  cancer  of  the 
stomach  often  produces  no  effect  upon  health.  In  fact,  a  specific  cachexia 
of  cancer  may  be  practically  eliminated  from  the  symptomatology  of  the 
gastric  disease.  Even  the  toxic  destruction  of  protein  reported  by  F.  Mtiller 
and  Klemperer  may  be  separated  with  difficulty  from  non-specific  influences. 
A  similar  phenomenon  occurs  in  starvation.  Hence  some  patients  remain 
in  fair  health  until  a  late  period  and  even  the  digestion  may  be  little  affected 
(Boas).  For  the  same  reason  marked  temporary  improvement  with  gain  in 
weight  and  relief  of  gastric  symptoms  may  occur  (Friedenwald). 


FIG.  308. — #-Ray  photograph  of  a  bulky  adenocarcinoma  arising  from  lesser  curvature, 
occupying  much  of  the  fundus,  without  pyloric  stenosis  or  dilatation. 

From  the  hematological  standpoint  the  cachexia  is  marantic  or  anemic. 
In  the  marantic  cases  the  blood  is  concentrated  often  to  a  remarkable  degree 
by  vomiting  and  defective  absorption,  so  that  the  patient  may  succumb 
with  over  100  per  cent,  of  Hb  and  polycythemia. 

Anemia  in  cancer  of  the  stomach  is  usually  secondary  and  of  the  chlorotic 
type,  but  it  often  becomes  so  severe  as  to  suggest  a  progressive  pernicious 
type.  Yet  a  low  Hb  index  and  leukocytosis  are  commonly  present.  In  these 
cases  malnutrition  and  repeated  losses  of  blood  from  ulcerating  tumors  are 
the  chief  factors.  Progressive  pernicious  anemia  is  occasionally  associated 
with  gastric  carcinoma.  In  one  group  of  cases  the  anemia  develops  as  a 
sequel  of  the  gastric  disease  and  is  preceded  by  hemorrhages  and  malnutri- 
tion and  occasionally  by  metastases  in  the  bone-marrow  (Frese).  The  tumor 
is  then  extensive  and  ulcerating,  but  in  Israel's  case  it  was  small  but  bleeding. 
I  have  seen  3  cases,  all  ulcerating.  In  another  group  the  gastric  tumor  is  small 


656 


NEOPLASTIC  DISEASES 


and  ulceration  is  missing.  Ehrlich  and  Lazarus  refer  to  3  cases  of  this  type, 
one  a  ring-shaped  growth  of  the  pylorus.  In  a  third  group  the  carcinoma  arises 
in  an  atrophic  mucosa  and  the  anemia  may  be  referred  chiefly  to  the  gastric 
atrophy.  All  these  relations  illustrate  the  peculiar  susceptibility  of  the  bone- 
marrow  in  predisposed  subjects  to  functional  disturbances  of  the  stomach. 

Acidemic  coma  was  first  observed  in  gastric  cancer  by  v.  Jaksch  and 
later  by  Senator,  Riess,  Klemperer,  Osier,  and  others.  The  usual  symptoms 
are  present  and  the  urine  contains  acetone  bodies  in  moderate  amount. 
Klemperer  noted  a  reduction  in  the  total  urinary  nitrogen  in  cases  previously 
showing  an  increase,  and  concluded  that  the  coma  was  referable  to  toxic 
derivatives  of  protein  destruction.  The  tumors  are  usually  large  and  ulcerat- 
ing, but  the  stomach  is  not,  as  a  rule,  dilated.  In  Osier's  case  there  was  a  small 
ulcerating  pyloric  growth.  Tetany  is  occasionally  observed  with  dilatation  of 
the  stomach  from  carcinoma  (Leube).  Progressive  degenerative  neuritis 


FIG.  309. — x-Ray  photograph  of  chronic  indurated  ulcer  of  lesser  curvature  of  stom- 
ach. Note  the  deep  pocket  outlined  by  dotted  line,  leading  into  ulcer.  On  greater 
curvature  is  a  normal  peristaltic  constriction. 

has  been  described  by  Miura  and  Klippel.  Sudden  blindness  from  toxic 
amaurosis  is  reported  by  Deutschmann. 

Relation  to  Anatomical  Varieties. — (i)  Adenocarcinoma  occurs  at  rela- 
tively early  ages.  It  is  the  chief  tumor  observed  in  the  second  decade,  be- 
comes less  prominent  in  the  third  decade,  while  one  group  of  cases  follows 
gastritis  polyposa,  and  miscellaneous  cases  occur  at  any  period.  Its  course 
is  chiefly  determined  by  the  stage  at  which  ulceration  is  established,  and  this 
complication  again  depends  much  on  the  location.  It  is  the  usual  type  of 
tumor  occurring  at  the  cardia,  in  which  situation  it  produces  unusually 
severe  pain,  dysphagia,  and  obstruction  to  the  esophageal  bougie,  while  a 
palpable  tumor  is  absent. 

(a)  At  the  pyloric  or  cardiac  orifice  it  ulcerates  early  and  this  destructive 
process  yields  most  of  the  pronounced  gastric  symptoms,  as  pain,  hemor- 
rhage, vomiting,  and  a  local  tumor,  followed  by  progressive  cachexia.  When 
obstructing  tumors  at  the  pylorus  break  down  the  event  is  often  indicated 


CARCINOMA  OF  STOMACH  657 

by  hemorrhage;  some  relief  of  vomiting,  increased  pain,  and  diarrhea  replacing 
constipation.  Clinical  observations  indicate  that  bulky  tumors  may  be 
excavated,  and  broad  superficial  adenocarcinomas  may  be  widely  eroded  in 
a  few  days,  during  which  the  vomitus,  previously  free  from  blood,  becomes 
bloody  or  chocolate  colored.  The  onset  of  symptoms,  which  may  be  abrupt, 
is  doubtless  preceded  by  a  latent  period,  but  the  active  course  is  usually 
severe  and  relatively  rapid,  but  surgically  considered  this  class  of  patients  is 
more  favorable  than  the  general  condition  might  indicate. 

Gastric  carcinoma  occurring  at  early  ages  is  usually  of  rapid  course  and 
since  adenocarcinoma  is  the  usual  type  in  young  subjects  the  age  of  incidence 
rather  than  any  peculiarity  in  the  growth  seems  to  determine  its  active 
progress.  Yet  in  adults  adenocarcinoma  is  occasionally  very  rapidly  fatal. 
Rohrer's  adult  patient  lived  only  3  months  with  a  rapidly  enlarging  epigastric 
tumor  and  fracture  of  femur  from  metastatic  adenocarcinoma. 


FIG.  310. — Carcinoma  of  pylorus,  with  pyloric  stenosis  and  invasion  of  subpyloric  nodes. 

In  a  similar  case  in  a  young  man  of  27  years  the  first  definite  symptoms 
observed  were  abdominal  pain  and  ascites,  which  led  to  laparotomy,  dis- 
closing multiple  metastases  over  the  peritoneum  from  a  relatively  small 
adenocarcinoma  of  the  pylorus. 

(6)  When  ulceration  is  long  delayed  these  tumors  may  reach  large  dimen- 
sions which  are  readily  palpable  and  when  located  away  from  the  orifices 
or  even  near  them,  they  may  long  remain  latent.  Ulceration  becoming  estab- 
lished leads  to  rapid  excavation  and  at  once  transforms  the  clinical  picture. 
Martin  describes  such  a  case  with  duration  of  symptoms  of  5  weeks,  with 
a  bulky  tumor  at  the  pylorus  and  extensive  metastases  in  the  liver.  They 
form  a  well-defined  group  of  cases  seen  at  autopsy  and  the  clinical  history 
can  usually  be  reconstructed  from  the  gross  appearance  of  the  tumor.  There 
are,  of  course,  many  variations  due  chiefly  to  factors  which  control  the  progress 
of  ulceration,  infection,  and  metastases.  Occasionally  after  a  severe  initial 
42 


658  NEOPLASTIC  DISEASES 

period  the  course  becomes  chronic.    Pronounced  anemia  is  common  and  may 
take  a  pernicious  type. 

(2)  Carcinoma  following  ulcer  is  the  best  defined  clinical  group,  but  the 
certainty  with  which  this  type  of  tumor  may  be  distinguished  from  ulcerating 
primary  carcinoma  is  often  overestimated.     Mathieu  considers  the  condition 
so  distinctive  that  he  describes  it  as  a  separate  clinical  entity  under  the  term 
"ulcerocancer."     Characteristic   cases   are  preceded   by  a   variable  period, 
months  or  years,  of  symptoms  of  ulcer.     The  development  of  carcinoma  is 
marked  by  gradual  diminution  of  free  HC1,  which,  however,  may  persist 
to  the  end;  by  increasing  anemia;  an  advancing  cachexia;  and  the  develop- 
ment of  a  tumor  which  is  usually  small  and  fixed.    As  a  rule,  the  pain  becomes 
more  severe  and  constant,  and  the  vomiting  may  be  aggravated.     Many 
authors  mention  a  selective  anorexia  against  meats.     The  later  course  of 
the  disease  varies  extensively  and  is  determined  chiefly  by  the  location.    Apart 
from  the  previous  history  it  is  not,  as  a  rule,  to  be  distinguished  from  other 
forms  of  advanced  ulcerating  carcinoma. 

The  total  duration  of  the  disease  including  the  period  of  simple  ulcer  is 
much  longer  than  that  of  ulcerating  primary  carcinoma.  Boekelmann 
observed  cases  for  15,  20,  and  29  years.  Yet,  as  a  rule,  after  the  establish- 
ment of  cancer  the  course  is  steadily  progressive  and  rather  rapid  (Mathieu). 

(3)  Gelatinous  carcinoma  is  one  of  the  more  chronic  types  of  the  disease, 
but  it  presents  few  distinctive  clinical  features.     Certain  adenocarcinomas 
undergo  mucoid  degeneration  and  the  history  of  these  cases  is  similar  to 
that  of  the  original   tumor.     The  diffuse  infiltrating  types  of  gelatinous 
carcinoma  usually  cause  contraction  of  the  stomach  and  great  thickening 
of  the  walls  which  may  be  demonstrated  by  x-ray  examination.     Ulceration 
and  hemorrhage  are  less  pronounced  than  with  many  other  types  of  the 
disease.     Many  cases  pursue  a  "latent"  course.     Storer's  case  was  remark- 
able for  the  slight  disturbance  of  digestion,  and  in  Amdion's  case  gastric 
symptoms  appear  to  have  attracted  little  attention.    In  a  case  reported  by 
Osier  and  McCrae  no  marked  gastric  symptoms  were  noted,  the  patients 
presenting  chiefly  nervous  and  mental  symptoms.    In  another  case  the  symp- 
toms began  with  bloody  ascites  and  the  only  gastric  symptom  was  occasional 
vomiting  of  mucus.    Extension  to  the  peritoneum  with  ascites  is  relatively 
common,  but  occurs  also  with  carcinoma  simplex  and  scirrhus. 

(4)  Carcinoma  simplex  is  characterized  clinically  by  its  steadily  progres- 
sive course  and  relatively  short  duration.    The  localized  form  of  this  tumor 
yields  severe  gastric  symptoms,  among  which  hemorrhage  and  pain  are  promi- 
nent.   Deep  ulceration  may  lead  to  fatal  hemorrhage  as  an  early  symptom. 
In  the  diffuse  form  of  carcinoma  simplex  the  gastric  symptoms  are  less  marked. 
The  metastases  which  develop  in  peritoneum,  liver,  lungs,  ovary,  nervous 
system,  and  elsewhere  produce  appropriate  symptoms  which  may  divert 
attention  from  the  stomach. 

A  characteristic  case  originating  in  the  cardial  region  is  that  of  Hosch: 
age  62  years,  initial  symptoms:  vomiting,  dysphagia,  loss  of  flesh  for  4  weeks, 
then  ascites,  supraclavicular  nodes  enlarged  in  sixth  week,  epigastric  tumor 
in  fourteenth  week.  Autopsy  revealed  a  contracted  stomach  diffusely  in- 
filtrated from  cardia  nearly  to  pylorus,  with  extensive  metastases  limited 
to  lymphatic  system. 

(5)  Scirrhous  carcinoma  is  regularly  of  slow  development,  but  the  early 
stages  are  often  latent  and  the  period  of  observed  symptoms  may  be  brief. 
The  clinical  characters  vary  greatly  and  depend  on  the  location  of  the  growth. 

Pyloric  scirrhus  is  one  of  the  more  characteristic  clinical  types  of  the 
disease.  It  frequently,  but  not  always,  produces  pyloric  stenosis  and  dilata- 


CARCINOMA  OF  STOMACH  659 

tion  of  the  stomach  with  characteristic  symptoms  of  this  condition.  Defec- 
tive motility,  constant  presence  of  lactic  acid,  and  absence  of  free  HC1  are 
prominent,  while  hemorrhage  is  slight  or  absent.  Since  stenosis  may  be 
produced  by  any  type  of  tumor  of  the  pyloric  region  these  symptoms  have 
only  limited  diagnostic  value. 

Diffuse  scirrhous  carcinoma  tends  almost  invariably  to  contract  the  stomach, 
so  that  its  capacity  is  small.  Ulceration  is  absent  or  superficial  and  hemor- 
rhages are  reduced  to  a  minimum.  When  the  stomach  is  very  small  it  may 
refuse  to  retain  even  small  quantities  of  fluid. 

(6)  Sderosing  Fibrocarcinoma.  Linitis  Plastica. — The  clinical  features 
of  this  condition  resemble  the  scirrhous  carcinoma  to  which  it  is  closely  related 
anatomically.  The  course  of  the  disease  is  always  prolonged,  but  the  observed 
symptoms  may  be  brief.  Tt  usually  begins  with  a  period  of  months  or  years 
marked  by  dyspepsia.  Later  there  is  pronounced  anorexia,  pain,  tenderness, 
and  frequent  vomiting.  A  transverse  elongated  tumor  may  be  demonstrated. 
Owing  to  the  integrity  of  the  mucosa,  hemorrhage  is  usually  absent.  Free 
HC1  is  diminished  or  absent.  The  x-ray  reveals  a  contracted  organ,  especially 
at  the  pylorus  (Jonas).  In  the  later  stages  peritoneal  extensions  fix  the  pylorus, 
increase  the  gastric  symptoms,  and  cause  ascites.  Pernicious  anemia  may 
dominate  the  picture.  The  terminal  stages  are  marked  by  persistent  vomiting, 
emaciation,  and  cachexia.  Yet  in  several  instances  the  gastric  condition  was 
masked  by  other  diseases  (Viti,  v.  Sury). 

The  duration  in  43  benign  cases  was  found  by  Lyle  to  average  49  months, 
the  shortest  course  being  3  months,  the  longest  20  years.  In  37  definitely 
malignant  cases  the  average  duration  was  23.9  months. 

The  lethal  tendencies  of  the  disease  have  long  been  noted.  The  apparent 
recoveries  3  and  5  years  after  gastro-enterostomy  do  not  affect  the  concep- 
tions of  the  nature  of  the  process,  since  long  survival  after  this  operation 
has  occurred  with  ordinary  scirrhous  cancer  (Le  Count). 

Surgical  Treatment. — Operability. — When  the  disease  is  recognized  early, 
is  confined  to  the  stomach  wall,  inflammatory  adhesions  limited,  and  lymph- 
nodes  not  invaded,  the  prognosis  from  resection  may  be  regarded  as  good. 
In  such  cases  much  depends  on  the  type  of  growth  and  the  probability  of 
discontinuous  metastases.  Most  cases  are  encountered  late,  with  infected 
adhesions  and  involved  lymph-nodes,  and  require  extensive  resection  of 
gastric  tissue  and  all  accessible  nodes.  Even  here  results  are  encouraging. 
Extensive  adhesions  and  invasion  of  nodes  and  surrounding  tissue  preclude 
resection,  but  Petersen  calculates  that  average  life  is  prolonged  5  months  by 
gastro-enterostomy.  Le  Count's  case  indicates  that  the  prolongation  may  be 
much  greater  in  slowly  advancing  tumors  which  may  be  induced  to  undergo 
fibrosis.  Rohdenburg  reports  a  case  which  survived  gastro-enterostomy  for 
10  years.  At  death  from  pneumonia,  cellular  carcinoma  was  still  found  in 
stomach  wall  and  liver,  but  it  had  produced  no  notable  symptoms  (N.  Y. 
Path.  Soc.,  1920). 

The  operative  mortality  has  steadily  diminished.  Matti  (1905)  collected 
rates  from  German  clinics  from  68  to  17  per  cent.  Petersen  at  Heidelberg 
saw  the  mortality  from  resection  fall  from  35  to  1 8  per  cent.,  and  from  gastro- 
enterostomy  from  35  to  17  per  cent.  From  1366  resections  Martin  derived  a 
mortality  of  25  per  cent.  Kocher's  mortality  was  17.7  per  cent.;  Mayo's,  13 
per  cent. 

Curability. — Leriche  collected  89  resections  for  cancer  well  after  3  years. 
H.  J.  Paterson  calculated  that  about  8  per  cent,  of  resections  for  carcinoma 
were  surgically  cured.  Of  101  resections  by  Kocher  up  to  1905,  Matti  re- 
ported 71  leaving  the  hospital,  of  whom  72  per  cent,  died  in  one  month  to 


660  NEOPLASTIC  DISEASES 

6  years,  average  life  18  months,  while  20  patients  remained  well.  Of  252 
pyloric  resections  by  the  Mayos,  the  condition  of  191  was  known,  of  whom 
39  (20  per  cent.)  were  well  after  3  years.  Other  similar  statistics  are  avail- 
able, indicating  that  of  selected  operable  cases  about  20  per  cent,  may  be 
surgically  cured.  Many  of  the  cured  cases  appear  to  have  been  very  early 
and  possibly  doubtful  ulcerocarcinomas.  Even  with  recurrence  Petersen 
ventured  to  calculate  that  resection  prolongs  life  an  average  of  7  months. 
Against  this  result  it  appears  necessary  to  charge  up  the  natural  duration  of 
the  disease,  the  operative  mortality,  and  certain  accelerations  of  course  in 
unfortunately  chosen  cases.  On  the  other  hand,  many  cases,  eventually 
fatal,  enjoy  freedom  from  gastric  symptoms  and  the  stomach  is  found  free 
from  the  disease  (Matti).  Recurrences  are  chiefly  in  liver,  peritoneum,  and 
retroperitoneal  nodes. 

Over  against  this  encouraging  outlook  based  upon  carefully  selected 
material  it  would  appear  from  Peck's  study  that  the  average  case  of  gastric 
cancer  has  little  to  hope  from  surgery.  This  author  collected  527  cases  of 
gastric  cancer  in  the  New  York  hospitals,  which  gave  480  operations,  143 
exploratory,  167  gastro-enterostomies,  98  radical  extirpations  with  an  opera- 
tive mortality  of  28  per  cent.,  33  patients  traced,  23  recoveries  for  a  variable 
period,  and  8  known  to  be  alive  after  3  to  4  years.  Friedenwald  reports  from 
TOGO  cases  266  operations,  138  exploratory,  9  gastrectomies,  i  living  over 
1 8  months,  but  all  dying  of  the  disease. 

The  study  of  individual  cases  is  more  significant  than  combined  statistics. 
Rapidly  growing  diffuse  carcinoma  carries  a  fatal  prognosis  even  with  early 
resection.  Not  a  few  cases  surviving  3  years  eventually  succumb.  The 
permanent  cures  observed  up  to  16  years  at  Kocher's  clinic  appear  to  have 
been  adenocarcinomas.  sometimes  bulky  and  ulcerating,  but  confined  to  the 
wall,  and  ulcerocarcinomas. 

The  surgical  results  support  the  view  that  certain  gastric  carcinomas,  as 
a  rule,  are  not  among  the  very  malignant  tumors.  A  more  careful  analysis 
of  operative  results  with  reference  to  anatomical  condition  is  highly  desirable. 


CHAPTER  XXXII 
CARCINOMA  OF  INTESTINE 

Statistics  collected  by  Stengel  from  German  sources  include  26,340  cases 
of  carcinoma,  2255  intestinal,  8.56  per  cent.  The  U.  S.  census  (1914)  shows 
among  52,420  deaths  from  cancer,  6234  (n.8  per  cent.)  of  the  peritoneum, 
intestine,  and  rectum;  2690  in  males,  3544  in  females,  4  in  infants  under  i 
year,  19  under  5  years,  and  the  highest  incidence  between  60  and  65  years. 
The  cecum  and  appendix  follow  the  rectum  as  the  chief  location.  The  in- 
creasing recognition  of  carcinoma  of  appendix  will  probably  raise  the  pro- 
portion above  previous  records.  Of  3563  cases  of  malignant  tumors  of  the 
intestine  Brill  found  only  89  (2.5  per  cent.)  in  the  small  intestine. 

Carcinoma  of  Duodenum. — From  Geiser's  statistics  it  appears  that  about 
4  per  cent,  of  intestinal  carcinomas  occur  in  the  duodenum.  The  age  of  inci- 
dence is  much  later  than  with  other  intestinal  carcinomas,  being  placed  at 
54  years  by  v.  Heurlin,  or  56  years  by  Geiser. 

Three  distinct  forms  of  this  disease  may  be  recognized:  (i)  Carcinoma 
following  ulcer;  (2)  carcinoma  at  the  papilla  of  Vater.  and  (3)  carcinoma  of 
the  third  portion  of  the  duodenum.  This  classification  corresponds  in  general 
to  the  topographical  division  given  by  A.  Pic,  viz.,  parapytoric,  peri-ampul- 
lary,  and  prejejunal.  Of  40  cases  collected  by  Rolleston,  8  were  in  the  first 
portion,  24  in  the  second,  and  3  in  the  third  portion,  while  the  distribution 
of  Geiser's  71  cases  was  in  the  same  order,  n,  51,  and  9. 

(1)  Carcinoma  following  duodenal  ulcer  has  been  recorded  in  10  cases 
by  Letulte,  Perry  and  Shaw,  and  Nattan-Larier.    Its  location,  chiefly  near 
the  pylorus,  accords  with  the  distribution  of  duodenal  ulcer,  which,  in  Collin's 
262  cases,  occurred  242  times  in  the  first  portion  of  the  duodenum,  14  times 
in  the  second  portion. 

The  gross  anatomy  and  the  symptoms  are  very  similar  to  those  of  pyloric 
ulcerocarcinoma.  Stenosis  and  adhesions  are  usually  present  and  metastases 
are  frequent  and  wide-spread.  The  stomach  is  usually  much  dilated. 
Letulle's  case  showed  colloid  changes  and  gave  secondary  tumors.  In 
Eichorst's  case  the  ulcer  followed  a  burn.  Ewald  found  a  carcinoma tous 
area  in  the  scar  of  a  healed  ulcer.  In  one  case  I  found  it  difficult  to  determine 
the  exact  significance  of  displaced  and  hyperplastic  gland  tissue  in  a  scarred 
duodenum.  Butz  reports  carcinoma  arising  in  an  actinomycotic  ulcer.  I 
have  seen  one  carcinoma  of  pylorus  extending  over  the  first  2  cm.  of  the  duo- 
denal mucosa,  ulcerating  into  gall-bladder,  and  causing  intense  jaundice. 

(2)  Carcinoma  in  the  second  portion  of  the  duodenum  usually  arises  in 
or  about  the  biliary  papilla.    Jaundice  is,  therefore,  an  early  and  very  con- 
stant symptom  occurring  in  23  of  25  cases  quoted  by  Mathieu.    The  jaundice 
is  less  severe  and  persistent  than  with  carcinoma  of  the  ampulla.    Even  in 
advanced  cases  the  occlusion  of  the  duct  may  be  incomplete,  jaundice  may 
be  absent,  and  gastric  symptoms  prominent  (Descos,  Beriel).     Dilatation 
.of  biliary  and  pancreatic  ducts  commonly  occurs  and  fat  necrosis  has  been 
observed  by  Krause,  Gerster,  and  Geiser. 

The  early  tumors  are  usually  papillary  growths  surrounding  the  papilla, 
and  in  this  stage  they  may  prove  fatal  by  biliary  obstruction  and  severe 

661 


662  NEOPLASTIC  DISEASES 

infection.  In  a  case  recently  studied  in  this  laboratory  a  small  duodenal 
papillary  carcinoma  surrounding  the  papilla  proved  fatal  from  a  single  con- 
tinuous hemorrhage.  More  extensive  growths  cause  much  dilatation  of 
biliary  and  pancreatic  ducts,  they  form  protuberant  ulcers  surrounding  the 
common  duct,  or  extend  laterally  over  a  considerable  area.  Geiser  describes 
an  ulcerating  carcinoma  which  secondarily  invaded  the  papilla.  Many  of 
these  tumors  are  difficult  to  distinguish  from  carcinoma  of  the  ampulla. 
Nothnagel  points  out  that  the  former  growths  are  sharply  circumscribed 
about  the  papilla,  while  the  true  duodena!  cancer  tends  to  encircle  or  extend 
along  the  intestine. 

The  structure  is  commonly  that  of  cylindrical-cell  adenocarcinoma  derived 
from  the  intestinal  mucosa.  An  origin  from  Brunner's  glands  has  been  sug- 
gested by  Orth,  and  from  aberrant  pancreatic  tissue  by  several  writers. 
Many  of  the  cases  are  difficult  to  separate  from  primary  cancer  of  the  pancreas. 

(3)  Carcinoma  of  the  third  portion  of  the  duodenum,  prejejunal,  is  rare. 
Geiser  has  collected  9  cases.  Most  of  these  took  the  form  of  a  broad,  flat 
ulceration  with  stenosis.  In  Fenwick's  case  the  ulceration  extended  over  8 
inches  of  the  mucosa,  and  the  duodenum  was  13  inches  in  circumference. 
Above  the  stricture  there  is  dilatation  of  duodenum  and  stomach,  and  gastric 
symptoms  with  vomiting  of  considerable  quantities  of  bile  are  prominent. 
Icterus  is  absent.  In  Syme's  case  the  ulceration  was  slight  and  the  vomitus 
was  free  from  bile.  In  2  of  Geiser's  cases  there  were  more  bulky  tumors  with 
ulceration  and  perforation  of  the  wall,  but  without  much  stenosis.  Local 
extensions  or  local  or  general  metastases  were  usually  present.  The  structure 
presented  cylindrical-cell  adenocarcinoma  or  alveolar  carcinoma. 

Carcinoma  of  Ileum  and  Jejunum. — Carcinoma  of  the  small  intestine 
is  comparatively  rare,  forming  about  3  per  cent,  of  all  intestinal  cancers. 
It  occurs  at  a  comparatively  early  age,  average  46^  years,  relatively  often 
before  40  years,  and  Duncan  records  a  scirrhous  cancer  in  a  child  of  3^  years. 
Schleips  in  1908  analyzed  43  cases,  28  in  males.  In  location  the  tumors  in- 
crease in  frequency  as  one  approaches  the  stomach  above  and  the  colon  below. 

The  disease  occurs  in  three  somewhat  distinct  forms  as  (i)  a  part  of  a 
local  or  general  intestinal  polyposis,  (2)  a  late  development  of  single  or  multiple 
carcinoid  tumors,  and  (3)  as  a  localized  adenocarcinoma  with  carcinomatous 
variations  in  structure. 

In  all  of  these  forms  certain  general  features  appear.  The  tumors  may 
produce  polypoid  outgrowths  obstructing  the  lumen,  or  the  lesions  may 
ulcerate  early,  or  the  main  result,  may  be  stenosis  from  invasion  of  muscular 
and  subserous  coats.  Often  there  is  dilatation  of  the  bowel  above  the  tumor, 
and  when  the  tumor  lies  in  the  upper  jejunum  the  disease  may  simulate 
pyloric  stenosis  (Riegel,  Routier). 

(i)  Carcinoma  following  intestinal  polyposis  is  rare  in  the  small  intestine, 
the  great  majority  of  such  cases  affecting  the  colon. 

Niemack  reported  papillary  adenoma  in  the  lower  ileum  in  a  child  of  12 
years  in  whose  colon  were  many  small  polyps.  Petrow  found  many  polyps 
in  stomach,  duodenum,  and  jejunum,  with  adenocarcinomatous  structure  in 
the  jejunum.  In  Kukula's  case  there  was  a  cylindrical  dilatation  extending 
over  8  cm.  of  the  jejunum,  with  polypoid  outgrowths  in  the  vicinity  and 
carcinomatous  metastases  in  the  mesentery.  Thorel  found  a  large  adeno- 
carcinoma of  the  lower  ileum,  20  polyps  in  the  ileum  and  one  in  the  colon. 
Kuttner  considers  that  some  multiple  carcinomas  of  the  ileum  with  stenosis 
arise  from  intestinal  polyposis,  as  in  Hahn's  case  in  which  there  were  four 
strictures  in  the  lower  ileum,  but  it  seems  more  probable  that  the  multiple 
stenosing  carcinomas  arise  from  the  carcinoid  tumors  of  Lubarsch.  Yet  in 


CARCINOMA  OF  INTESTINE 


663 


one  of  Kuttner's  cases  there  were  18  strictures  in  the  small  and  4  in  the  large 
intestine. 

(2)  Multiple  benign  embryonal  carcinoid  tumors  of  the  intestine  constitute 
a  peculiar  group  of  tumors  of  the  small  intestine  first  described  by  Lubarsch. 
They  are  found  in  ileum,  jejunum  and  mesentery,  and  probably  in  the  appen- 
dix, in  the  form  of  single  or  multiple,  firm,  opaque  nodules  as  large  as  a  pea 
or  bean.  They  lie  in  the  mucosa  or  submucosa  and  the  muscularis  mucosa 
may  be  lost  in  the  stroma  of  the  tumor.  In  structure  they  form  three  groups, 
resembling  (a)  pancreatic  island  tissue,  (6)  heterotopic  intestinal  mucosa,  or 
(c)  Brunner's  glands.  Most  of  the  tumors  have  been  referred  to  heterotopic 


FIG.  311. — Small  carcinoma  of  ileum  causing  marked  stenosis,  with  dilatation  above. 

intestinal  glands,  and  Notthaft  found  a  direct  connection  with  the  normal 
follicles.  The  cells  then  form  compact  densely  staining  groups  with  traces  of 
alveolar  arrangement  or  with  mucous  foci  producing  the  appearance  of  cylin- 
droma.  The  endothelium  of  the  lymph  spaces  may  be  hyperplastic,  but  does 
not  participate  in  the  tumor  process  (Lubarsch).  The  resemblance  to  basal- 
cell  carcinoma  has  been  noted  by  Bunting  and  Oberndorfer.  Smooth  muscle- 
tissue  may  be  found  in  the  stroma  and  such  growths  have  been  described 
by  Trappe  and  others  as  adenomyoma.  The  prominence  of  muscle-tissue 
and  the  more  typical  adenomatous  structure  serve  to  distinguish  the  adeno- 
myomas  from  the  carcinoid  tumors.  A  congenital  misplacement  of  tissue 
must  be  assumed  for  the  adenomyomas,  while  the  carcinoid  tumor  may  be 


664 


NEOPLASTIC  DISEASES 


satisfactorily  derived  from  acquired  inflammatory  heterotopia  and  over- 
growth. 

In  another  group  the  structure  resembles  the  parenchyma  or  islands 
of  Langerhans  of  the  pancreas.  In  fact,  Saltykow  considers  that  all  the  tumors 
represent  heterotopic  pancreatic  nodules.  The  cells  are  cylindrical,  cubical 
or  rounded,  and  they  surround  pervious  or  closed  capillaries,  sometimes  in 
rosette  form,  or  exactly  reproducing  islands  of  Langerhans.  Heterotopic 
Brunner's  glands  were  identified  in  portions  of  a  carcinoma  described  by 
Schapper. 

The  significance  of  these  small  tumors  has  been  much  discussed.  In 
their  simplest  form  they  probably  represent  anomalies  of  development  and 
misplacement  of  gland  tissue  and  are  not  true  tumors  (Toennissen,  Saltykow). 


FIG.  312. — Gelatinous  carcinoma  of  duodenojejunal  flexure. 

Yet  others  show  various  grades  of  cellular  overgrowth  and  invade  the  sub- 
mucosa  and  muscularis  and  are  true  scirrhous  neoplasms  (Verse).  In  this 
form  they  long  remain  localized,  although  sometimes  reaching  sufficient  size 
to  obstruct  the  lumen.  Others  again  form  the  source  of  malignant  carcinomas 
and  produce  metastases.  Thus  Ransom  found  extensive  secondary  tumors 
in  the  liver.  Verse  found  metastases  in  the  lymph-nodes  with  a  small 
intestinal  growth  and  malignant  cases  are  described  by  Saltykow  and 
Schapper.  It  is  probable  that  many  small  simple  primary  carcinomas  of 
the  intestine  and  appendix  with  metastases  originate  in  this  way. 

(3)  The  third  group  of  intestinal  carcinomas  includes  lesions  which  arise 
under  various  conditions.  Some  develop  from  single  intestinal  polyps  and 
tend  to  maintain  an  adenocarcinomatous  structure.  The  majority  of  in- 
testinal carcinomas  are  of  this  type.  When  ulceration  is  delayed  the  tumors 
may  reach  a  size  sufficient  to  obstruct  the  lumen  (Riedel).  Ulceration  and 


CARCINOMA  OF  INTESTINE  665 

stricture  more  commonly  result  and  the  structure  becomes  more  atypical 
and  scirrhus.  Metastases  in  mesentery,  liver,  lungs,  peritoneum,  or  elsewhere 
were  present  in  16  of  42  cases  collected  by  Schleips  and  adhesions  were  much 
more  frequent.  That  carcinoma  may  result  from  catarrhal,  typhoidal, 
or  other  forms  of  intestinal  ulcers  seems  possible,  but  definite  observations 
are  wanting.  It  is  difficult  to  separate  tumors  of  this  group  from  those  arising 
from  carcinoid  growths,  but  the  former  are  usually  adenocarcinomatous, 
bulky,  and  more  malignant;  the  latter  atypical,  scirrhous,  and  comparatively 
benign.  Gelatinous  adenocarcinoma  is  described  by  Marckwald  and  by 
Kanzler. 

Carcinoma  of  Appendix. — The  occurrence  of  carcinoma  of  the  appendix 
has  long  been  recognized,  but  its  importance  was  first  suitably  emphasized 
in  1903  by  Elting  and  by  Moschkowitz.  It  is  interesting  to  note  how  the 
recorded  cases  of  this  form  of  carcinoma  have  increased  in  proportion  to  the 
attention  devoted  to  it. 

Of  intestinal  carcinomas  the  appendix  furnished  about  0.39  per  cent,  in 
Batzdorff's  collection  of  2336  cases,  but  this  proportion  is  probably  much  too 
low.  Of  13,083  appendices  removed  at  operation  and  included  in  the  lists 
of  Batzdorff,  McCarthy,  and  the  Bender  Laboratory,  there  were  60  cases  of 
carcinoma,  0.46  per  cent.  Batzdorff  refers  to  186  recorded  cases.  Over  50 
per  cent,  are  found  with  chronic  appendicitis  (Zaaijer),  or  85  per  cent.,  accord- 
ing to  Milner.  The  age  of  incidence  has  been  from  5  to  80  years,  and  chiefly 
in  the  third  decade,  while  other  intestinal  carcinomas  occur  chiefly  in  the 
sixth  decade. 

Gross  Anatomy. — The  tumors  are  located  chiefly  at  the  tip  of  the  appendix 
(59  per  cent.),  which  is  moderately  swollen  and  stenosed  or  contains  a  small 
tumor  nodule  which  is  readily  overlooked  and  requires  microscopic  identifi- 
cation. Over  half  the  tumors  were  recognized  only  after  laying  open  the 
appendix  (McWilliams).  In  more  advanced  stages  there  is  a  definite  tumor 
and  the  appendix  is  inflamed  and  bound  by  adhesions.  In  several  cases  the 
whole  organ  was  diffusely  enlarged  (Kudo) .  Cystic  forms  of  the  disease  occur, 
especially  when  there  is  mucous  degeneration  of  the  tumor  and  the  mass  may 
be  composed  of  a  fibrous  wall  and  gelatinous  contents  (Rokitansky).  Whether 
the  disease  may  produce  the  typical  condition  known  as  mucocele  remains 
uncertain,  but  is  not  improbable.  Many  mucoceles,  however,  are  free  from 
any  tumor  element.  An  irregular  cicatrix  deforming  the  organ  and  obliter- 
ating the  lumen  has  been  described  in  several  instances.  Rarely  the  lesion 
takes  the  form  of  an  ulcer  (Baldauf).  At  the  ileocecal  valve  the  tumor  may 
project  into  or  constrict  the  cecum  and  be  difficult  to  distinguish  from  a  tumor 
of  the  cecum  (Draper). 

Extension  of  the  tumor  process  beyond  the  appendix  is  relatively  un- 
common, occurring  in  about  6  per  cent,  of  the  cases  (Batzdorf).  The  mesen- 
teric  and  retroperitoneal  nodes  are  first  involved.  Extensive  peritoneal 
carcinosis  was  observed  by  Elting,  Konjetzny,  Kelly,  and  Neugebauer.  In 
Whipham's  case  the  patient  died  with  secondary  growths  in  nodes,  liver,  and 
ovary.  Ruyter's  tumor  was  found  in  the  stump  of  an  amputated  appendix. 
As  a  rule  the  cases  with  metastases  have  been  of  the  columnar  cell  or  gelatinous 
type. 

The  clinical  course  is  usually  merged  with  that  of  chronic  appendicitis 
(McWilliams,  Rolleston,  Jones,  Lit.). 

Structure.— Two  main  varieties  of  the  tumor  appear:  (i)  columnar  cell 
or  gelatinous  adenocarcinoma,  and  (2)  small  polygonal,  spheroidal  cell, 
alveolar  carcinoma.  The  former  type  presents  the  same  age  incidence  (52 
years)  and  general  malignancy  as  other  similar  intestinal  carcinomas,  while 


666  NEOPLASTIC  DISEASES 

the  former  occur  at  any  early  age  and  are  almost  invariably  benign  (Rolleston, 
Jones).    Transitional  forms  of  intermediate  age  incidence  are  observed. 

The  columnar  cell  tumors  show  the  usual  structure  of  small  or  large 
alveolar  adenocarcinoma.  In  the  gelatinous  tumors  mucous  degeneration 
may  be  extensive  and  destroy  most  of  the  tumor-cells.  In  the  small  alveolar 
type  the  cells  are  composed  chiefly  of  nuclei  which  are  large  and  hyperchro- 
matic.  They  are  compactly  grouped  in  small  or  large  masses  and  foci  of 
mucous  degeneration  may  give  the  structure  of  cylindroma.  The  appearance 
often  resembles  that  of  basal-cell  carcinoma.  The  stroma  may  be  scanty  or 
so  abundant  as  to  give  a  scirrhous  structure.  Both  of  these  tumors  are  prob- 
ably derived  from  the  gland  crypts.  The  small-cell  tumors  seem  to  be  homol- 


FIG.  313. — Carcinoma  of  appendix. 

ogous  with  the  small  multiple  tumors  of  the  ileum  described  by  Lubarsch, 
Bunting,  and  others. 

In  some  cases  the  epithelial  cells  possess  little  growth  capacity  and  become 
more  intimately  incorporated  with  the  increasing  stroma  so  that  the  struc- 
ture resembles  that  of  endothelioma  arising  from  the  lymph  spaces  of  inflam- 
matory connective  tissue.  These  cases  have  apparently  been  interpreted 
as  endothelioma  by  Glazebrook,  A.  O.  J.  Kelly,  and  others.  Sudsuki  and 
Milner  regard  this  structure  as  indicating  an  inflammatory  origin  and  hold 
that  the  great  majority  of  appendix  carcinomas  are  spurious.  Yet  the  ten- 
dency of  fibrosing  basal-cell  carcinoma  to  suggest  an  endothelial  origin'  is 
well  known. 

The  occurrence  of  a  specific  type  of  carcinoma  in  an  atrophying  organ 
which  is  often  the  seat  of  chronic  inflammatory  changes  is  of  much  theo- 


CARCINOMA  OF  INTESTINE  667 

retical  interest,  and  its  peculiar  structure  and  benign  course  serve  to  empha- 
size the  principle  that  each  organ  has  its  own  forms  of  carcinoma. 

Carcinoma  of  Large  Intestine. — Statistical. — At  the  Pathologic  Institute 
at  Vienna,  between  1870  and  1893,  343  intestinal  carcinomas  came  to  autopsy, 
of  which  164  were  in  the  colon  and  162  in  rectum,  while  only  7  were  found  in 
the  duodenum  and  n  in  the  ileum  (Nothnagel).  Schleips  collected  542 
intestinal  carcinomas,  of  which  259  were  in  the  colon,  257  in  rectum,  20  in 
duodenum,  16  in  ileum.  In  Brill's  statistics  covering  3563  intestinal  tumors 
97.5  per  cent,  were  in  the  colon,  appendix,  or  rectum.  The  tumors  increase 
in  frequency  from  the  cecum  toward  the  rectum.  Of  123  intestinal  carci- 
nomas Kaufmann  found  36  in  the  colon,  28  in  sigmoid,  and  51  in  rectum.  He 
also  states  that  over  60  per  cent,  of  intestinal  carcinomas  and  5.25  per  cent, 
of  all  carcinomas  occur  in  the  rectum,  which  is,  therefore,  fifth  in  the  list  of 
primary  seats  of  cancer.  Of  297  colon  carcinomas  reported  by  Korte, 
Petermann,  and  Anschutz,  47  were  in  cecum,  22  in  ascending  colon,  19  at 
hepatic  flexure,  44  in  transverse  colon,  31  at  splenic  flexure,  10  in  descending 
colon,  1 24  in  sigmoid. 

Lonart  collected  61  cases  of  carcinoma  of  large  intestine  between  the 
ages  of  20  and  30  years.  The  disease  is  rather  frequently  observed  at  much 
earlier  periods,  in  the  cecum  at  12  years  (Nothnagel),  in  the  rectum  at  n  to 
17  years  (Czerny,  Stern,  Schoning"),  in  the  sigmoid  at  12  years  (Garrard), 
in  the  colon  at  3  years  (Clar) . 

General  Etiology. — A  tissue  predisposition  appears  definitely  only  in  those 
cases  arising  on  multiple  polyposis.  The  carcinomatous  transformation 
of  single  polyps  is  described  by  Hauser,  Kraske,  Verse,  Allen,  and  many 
others.  In  the  origin  of  these  polyps  a  previous  abnormality  of  structure 
is  to  be  assumed. 

Although  carcinoma  often  develops  in  subjects  of  hemorrhoids,  and  this 
relation  has  been  emphasized  by  Volkmann,  there  is  no  satisfactory  evidence 
that  cancer  develops  in  tissues  altered  by  hemorrhoids,  fistulie,  or  cicatrices 
(Kraske).  The  slow  development  of  rectal  carcinoma  extending  over  2  or 
3  years  suggests  rather  that  the  early  symptoms  commonly  referred  to  hemor- 
rhoids are  due  to  the  beginning  carcinoma.  On  the  other  hand,  the  sudden 
development  of  carcinoma  is  a  common  result  and  an  early  symptom  of  rectal 
carcinoma.  Zinner  reports  that  38  per  cent,  of  his  cases  of  carcinoma  of  pars 
perinealis  complained  of  hemorrhoids.  It  is  somewhat  remarkable  that  carci- 
noma very  rarely  develops  in  chronic  ulcerative  proctitis  or  colitis. 

The  traumatic  origin  of  rectal  carcinoma  has  occasionally  been  asserted. 
Illustrative  cases  have  been  reported  by  Goeckel,  Korte,  and  Anschutz.  The 
age  of  incidence  is  later  than  with  other  intestinal  carcinomas.  Cripps 
in  380  rectal  cases  found  between  20  and  30  years  3  cases;  30  and  40  years, 
21 ;  40  and  50  years,  78;  50  and  60  years,  93;  60  and  70  years,  119;  70  and 
80  years,  53;  over  80  years,  4.  The  incidence  of  colon  carcinoma  is  much 
earlier. 

Some  general  and  many  special  factors  favor  the  development  of  carci- 
noma in  this  region.  Anatomical  relations  influence  the  development  of 
tumors  at  the  ileocecal  valve,  at  the  junction  of  the  appendix,  at  the  rectal 
folds,  and  at  the  anus,  where  there  are  more  or  less  definite  interruptions  of 
the  structure  of  the  intestinal  wall.  The  considerable  number  of  cases  occur- 
ring in  children  indicates  that  developmental  anomalies  at  these  points  serve 
as  sources  of  carcinoma.  While  various  gross  abnormalities,  as  megacolon 
or  megasigmoideum,  atresia  recti,  and  diverticula  sufficiently  indicate  the 
frequency  of  disturbed  development,  none  of  these  conditions  seems  to  be 
directly  connected  with  tumors  (Mya,  Lowenstein,  Keibel,  Stieda).  Kraske 


668  NEOPLASTIC  DISEASES 

could  find  no  grounds  for  assuming  that  misplaced  embryonal  tissue  is  con- 
cerned in  the  development  of  rectal  carcinoma.  He  reported  2  cases  of  adeno- 
carcinoma,  probably  derived  from  embryonic  rests,  but  the  tumors,  which 
were  of  considerable  size,  lay  behind  the  rectum,  were  attached  to  the  bones, 
and  secondarily  involved  the  rectal  mucosa.  Similar  cases  are  reported  by 
R.  Meyer  and  Cohn.  The  chief  factors  leading  to  carcinoma  are  irritations 
acting  most  effectively  at  relatively  fixed  points,  as  cecum,  the  flexures,  and 
the  rectal  valves.  More  than  half  the  rectal  cancers  arise  between  2  and  4 
inches  above  the  anus  (R.  Williams).  Kraske,  however,  finds  most  carcinomas 
in  the  upper  rectum,  so  that  excision  requires  opening  the  peritoneum.  Zinner 
explains  the  high  proportion  of  rectal  carcinomas  on  the  anterior  wall  (75 
per  cent.)  as  the  result  of  pressure  against  the  prostate. 

The  gross  and  microscopical  anatomy  presents  several  distinct  forms 
ivhich  give  a  satisfactory  basis  for  clinical  and  pathological  classification. 
These  include:  (i)  Adenoma  destruens;  forming  a  broad  superficial  ulcerating 
tumor  with  obstruction,  (2)  stenosing  fibrocarcinoma;  (3)  gelatinous  adeno- 
carcinoma;  (4)  bulky  polypoid  or  papillary  carcinoma  derived  from  polyps; 
(5)  multiple  carcinoma  following  polyposis;  (6)  acanthoma;  (7)  melanoma. 
The  frequency  is  in  the  same  order. 

In  nearly  all  cases  secondary  infection  plays  a  prominent  part  in  the 
progress  of  the  lesion,  causing  local  or  spreading  suppuration,  peritonitis, 
fistulous  tracts,  and  communications  between  adjoining  coils  of  colon,  or 
with  stomach,  small  intestine,  and  bladder.  Above  the  tumor  the  intestine 
is  usually  dilated,  hypertrophied,  chronically  inflamed  or  thinned,  and  even 
subject  to  perforation.  These  secondary  conditions  are  almost  wholly  re- 
sponsible for  the  cachexia  which  develops  and  which  may  be  duplicated  by 
similar  inflammatory  processes  without  carcinoma.  Hence  few  subjects 
of  this  disease  succumb  because  of  the  extent  of  the  tumor. 

It  is  a  rule  to  which  there  are  notable  exceptions  that  carcinoma  of  the 
colon  and  rectum  is  only  moderately  malignant.  The  course  is  compara- 
tively slow,  extensions  beyond  the  intestinal  wall  occur  late,  and  metastases 
are  less  frequent  than  with  similar  growths  in  other  regions.  Hauser  points 
out  that  gelatinous  tumors  tend  to  perforate  the  wall  and  produce  metastases 
in  peritoneum  and  adjoining  nodes,  and  rarely  in  the  bone-marrow,  medullary 
carcinoma  limits  its  metastases  to  lymph-nodes,  while  scirrhous  tumors  often 
produce  growths  in  the  liver.  Zinner  supports  these  conclusions. 

Lymphatics. — The  lymphatics  of  the  colon  follow  the  blood-vessels  of 
the  mesenteric  system.  In  the  rectum  the  lymph  system  is  more  complex. 
Gerota  describes  four  rectal  groups:  (i)  The  anal  vessels  form  4  to  5  branches 
which  traverse  the  skin  of  the  perineum  and  thigh  and  reach  inguinal  nodes 
in  Scarpa's  triangle.  Other  deeper  branches  join  with  those  of  the  zona  inter- 
media and  reach  the  anorectal  nodes.  (2)  Branches  from  the  zona  inter- 
media pass  backward  and  follow  the  superior  hemorrhoidal  veins,  to  the 
anorectal  nodes,  but  occasional  branches  pass  to  a  node  at  the  foramen  ischiad- 
icum  (Quenu's  node).  (3)  Branches  from  the  zona  columnaris  follow  the 
same  course.  (4)  The  pars  pelvina  is  drained  by  vessels  which  pass  below  to 
the  anorectal  nodes  and  above  to  the  mesenteric  nodes  of  the  colon.  Lymph- 
nodes  are  missing  'in  the  wall  of  the  anal  portion,  but  in  the  fat  tissue  lying 
between  the  muscular  wall  of  pelvic  and  intermediate  segments  and  the 
rectal  fascia  lymph-nodes  (anorectal)  are  abundant.  Metastases  in  adjacent 
lymph-nodes,  while  common  in  autopsy  material,  are  less  frequent  in  opera- 
tive cases.  In  59  postmortems  collected  by  Kraske  and  Iverson  metastases 
were  present  in  32  in  nodes,  liver,  peritoneum,  lungs,  and  brain.  They  usually 
reproduce  the  original  structure.  From  these  data  and  from  the  long  dura- 


CARCINOMA  OF  INTESTINE  669 

tion  of  most  cases  it  is  clear  that  carcinoma  of  the  intestine  is  a  favorable 
field  for  aggressive  surgery. 

The  surgical  treatment  of  rectal  carcinoma  is  in  a  very  unsatisfactory 
state,  chiefly  because  of  the  failure  of  early  diagnosis.  Although  this  disease 
gives  symptoms  in  its  early  stages,  it  is  a  general  experience  to  find  that  60 
to  70  per  cent,  of  these  cases  are  treated  for  weeks  or  months  for  piles,  or 
catarrh,  or  other  vague  benign  conditions,  and  that  a  competent  rectal  exami- 
nation is  delayed  or  omitted.  Moreover,  true  adenoma  destruens  early  pene- 
trates the  muscularis,  transforming  a  comparatively  simple  into  a  very  difficult 
therapeutic  problem. 

The  proportion  of  cases  deemed  operable  was  found  by  Kuttner  to  be 
32  per  cent.;  by  Cripps,  25  per  cent.;  by  Tuttle  and  Lynch,  31  per  cent.  The 
operative  mortality  runs  rather  uniformly  about  15  per  cent.,  but  varies  in 
German  clinics  from  6.4  to  32  per  cent.  Pennington  collected  966  records 
of  operations  which  gave  218  3-year  survivals.  Of  753  cases  applying  at  the 
Mayo  Clinic,  430  were  operated  upon;  364  recovered  from  the  operation: 
of  these,  excluding  cases  operated  upon  less  than  3  years  before,  33  per  cent, 
lived  3  years  or  more,  28.5  per  cent.  5  years  or  more.  Of  Kuttner's  1021 
cases,  32  per  cent.  (316)  were  operable,  of  whom  32.5  per  cent.  (117)  survived 
more  than  3  years,  21.6  per  cent.  (76)  over  5  years,  16.4  per  cent.  (58)  over 
8  years,  12.8  per  cent.  (45)  over  10  years,  while  42  died  from  recurrence  be- 
tween the  third  and  tenth  years. 

Histo  genesis. — The  histogenesis  of  carcinoma  of  the  large  intestine  has 
been  fully  traced  by  Hauser,  Verse,  and  others.  It  has  been  shown  that  the 
disease  arises  usually  in  a  circumscribed  area  of  mucosa  in  which  the  glands 
become  enlarged,  the  lining  cells  hypertrophied  and  multiplied,  the  production 
of  mucous  cells  increased,  and  the  lumina  elongated  and  bifurcated.  The 
neoplastic  alveoli  soon  break  through  the  muscularis  mucosae  and  extend 
along  the  submucosa,  often  reaching  the  surface  at  lateral  points,  and  thus 
extending  the  lesion  or  penetrating  the  muscularis  along  lymph  and  blood 
paths.  In  the  early  stages  of  most  cases  and  in  some  throughout  the  disease 
there  is  a  gradual  extension  of  the  area  of  origin  by  the  progressive  trans- 
formation of  normal  into  neoplastic  alveoli.  This  process  is  more  pronounced 
in  the  colon  than  in  the  stomach  and  is  often  indicated  by  a  peripheral  zone 
of  papillary  outgrowths  of  mucosa  about  the  ulcerated  tumor,  as  well  as  by 
microscopical  evidence  of  such  transition.  Similar  transitions  have  been 
traced  in  originally  benign  polyps. 

The  extent  to  which  the  lateral  growth  proceeds  by  this  method  is  diffi- 
cult to  determine.  In  some  cases  there  is  a  very  wide  superficial  tumor  in- 
volving 10  to  15  cm.  of  the  mucosa,  a  form  strongly  suggesting  a  gradual 
inclusion  of  normal  areas  of  mucosa.  The  structure  is  then  typical  malignant 
adenoma. 

In  more  atypical  and  rapidly  growing  tumors  the  lateral  extension  is 
slight  and  exclusively  by  invasion  and  replacement  of  normal  glands  by 
tumor-cells. 

In  intestinal  polyposis  the  transition  of  hypertrophic  mucosa  and  papillae 
into  multiple  carcinoma  has  been  clearly  traced  (Bardenhauer,  Wulf,  Verse, 
Doering).  In  certain  cases  of  chronic  colitis  in  young  subjects  preceding 
definite  polyposis  the  entire  mucosa  is  lined  by  markedly  hypertrophic  epi- 
thelium closely  resembling  adenoma  destruens,  but  lacking  the  heterotopia 
of  a  neoplasm. 

Anatomical  Varieties. — (i)  Adenoma  destruens  produces  at  first  circum- 
scribed elevations  in  the  mucosa  which  gradually  extend  deeply  and  laterally, 
obstructing  the  bowel  and  soon  ulcerating.  At  the  ileocecal  valve  it  pro- 


670 


NEOPLASTIC  DISEASES 


duces  a  fungating  tumor  inclosing  the  orifice  without  marked  stenosis 
(Kaufmann).  In  the  cecum  the  tumors  are  usually  bulky  and  ulcerating, 
with  obstruction  of  the  lumen,  fistulae,  and  anastomoses.  Particularly  wide 
superficial  extension  is  often  observed  in  the  colon  proper,  as  in  Hauser's 
cases.  I  have  seen  14  inches  of  the  transverse  colon  involved  in  a  cylindrical 
tumor  with  few  adhesions.  In  the  sigmoid  and  rectum  adenoma  destruens 
is  the  common  tumor,  and  here  early  ulceration,  obstruction,  and  local  exten- 
sions are  relatively  early. 

The  structure  presents  the  most  typical  form  of  malignant  adenoma,  and 
its  usual  variations.    In  some  cases  the  structure  is  more  atypical  and  car- 


FIG.  314. — An  early  circumscribed  malignant  adenoma  of  sigmoid. 

cinomatous  and  occasionally  the  growth  is  highly  atypical,  diffuse,  and  re- 
sembles lymphosarcoma. 

(2)  Stenosing  fibrocarcinoma  produces  first  a  superficial  ulcer  with  pro- 
nounced induration  due  to  fibrosis.  The  lesion  may  be  circumscribed  while 
involving  all  the  coats,  but  there  is  a  tendency  to  encircle  the  lumen  and 
produce  a  tight  annular,  structure,  with  its  various  complications.  In  ad- 
vanced stages  of  sclerosing  and  other  carcinomas  the  length  as  well  as  the 
lumen  of  the  affected  segment  is  reduced  at  times  to  a  remarkable  degree. 
This  result  is  due  to  cicatricial  contraction  and,  as  Schuchardt  explains,  to 
loss  of  tissue  by  ulceration.  Small  annular  strictures  of  the  intestines  may 
occur  at  any  point.  Korte  reports  three  of  the  transverse  colon,  six  of  the 


CARCINOMA  OF  INTESTINE 


671 


splenic  flexure,  and  several  of  sigmoid.  These  annular  tumors  may  be  multiple 
(Brosch). 

The  structure  of  this  tumor  usually  presents  diffusely  growing  small 
groups  of  atypical  cells  widely  infiltrating  the  coats  of  the  intestine  and  the 
abundant  new  connective  tissue.  Transition  stages  from  adenoma  destruens 
and  adenocarcinoma  are  often  found  and  suggest  that  the  process  begins 
as  adenoma  destruens  and  that  early  ulceration  in  a  relatively  resistant  tissue 
leads  to  early  fibrosis  and  cicatrization.  Yet  this  tumor  infiltrates  neigh- 
boring tissues  and  nodes  rather  early  and  offers  an  unfavorable  surgical 
prognosis,  unless  excision  occurs  before  the  intestine  becomes  fixed. 

(3)  Gelatinous  adenocarcinoma  of  the  large  intestine  is  rather  frequent 
and  occurs  both  in  the  colon  and  in  the  rectum.  Kanthack  and  Furnival 
described  such  a  tumor  of  the  ascending  colon  in  a  boy  of  17  years.  Israel 


FIG.  315. — Structure  of  a  bulky  gelatinous  carcinoma  of  colon. 

reports  a  case  in  the  splenic  flexure  in  a  boy  of  13  years.  Among  51  colon 
tumors  Korte  had  six  of  the  gelatinous  type,  while  of  Zinner's  123  cases  of 
rectal  tumors  41  per  cent,  were  gelatinous.  It  is  characterized  by  a  tendency 
to  spread  widely  over  a  considerable  length  of  intestine,  by  the  production 
of  a  bulky  tumor  mass  in  which  the  original  tissues  are  extensively  replaced 
by  gelatinous  material.  The  usual  tendency  to  stenosis  may  be  missing, 
but  the  tumor  ulcerates  early  and  excavates  the  lumen  in  a  thick  rigid  tube. 
Extension  to  the  peritoneum  produces  miliary  nodules  or  bulky  masses  of 
gelatinous  tissue.  I  have  found  the  pelvis  completely  filled  by  gelatinous 
material  containing  little  tumor  tissue  derived  from  a  localized  ulcerating 
tumor  of  the  rectum.  Lymphatic  invasion  is  not  prominent.  Kaufmann 
describes  a  case  of  colloid  rectal  cancer  with  a  single  metastasis  in  the  liver 
invading  the  hepatic  duct  with  fatal  icterus. 

(4)  Carcinoma  Developing  from  Solitary  Polyps. — The  most  common  seat 


672 


NEOPLASTIC  DISEASES 


of  these  polypoid  adenomas  is  the  posterior  raphe  of  the  lower  third  of  the 
rectum,  where  Rotter  finds  them  often  the  source  of  carcinoma.    They  often 
develop  in  childhood  and  become  carcinomatous  in  later  years. 
Of  the  benign  polyps  there  are  several  varieties: 

(a)  The  broad  flat  adenoma  is  usually  found  in  the  rectum  just  above 
the  squamous  junction.    It  is  of  simple  cylindrical  cell  adenomatous  structure 
and  its  position  renders  it  specially  liable  to  malignant  change. 

(b)  The  common  pedunculated  adenoma  occurs  throughout  the  intestinal 
tract,  chiefly  in  rectum  and  colon.    It  is  single  or  multiple,  small  or  as  large 
as  the  fist,  and  intussusception,  obstruction,  or  prolapse  may  result.     An 
original  structural  anomaly  or  local  tissue  predisposition  is  probably  present, 


FIG.  316. — A  diffuse  papillary  adenoma  of  rectum. 


but  mechanical  and  inflammatory  factors  have  much  influence  on  the  pro- 
gressive growth.  The  multiple  polyps  are  probably  related  to  intestinal 
polyposis.  The  structure  presents  large  and  small  alveoli  lined  by  high 
cylindrical  epithelium  and  often  filled  or  distended  with  mucus.  All  grades 
of  atypical  cell  growth  are  observed  and  some  localized  pedunculated  tumors 
have  the  typical  structure  of  adenoma  destruens  with  slight  invasion  of  sub- 
mucosa.  When  the  stroma  predominates  the  tumor  may  be  designated 
"fibre-adenoma."  The  carcinomatous  transformation  of  these  polyps  has 
been  observed  by  Hauser,  Verse,  and  many  others.  The  change  may  begin 
at  the  base  or  tip  or  throughout  the  tumor.  Albu  saw  the  recurrence  as 
carcinoma  of  a  polyp  showing  some  years  before  suspicious  signs  of  adeno- 


CARCINOMA  OF  INTESTINE  673 

carcinoma.  Yeomans  describes  several  conditions  in  which  malignant  trans- 
formation seemed  to  occur. 

(c)  Villous  papilloma  is  a  well-defined  variety  characterized  by  a  finely 
papillary  appearance,  great  vascularity,  hemorrhages,  and  a  pronounced 
tendency  toward  recurrence  and  malignant  changes  (Esmarch).  It  occurs 
at  a  later  age  than  other  intestinal  polyps,  the  youngest  of  Quenu's  14  patients 
being  28  years  old.  The  structure  shows  single  or  multiple  layers  of  cylindrical 
cells  supported  by  delicate  vascular  adenoid  tissue.  They  require  thorough 
extirpation  of  the  base.  T  have  observed  a  remarkable  tumor  of  this  type 
which  covered  an  area  of  13  X  9  cm.  in  the  sigmoid.  It  appeared  to  be  com- 
posed of  a  congeries  of  papillomas  which  had  become  fused.  The  papillae, 
\  to  i\  cm.  in  height,  were  closely  packed,  coherent,  and  flattened  at  the  tips. 
The  muscularis  was  intact. 

(5)  Intestinal  Polyposis,  Colitis  Polyposa. — The  chief  seat  of  intestinal 
polyposis  is  the  rectum  and  the  great  majority  of  carcinomas  following  this 
condition  develop  in  the  rectum  or  colon.  The  ileum  or  jejunum  is  rarely 
affected,  but  Hauser  and  Kaufmann  saw  the  involvement  of  the  entire  mucosa 
from  pylorus  or  cardia  to  'anus,  and  lesions  in  duodenum,  jejunum,  and  ileum 
are  reported  by  Lubarsch,  Niemack,  Petrow,  and  others.  Albu  found  the 
lesion  in  isolated  segments  of  sigmoid  and  rectum.  Of  34  cases  collected  by 
Thorbecke,  23  were  in  rectum,  5  in  colon  and  rectum,  and  6  in  colon  alone. 

The  disease  affects  both  old  and  young  subjects  and  exhibits  an  heredi- 
tary, individual,  and  local  predisposition  (Cripps,  Smith,  Bickerstedt,  Port). 
In  the  early  stages  I  find  a  diffuse  and  pronounced  hypertrophy  of  the  entire 
epithelial  lining,  a  condition  which  supports  Verse's  view  that  the  sole  element 
in  the  predisposition  is  the  excessive  reaction  of  the  epithelium  to  irritants. 
Peculiar  catarrhal  symptoms  mark  the  onset  of  the  disease,  and  hemorrhage, 
anemia,  emaciation,  intussusception,  and  prolapse  occur  in  advanced  cases. 
Some  of  the  polyps  may  be  discharged  per  anum. 

Although  many  cases  maintain  their  inflammatory  character  throughout, 
there  is  a  striking  tendency  toward  the  development  of  malignant  adenoma 
and  carcinoma.  According  to  Quenu  and  Landel  about  half  the  cases  are 
associated  with  carcinoma,  while  Hauser  found  this  combination  as  the  rule, 
and  Doering  analyzed  50  cases  in  which  of  37  fatalities  31  were  from  carci- 
noma. Spontaneous  regression  has  been  observed  after  sidetracking  the 
affected  region  and  after  partial  excision  (Rotter).  Some  respond  to  the 
£-ray. 

The  anatomical  form  of  the  carcinoma  varies  extremely.  The  polyps 
may  be  very  small,  very  numerous,  widely  distributed,  and  the  entire  mucosa 
hyperplastic,  or  they  may  be  larger  and  less  numerous.  The  carcinomatous 
process  usually  begins  in  a  single  polyp,  involving  others  later.  Steinthal 
found  a  larger  single  carcinomatous  polyp  in  rectum  and  many  small  benign 
polyps  in  the  vicinity.  Annular  carcinoma  with  many  benign  polyps  scat- 
tered over  a  wide  area  are  reported  by  Wechselmann  and  Brentano.  Diffuse 
polyposis  of  entire  colon  and  adenocarcinoma  of  submucosa  throughout 
is  described  by  Babler.  As  a  rule  one  or  more  of  the  polyps  are  malignant, 
the  others  benign.  Thorbecke  comments  on  the  high  mortality  of  the  disease, 
which  is  referable  to  metastases  from  the  carcinomatous  polyps,  to  the  pro- 
gressive malignant  changes  in  previously  benign  areas,  and  to  the  functional 
disturbance  of  the  organ.  Oseki  found  metastases  in  many  retroperitoneal 
nodes,  liver,  lung,  adrenal,  and  ovary. 

In  structure  the  tumors  show  various  types  of  malignant  adenoma,  adeno- 
carcinoma, and  alveolar  carcinoma.  In  Babler's  case  there  was  diffuse  adeno- 
carcinoma and  alveolar  carcinoma  in  the  submucosa  without  metastases. 
43 


674  NEOPLASTIC  DISEASES 

Wechselmann  describes  carcinomatous  invasion  of  the  base  of  a  polyp,  the 
tip  of  which  was  also  carcinomatous. 

(6)  Squamous-cell  carcinoma  arises  from  the  anal  epidermis  or  by  meta- 
plasia from  the  lower  rectal  mucosa.    The  frequency  of  this  tumor  is  esti- 
mated at  3  to  4  per  cent.  (Funke)  or  20  per  cent.  (Quenu)  of  all  rectal  car- 
cinomas.   It  presents  the  usual  features  of  this  tumor  in  its  more  malignant 
form.     Kraske  describes  4  cases,  3  of  which  produced  ulcerating  nodules 
destroying  the  sphincter,  while  i  extended  laterally  over  a  very  wide  ulcerat- 
ing area.    I  have  seen  a  very  extensive  and  highly  destructive  tumor  following 
condyloma  latum. 

(7)  Melanoma  of  the  rectum  is  rare,  but  nearly  all  writers  in  this  field 
describe  one  or  more  cases  (Kraske,  Cripps,  Ball,  Heaton,  Strasberger,  De 
Buck,  Vanderlinden).    Paneth  collected  8  cases,  and  Wiener  refers  to  several 
others.    Bulky,  firm,  relatively  benign  melanomas  of  the  rectum  are  frequent 
in  horses  (Eiselt). 

The  tumors  are  usually  of  considerable  size,  and  form  circumscribed  or 
pedunculated  growths  which  obstruct  the  lumen  and  later  suffer  ulceration 
and  necrosis.  In  structure  they  have  been  described  as  carcinoma  or  sarcoma. 
Kraske's  carcinoma  was  a  medullary  growth  composed  of  large  polyhedral 
cells  with  little  stroma.  The  pigment  was  limited  to  the  epithelium  and 
adjacent  lymph-nodes.  Two  polypoid  melanotic  tumors  were  composed  of 
pigmented  spindle-cells.  The  source  and  significance  of  the  rectal  tumors 
present  the  same  obscurities  as  surround  other  heterotopic  melanomas. 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER 

Classification. — The  difficulties  in  presenting  an  orderly  arrangement  of 
primary  epithelial  tumors  of  the  liver,  so  obvious  in  the  older  literature,  are 
still  apparent  in  many  recent  studies. 

There  is  first  the  occurrence  of  a  wide  variety  of  very  rare  tumors  which 
requires  the  admission  of  small  groups  of  cases  distinguished  by  their  peculiar 
etiology,  gross  anatomy,  and  histogenesis.  Thus  Simmonds  finds  that  local 
hyperplasia  in  the  liver  occurs  as:  (i)  A  solitary  focus  of  congenital  origin 
in  a  normal  liver;  (2)  multiple  nodular  hyperplasia;  (3)  multiple  adenoma; 
(4)  solitary  adenoma.  All  of  these  conditions  occur  with  and  without  cir- 
rhosis and  many  of  the  simple  hyperplastic  processes  lead  through  benign 
tumors  into  malignant  neoplasms,  thus  complicating  the  task  of  separation 
into  groups.  Secondly,  the  remarkable  regenerative  capacity  of  the  liver- 
cells  leads  to  the  frequent  occurrence  of  partially  neoplastic  processes  which 
have  been  variously  graded  and  named  by  different  authors.  Third,  while 
the  typical  structure  of  liver-cell  tumors  cannot  readily  be  confused  with 
that  of  typical  bile-duct  adenomas  and  carcinomas,  there  remain  many  struc- 
tures of  uncertain  significance,  resulting  probably  from  a  growth  derived 
from  both  these  elements.  Hence  there  will  always  be  a  fluctuating  group 
of  mixed  epithelial  tumors  of  the  liver.  Moreover,  not  a  few  cases  of  homo- 
geneous type  and  evidently  single  origin  are  so  far  removed -from  the  usual 
morphology  that  some  doubt  must  remain  regarding  their  true  origin. 
Finally  there  are  highly  atypical  tumors  of  the  liver  which  have  been  named 
and  classified  on  rather  superficial  resemblance  to  various  forms  of  carcinoma 
or  sarcoma,  which  still  require  more  careful  analysis  before  their  exact  nature 
can  be  established. 

Two  main  classes  of  primary  epithelial  tumors  of  the  liver  are  univer- 
sally recognized  as  derived  from  (i)  liver-cells,  and  (2)  intrahepatic  bile- 
ducts.  A  third  or  subgroup  includes  (3)  mixed  tumors,  in  which  both  liver- 
cells  and  bile-ducts  contribute.  The  simplest  terms  designating  these  tumors 
are  liver-cell,  biliary,  and  mixed  hepatic  carcinoma,  or  adenoma.  The  term 
"hepatoma"  has  come  into  very  general  use  and  has  the  great  advantage 
of  avoiding  implications  with  adenoma  and  carcinoma,  while  it  sufficiently 
designates  any  tumor  of  liver-cells.  Cholangioma  is  a  parallel  but  less  satis- 
factory term  designating  tumors  of  bile-ducts.  Rigid  terminology  calls  for 
such  phrases  as  "hepatoma  adenoides,"  etc.,  or  "adenoma  hepatocellulare, 
vel  cholangiocellulare."  According  to  their  gross  anatomy  the  tumors  are 
solitary  or  massive,  multiple  or  nodular,  and  rarely  diffuse. 

SCHEME  OF  FORMS  OF  EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  THE  LIVER 

(i)  Simple  hypertrophy  and  hyperplasia: 

(a)  Regeneration. 

(b)  Congenital  solitary  hyperplasia. 

(c)  Nodular  hyperplasia  in  stasis,  or  cirrhosis. 

(d)  Diffuse  hyperplasia  (diabetes). 

675 


676 


NEOPLASTIC  DISEASES 


(2)  Neoplastic  hyperplasia : 

(a)    Hepatoma: 

(1)  Adenoma. 

(2)  Adenocarcinoma. 

(3)  Carcinoma,  solitary,  multiple,  atypical. 
(6)  Cholangioma: 

(1)  Adenoma,  solid,  cystic. 

(2)  Adenocarcinoma. 

(3)  Carcinoma, 
(c)  Mixed  tumors. 

Hepatic  Regeneration. — The  regenerative  capacity  of  the  liver  as  exhib- 
ited in  destructive  and  inflammatory  conditions  furnishes  necessary  standards 
in  estimating  nedplastic  processes  in  this  organ. 


FIG.  317. — Adenomatoid  hyperplasia  of  liver  following  acute  yellow  atrophy. 

men  of  Dr.  Elser's. 


Speci- 


Experimental  excision  of  large  portions  of  the  liver  in  lower  animals  reveals 
rather  astonishing  capacity  for  restitution  (Ponfick,  Podwyssoski,  Jr.).  V. 
Meister  extirpated  up  to  four-fifths  of  the  organ  in  rabbits,  rats,  and  dogs. 
The  remaining  lobes  exhibited  hyperemia,  hypertrophy,  mitoses  and  multi- 
plication of  peripheral  cells  of  lobules,  great  increase  in  the  size  of  the  lobules, 
and  eventual  restoration  of  much  of  the  lost  tissue.  This  type  of  regeneration 
has  been  called  morphallaxis  (Morgan).  Functional  hypertrophy  of  the 
whole  organ  is  observed  in  diabetes. 

Extensive  regeneration  of  necrotic  areas  is  observed  after  focal  lesions 
produced  by  hemolytic  agents  (Jackson,  Pearce),  and  especially  in  acute 
yellow  atrophy.  Prolonged  cases  of  this  disease  may  show  many  islands 
of  new  liver  tissue  springing  from  the  surviving  liver-cells  on  the  peripheries 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER 


677 


of  lobules  and  producing  irregular  masses  of  deformed  '.lobules  which  may 
present  a  very  bizarre  and  almost  adenomatous  appearance  (Stroebe). 
In  one  of  Barbacci's  cases  a  hyperplastic  mass  reached  the  size  of  an  apple 
and  the  structure  approached  that  of  adenoma.  In  these  cases  Meder  traces 
rather  clearly  the  origin  of  new  liver-cells  from  proliferating  bile-ducts,  but 
most  observers  have  failed  to  determine  this  origin  with  certainty  and  believe 
that  the  regeneration  begins  in  islands  of  liver-cells.  In  Laehnec's  cirrhosis 
the  incarcerated  lobules  are  often  markedly  hypertrophic,  and  in  Hanot's 
cirrhosis  in  younger  subjects  the  hypertrophy  is  diffuse  and  associated  with 
hyperplasia. 


•  ^  ^W-         "       -  '.-  W*  »      '  •'         *f   ' 

o   *   °      i«  '  *.   o  ^,         ,^  ^^i<: 


•e-~~T*S*'3-*i* 
FIG.  318. — Adenomatoid  hyperplasia  of  liver  following  acute  yellow  atrophy. 


Multiple  nodular  hyperplasia  is  a  term  applied  to  pronounced  focal  over- 
growth of  liver-cells  in  cirrhosis  and  other  conditions.  In  cirrhotic  livers 
these  nodules  may  be  very  numerous,  firm,  opaque,  and  yellowish,  or  soft- 
ened, fatty,  or  hemorrhagic.  In  malarial  cirrhosis,  Kelsch  and  Kiener  de- 
scribed adenomatoid  nodules  arising  in  areas  of  compressed  liver  tissue, 
composed  of  regular  cords  of  large  liver-cells  often  undergoing  fatty  degenera- 
tion, or  caseation,  with  hemorrhage  and  liquefaction.  In  both  of  these  con- 
ditions loose  masses  of  hypertrophic  liver-cells  may  be  found  in  the  portal 
and  hepatic  veins  and  should  not  be  confused  with  the  solid  intravenous 
growths  of  malignant  tumors  (Delepine). 

In  acute  yellow  atrophy  the  regenerating  tissue  may  yield  a  pronounced 
picture  of  multiple  nodular  hyperplasia  without  genuine  neoplastic  features 


678  NEOPLASTIC  DISEASES 

(Meder,  Marchand).  It  is  difficult  to  separate  the  reported  cases  of  nodular 
hyperplasia  from  those  of  the  more  advanced  cancerous  cirrhosis  and  adenoma. 
Sabourin's  observations  refer  to  areas  of  simple  hyperplasia  which  he  finds 
about  proliferating  branches  of  the  portal  biliary  connective  tissue. 

A  very  pure  form  of  nodular  hyperplasia  without  cirrhosis  or  previous 
destructive  lesion  was  observed  by  A.  Jacobi  and  the  writer  in  a  child  suffer- 
ing from  hepatic  stasis  from  enlarged  retrohepatic  lymph-nodes.  Here  the 
otherwise  normal  liver  was  studded  with  myriads  of  miliary  nodules  resem- 
bling tubercles,  and  composed  of  hypertrophic  cords  of  liver-cells  regularly 
incorporated  in  the  liver  lobules.  Very  similar  changes,  but  not  in  normal 
livers,  are  described  by  Simmonds. 

That  all  of  these  form?  of  hyperplasia  may  pass  into  single  or  multiple 
progressive  adenoma  is  fully  attested  by  the  difficulty  of  separating  them 
from  destructive  adenomas  and  cancerous  cirrhosis.  Nevertheless  the  con- 
dition actually  observed  in  many  cases  at  autopsy  is  quite  different  from 
that  of  true  adenoma. 

PRIMARY  EPITHELIAL  TUMORS  OF  LIVER 

General  Etiology. — Orth  found  primary  carcinoma  of  the  liver  four  times 
among  258  cases  of  hepatic  cancer  and  713  cancers  of  all  types  (0.28  per  cent.). 
The  statistics  of  Orth,  Hansemann,  and  Rindfleisch  give  0.5  per  cent,  of  all 
cancers  as  primary  in  the  liver.  Yet  Goldzieher  and  Bokay  saw  18  cases, 
1.3  per  cent.,  among  6000  general  autopsies,  in  5  years. 

The  chief  age  of  incidence  is  between  40  and  60  years,  especially  50  to  60, 
average  43  to  53.  Biliary  carcinoma  occurs  later  than  hepatoma,  rarely 
before  40  years,  and  more  frequently  in  women.  Aside  from  the  congenital 
local  hyperplasia  of  Simmonds,  congenital  malignant  adenoma  has  been 
described  by  Ribbert,  Prescott,  Miller,  Cleland,  Karsner,  and  Milne,  and 
multiple  hemorrhagic  hepatoma  by  Mair.  Pepere  concludes  that  all  solitary 
adenomas  are  congenital.  Of  29  reported  cases  in  children  Philipp  accepts 
12  as  genuine.  Rolleston  adds  several  others.  Reports  of  sarcoma  show 
much  the  same  age  incidence  (Vecchi,  Guerrini).  Rolleston  collected  32 
cases  under  10  years  of  age. 

Congenital  maladjustment  of  groups  of  liver-cells  predisposing  them  to 
tumor  growth  seems  to  be  a  very  rare  factor  in  adults,  while  possibly  of  more 
importance  in  infants  and  with  solitary  tumors.  Among  20  cases  of  solitary 
adenoma  Caminiti  found  only  4  with  cirrhosis.  All  liver-cells  appear  to  be 
capable  of  neoplastic  overgrowth.  A  previous  fatty  and  atrophic  degenera- 
tive process  is  described  by  Oertel  as  a  preliminary  to  further  neoplastic 
degeneration  in  islands  of  cells  separated  by  connective  tissue,  but  this  pre- 
liminary change  is  not  constant. 

Yamagiwa  describes  several  cases  of  hepatoma  in  children,  in  two  of 
which  he  found  islands  of  bone  and  mucoid  tissue.  The  tumors  lay  deep, 
were  partly  encapsulated,  cells  small,  embryonal  and  rich  in  glycogen,  and 
the  vessels  dilated.  These  features  he  interprets  as  those  of  an  autochthonous 
teratoma,  with  metaplasia  of  superfluous  mesenchymal  material.  Islands  of 
metaplastic  cartilage  and  squamous  epithelium  occurred  in  cases  of  v.  Hippel 
and  Philipp. 

Relation  to  Cirrhosis. — Cirrhosis  is  the  chief  predisposing  factor,  occur- 
ring in  about  85  per  cent,  of  hepatomas,  and  50  per  cent,  of  biliary  tumors 
(Eggel).  The  cirrhosis  is  usually  portal  and  biliary  in  type  and  often  of 
alcoholic  or  syphilitic  origin.  Carcinoma  was  associated  with  hemochroma- 
tosis  in  the  cases  of  Lohlein  and  Rindfleisch.  Echinococcus  cvsts  were  ob- 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER  679 

served  in  the  cases  of  Dibbelt,  Lohlein  and  Necker,  and  Yamagiwa  reports 
cases  with  distomiasis  and  schistosomiasis.  There  is  little  doubt  that  cir- 
rhosis and  the  factors  that  lead  to  it  cause  degeneration  followed  by  regenera- 
tive overgrowth  which  may  become  excessive  and  neoplastic.  This  excessive 
hyperplasia  signifies  failing  compensation  and  is  favored  by  fatty  de- 
generation and  thrombosis  of  veins  (Rolleston).  Hence  the  cirrhotic 
process  must  be  regarded  as  both  contributing  to  and  coincident  with 
the  tumor  growth.  There  seems  little  point  in  the  effort  to  disconnect 
these  interrelations.  A  secondary  fibrosis  may  develop  about  old  nodules 
of  liver-cell  tumors,  while  biliary  carcinoma  is  desmoplastic  from  the 
first. 

Hepatic  stasis  frequently  antedates  the  cirrhosis  and  the  tumor  process, 
is  very  effective  in  stimulating  overgrowth  in  the  form  of  nodular  hyper- 
plasia, is  often  observed  without  cirrhosis,  and  is  a  prominent  predisposing 
factor  in  hepatic  tumors.  Local  interference  with  the  blood  supply  appears 
responsible  for  some  solitary  tumors. 

Histogenesis. — The  growth  of  hepatoma  from  the  hypertrophic  liver 
cords  was  first  clearly  demonstrated  by  v.  Heukelom,  has  been  traced  in 
greater  detail  by  Goldzieher  and  Bokay,  and  these  observations  have  been 
verified  by  many  others.  It  has  also  been  shown  that  there  is  a  uniform 
gradation  between  nodular  hyperplasia,  multiple  adenoma,  and  multiple 
carcinoma.  These  gradations  may  even  be  observed  in  the  same  liver,  so 
that,  as  Muir  has  stated,  there  is  no  essential  distinction  between  the  com- 
paratively benign  and  the  atypical  malignant  forms  of  the  tumor.  Ribbert 
and  Heussi  contest  the  multiple  origin  of  many  hepatomas,  finding  very  sharp 
separation  between  hypertrophic  and  invading  tumor-cells  without  great 
disorder  of  the  cords.  Yet  such  a  sudden  transformation  of  hyperplastic 
into  neoplastic  cells  is  characteristic  of  many  tumor  processes.  During  the 
transition  the  cells  may  retain  the  granular  character  of  liver-cells  while 
staining  more  intensely  with  basic  dyes,  or  they  may  lose  granules  and  pig- 
ment and  assume  the  transparent  supposed  embryonal  character  described 
by  Adler.  Bile  secretion  diminishes  with  increasing  anaplasia,  but  may  be 
entirely  missing  in  massive  adenocarcinomas.  Nuclear  hypertrophy  and 
hyperchromatism  is  very  constant,  multinucleated  and  giant-cells  appear, 
and  mitosis  and  amitosis  are  frequent.  Notable  changes  in  the  nuclei  are 
often  seen  in  neighboring  liver  tissue,  forming  a  feature  of  collateral  hyper- 
plasia. The  first  generations  of  tumor-cells  are  usually  large,  later  they 
become  smaller  and  atypical.  The  preservation  and  new  growth  of  capil- 
laries is  a  remarkable  feature,  may  accompany  the  intravascular  growths 
(Parcelier),  and  reaches  its  highest  activity  in  the  so-called  angioplastic 
pseudosarcomas.  Renon,  Geraudel,  and  Monier-Vinard  particularly  empha- 
size the  presence  of  a  neoplastic  process  residing  in  the  endothelium  of  the 
capillaries  and  they  conceive  the  hepatoma  as  a  new  formation  of  complete 
embryonal  liver  tissue  from  the  adult.  It  seems  possible  to  overestimate 
the  importance  of  the  endothelium  in  these  cases.  Yet  Dominici  and  Merle 
trace  a  sarcomatous  process  to  the  excessive  growth  of  endothelium  in  an 
atypical  hepatoma. 

Biliary  carcinomas  have  also  been  traced  satisfactorily  to  the  proliferat- 
ing bile-ducts  in  cirrhotic  and  other  livers,  and  the  usual  series  of  graded 
cases  from  adenoma  to  carcinoma  is  abundantly  supplied  in  the  literature  (v. 
Hippel,  Fischer,  Herxheimer).  Precancerous  changes  are  supplied  by  Milne 
and  Yamagiwa  in  the  form  of  angiocholitis  proliferans.  The  multiple  nodules 
must  be  referred  to  the  universally  distributed  small  ducts,  while  the  solitary 
and  cystic  growths  show  some  predilection  for  the  hilus  and  subcapsular 


680  NEOPLASTIC  DISEASES 

areas.  Yamagiwa  finds  that  tumors  of  the  larger  bile-ducts  yield  tubular  and 
papillary  adenocarcinomas,  while  the  small  ducts  produce  chiefly  carcinoma 
simplex. 

For  the  atypical  and  highly  malignant  growths  from  both  sources  there 
are  no  observations  to  indicate  their  exact  origin.  They  probably  originate 
in  few  or  single  foci,  as  Ribbert  urges,  and  are  rapidly  disseminated  through- 
out the  liver. 

The  histogenesis  of  the  tumors  of  mixed  type  is  not  clear.  Most  of  these 
cases  arise  in  extensively  cirrhotic  organs  in  which  the  formation  of  pseudo- 
bile-ducts  from  incarcerated  liver-cells  and  the  elongation  of  tortuous  bile- 
ducts  render  the  picture  very  complex.  The  uniform  mingling  of  two  tumor 
processes  affecting  liver-cells  and  bile-ducts  must  be  accepted  with  caution, 
and  Muir  and  Rolleston  emphasize  the  fact  that  typical  hepatomas  may 
produce  canals  resembling  bile-ducts. 

Metastases. — Both  single  and  multiple  hepatomas  very  early  invade  the 
capillaries,  even  when  devoid  of  other  malignant  properties.  Hence  loose 
intravascular  thrombi  may  appear  in  relatively  benign  tumors  which  are 
incapable  of  surviving  a  dislocation  from  the  liver.  They  are,  however, 
capable  of  forming  secondary  nodules  in  the  liver,  and -by  this  means  of  dis- 
semination malignant  tumors  may  be  rapidly  distributed  over  most  of  the 
organ.  Ribbert  and  Heussi,  and  many  others,  believe  that  this  process, 
rather  than  a  multicentric  origin,  explains  the  distribution  of  tumor  nodules 
in  many  cases.  Yet  in  not  a  few  instances  bulky  tumor  masses  are  found 
in  the  portal  and  hepatic  veins  without  very  many  secondary  nodules. 
Thrombosis  of  the  hepatic  or  portal  veins  may  occur  without  extensive  tumor 
invasion,  by  a  passive  discharge  of  softened  tumor  tissue.  Occasionally 
the  tumor  thrombus  extends  into  the  vena  cava  and  even  up  to  the  heart. 
While  no  point  of  perforation  of  the  large  veins  can  usually  be  found,  yet 
Engelhardt  describes  the  penetration  of  the  wall  of  a  large  vein  by  infiltrating 
tumor-cells. 

The  frequency  of  metastases  is  not  great.  Of  163  cases  tabulated  by 
Eggel  46  were  free  from  definite  extensions,  50  showed  growths  limited  to 
the  portal  or  hepatic  branches,  30  gave  metastases  in  thorax  or  lungs,  18  in 
regional  lymph-nodes  only,  and  9  secondary  tumors  were  distributed  in  colon, 
pancreas,  ovary,  kidney,  omentum,  thyroid,  and  cranium.  Giachetti's  mas- 
sive carcinoma  gave  very  numerous  metastases  only  in  the  brain. 

Extrahepatic  metastases  are  much  earlier  and  more  frequent  in  biliary 
cancer  than  with  hepatoma.  In  many  instances  the  distant  metastases 
of  hepatoma  have  shown  secretion  of  bile  (Schmidt,  Hanot,  Gilbert,  Clan, 
Pryn,  Wegelin,  Mair).  Secondary  hepatoma  is  often  distinctly  organoid  in 
structure,  exhibiting  liver  cords,  Kupfer's  cells  (Mirolubow),  capillaries,  and 
bile  secretion. 

Clinical  Course. — The  history  of  carcinoma  of  the  liver  varies  greatly 
with  the  type  of  the  disease.  The  presence  of  a  malignant  tumor  is  usually 
indicated  by  anemia  and  emaciation,  but  Rolleston  refers  to  cases  which 
gained  19  and  7  pounds  in  weight  during  rapid  terminal  growth  of  the  tumor, 
the  liver  weighing  16  pounds.  After  the  appearance  of  a  malignant  tumor 
life  is  seldom  prolonged  over  4  months  (Hale  White).  Fever  is  observed 
with  rapidly  growing  tumors  and  from  infections.  Eggel  found  fever  in  14 
per  cent,  of  his  cases,  jaundice  in  61  per  cent.,  ascites  in  58.5  per  cent.  In 
the  urine  no  specific  changes  have  been  demonstrated.  Several  well-defined 
clinical  groups  are  observed : 

(i)  No  symptoms  are  detected  and  the  patient  dies  suddenly  from  hemor- 
rhage, or  after  an  illness  of  a  few  days,  as  noted  by  Karsner. 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER 


681 


(2)  Latent  carcinoma  is  found  in  patients  succumbing  to  cirrhosis  or  other 
diseases. 

(3)  The  usual  history  of  cirrhosis  terminates  rapidly  with  hepatic  tumor, 
jaundice,  ascites,  and  cachexia. 

(4)  The  usual  history  of  a  malignant  tumor  pointing  from  the  first  to  the 
liver,  develops  in  previously  healthy  subjects. 

Recovery  from  the  disease  is  very  rare,  but  Keen  and  Yeomans  report 
successful  excisions,  some  of  which  appear  to  have  recovered  permanently. 
Yeomans  states  that  a  patient  from  whom  he  excised  a  portion  of  a  large 
tumor  mass  in  the  liver  remains  well  after  5  years.  A  section  of  this  tumor 
I  found  to  show  typical  trabecular  and  perithelial  adenocarcinoma. 

ANATOMICAL  AND  CLINICAL  VARIETIES 

(i)  Hepatoma. — (a)  Solitary  Adenoma.  Solitary  Hepatoma. —  Solitary 
liver-cell  adenomas  are  rarely  encountered,  but  typical  cases  are  described 


FIG.  319. — Solitary  adenoma  of  liver. 

by  Rokitansky,  Salter,  Engelhardt,  Wegelin,  Rolleston,  and  others.  Two 
or  more  massive  tumors  in  one  liver  are  properly  included  in  this  group. 
Caminiti  collected  20  cases,  several  of  which  occurred  in  cirrhotic  livers. 
Many  appear  in  early  life  from  3  months  and  later  (Milne).  Hence  they  are 


682 


NEOPLASTIC  DISEASES 


often  regarded  as  of  congenital  origin,  but  it  is  probable  that  acquired  lesions 
may  give  rise  to  neoplastic  overgrowth  of  isolated  portions  of  the  organ. 
Christiani  describes  congenitally  displaced  lobules  of  liver  tissue  in  Glisson's 
capsule,  and  Pepere  found  such  lobules  in  liver  and  scattered  over  the  perito- 
neum. In  Engelhardt's  case  the  quadrate  lobe  was  missing. 

The  solitary  adenoma  produces  a  gray,  yellow,  or  bile-stained,  projecting 
and  encapsulated  tumor,  varying  in  size  from  a  small  nodule  to  a  mass  8 
inches  in  diameter. 

The  tumor  is  composed  of  cords,  tubes,  and  alveoli  closely  resembling 
the  structure  of  the  liver.  In  a  case  of  the  writer's  all  three  structures 
were  illustrated  in  different  areas.  The  cells  are  granular  and  acidophile, 
or  very  fatty.  Bile  stasis  is  usually  absent,  but  many  phases  of  its  secretion 
are  often  observed  (Ciechanowski).  The  stroma  is  composed  chiefly  of  capil- 
laries. 

The  veins  are  not  invaded  in  the  typical  solitary  adenoma,  but  the  benign 
character  is  due  chieflv  to  encapsulation  and  transitional  forms  to  adeno- 


FIG.  320. — Varying  structure  in  adjoining  lobules  of  malignant  adenoma  of  liver  cells. 

carcinoma  occur  in  which  there  is  invasion  of  veins  and  multiplication  of 
tumors.  B.  Fischer  describes  a  solitary  adenocarcinoma  with  metastases  in 
lymph-nodes. 

Adrenal  rests  in  the  liver  have  been  described  by  Schmorl  and  others, 
and  yellow  tumors  possibly  derived  from  these  structures  and  closely  resem- 
bling adrenal  tumors  in  other  situations  are  described  by  Schmorl,  Pepere, 
de  Vecchi,  et  al.  Glynn,  however,  properly  doubts  the  adrenal  origin  of  these 
tumors.  Hirschler  emphasizes  the  structure  and  very  fatty  character  of  his 
tumor,  but  the  lipoids  were  chemically  unlike  those  of  the  adrenal. 

(&)  Primary  Massive  Liver-cell  Carcinoma. — This  form  of  primary  carci- 
noma of  the  liver  is  highly  characteristic.  It  occurs  in  young  adults,  but  more 
often  in  elderly  subjects,  and  apart  from  the  cirrhosis  which  frequently  accom- 
panies the  tumor  it  yields  few  symptoms  until  a  brief  terminal  period  is 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER 


683 


'• — :    .<' 

FIG.  321. — Adenocarcinomatous  structure  in  a  primary  tumor  of  liver-cells. 


-FiG.  322. — Variations  in  cell  types  in  malignant  hepatoma. 


684 


NEOPLASTIC  DISEASES 


reached.  Eggel  collected  14  cases  at  ages  from  21  to  67  years,  duration  2 
weeks  to  6  months.  I  have  reported  a  case  in  an  old  man  who  died  suddenly 
and  unexpectedly  from  abdominal  hemorrhage. 

The  tumor  appears  as  a  large  single  yellowish  friable  mass,  as  large  as  a 
child's  head  or  occupying  the  whole  right  or  left  lobe.  Small  secondary  tumors 
in  the  liver  may  be  present.  The  consistence  is  usually  soft,  and  extensive 
liquefaction  necrosis  and  hemorrhage  may  produce  a  cystic  appearance,  or 
rupture  into  the  peritoneum.  The  large  veins  are  usually  invaded  and 
thrombosed  and  metastases,  while  occasionally  absent,  may  be  wide-spread 
and  bulky,  especially  in  the  lungs. 

The  structure  presents  wide  variations,  but  always  reveals  at  some  points 
a  definite  resemblance  to  liver-cells.  In  the  writer's  case  four  separate  struc- 
tures were  presented  in  different  portions:  (i)  Trabecular  adenocarcinoma, 
composed  of  cords  of  very  large  granular  acidophile  cells  resembling  large 
liver-cells,  and  separated  by  capillaries.  Giant-cells  of  very  large  dimen- 
sions were  abundant  in  these  areas.  These  cells  have  been  described  by 

Hanot  and  Gilbert  and  by  C.  P.  White 
as  a  characteristic  feature.  (2)  Alveo- 
lar adenoma.  These  areas  presented 
compact  groups  of  smaller  granular 
epithelium  sharply  bounded  by  very- 
numerous  wide  capillaries.  (3)  Peri- 
theliomatous  areas  composed  of  capil- 
laries surrounded  by  one  or  more  rows 
of  cubical  granular  cells  appeared  in 
certain  portions.  This  structure  has 
been  noted  by  Goldzieher  and  Bokay, 
Yamagiwa,  and  others.  (4)  Diffuse 
carcinoma.  In  many  softened  or  ne- 
crosing areas  all  traces  of  the  orderly 
arrangement  of  cells  were  lost,  and  the 
growth  was  composed  of  diffuse  round, 
polyhedral,  or  spindle-cells  with  strongly 
hyperchromatic  nuclei. 

These  structural  types  cover  most 
of  those  observed  by  other  authors. 
It  is  evident  that  this  tumor  repre- 
sents a  more  rapidly  growing  atypical 
and  malignant  form  of  the  solitary 
adenoma. 

(c)  Multiple  Liver-cell  Carcinoma  or 


am 

FIG.     323. — Pseudoperitheliomatous 
structure  in  multiple  hemorrhagic  hepa- 
(L'Esperance.) 


toma. 


Hepatoma. — In  this  group  are  included 
the  highly  malignant  rapidly  growing 
tumors  occurring  in  livers  in  which 
cirrhosis  is  either  absent  or  so  slight 
as  to  be  of  secondary  importance.  The  peculiar  clinical  course,  gross  appear- 
ance of  the  liver,  and  the  microscopical  structure  which  is  often  atypical, 
justify  the  separate  consideration  of  these  cases.  There  is,  however,  no  sharp 
division  between  this  group  and  solitary  massive  carcinoma,  on  the  one  hand, 
and  multiple  carcinoma  following  cirrhosis  on  the  other. 

While  the  highly  characteristic  cases  are  somewhat  rare,  the  group  as  a 
whole  is  rather  numerous.  Eggel  collected  many  examples,  most  of  which 
were  associated  with  advanced  cirrhosis.  Hanot  and  Gilbert  describe  several 
characteristic  cases.  There  is  reason  to  believe  that  many  of  the  so-called 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER 


685 


angiosarcomas  of  Arnold,  v.  Kahlden,  Steinhaus,  and  Marx  are  atypical 
forms  of  multiple  hepatoma,  and  it  is  probable  that  ,other  cases  described  as 
alveolar  or  lymphosarcoma  are  of  the  same  nature  (Dominici,  Merle). 

The  clinical  course  is  chiefly  notable  for  its  rapidity,  many  cases  lasting 
only  a  few  weeks,  few  continuing  more  than  3  or  4  months,  and  some  dying 
suddenly  without  very  definite  previous  disturbance.  Jaundice  is  uncom- 
mon, but  serous  or  bloody  peritoneal  effusions  are  often  observed.  Rapid 
cachexia  with  enlargement  of  the  liver  and  ascites  are  the  usual  clinical  signs. 
These  tumors  occur  chiefly  after  middle  life,  but  De  Haan,  Mair,  and  others 
report  cases  in  infants  and  children. 

The  liver  is  usually  enlarged,  at  times  to  very  considerable  dimensions, 
and  is  the  seat  of  multiple  nodules  and  tumor  masses  which  are  grayish  or  bile 
stained  or  hemorrhagic  and  necrotic.  A  resemblance  to  multiple  secondary 
chorioma  has  been  noted  by  Marx,  Teacher,  and  L'Esperance.  Although  the 


FIG.  324.— Multiple  hemorrhagic  hepatoma.     (After  L'Esperance.) 

size  of  the  tumor  masses  varies,  it  may  be  impossible  to  choose  any  one  as  a 
single  primary  focus.  Many  small  nodules  are  doubtless  secondary.  In 
other  cases,  usually  of  slower  development,  there  are  one  or  more  larger 
masses  with  more  numerous  and  probably  secondary  tumors  in  the  liver. 

Metastases  are  usually  missing,  but  local  extensions  to  the  portal  nodes, 
diaphragm,  and  gall-bladder  are  observed,  and  in  the  more  prolonged  cases 
they  may  be  found  in  the  lungs  and  other  organs.  Most  tumors  yielding 
extensive  metastases  are  associated  with  cirrhosis.  The  structure  varies 
greatly  even  in  different  portions  of  the  same  tumor  and  reproduces  the  more 
malignant  structures  of  solitary  carcinoma.  Thus  one  finds  trabecular  car- 
cinoma with  giant-cells,  small  alveolar  carcinoma  with  numerous  capillaries, 
perithelioma,  and  diffuse  carcinoma.  A  definite  encapsulation  of  tumor 
masses  does  not  occur,  but  Mirobolew  points  out  that  distended  venules  may 
inclose  tumor  nodules. 


686 


XEOPLASTIC  DISEASES 


L'Esperance  has  described  an  atypical  form  of  primary  multiple  hemor- 
rhagic  hepatoma,  which  probably  includes  many  cases  of  pseudosarcoma. 
In  portions  of  these  tumors  the  original  structure  appears  chiefly  as  a  perithe- 
lioma,  with  large  or  small  cubical  granular  cells  surrounding  capillaries.  In 
hemorrhagic  and  necrotic  areas  this  structure  is  lost  and  the  tumor  detritus 
appears  as  a  large  spindle-cell  or  alveolar  sarcoma.  The  occurrence  of  such 
pseudosarcomatous  areas  in  combination  with  typical  hepatoma,  as  occurred 
in  one  of  my  cases,  reveals  the  true  nature  of  the  atypical  forms  of  hepatoma. 
The  structure  may  sorhewhat  resemble  chorioma  of  the  liver,  as  noted  by 
Cruikshank  and  Teacher  and  Marx,  but  secondary  chorioma  from  uterus  or 
testis  regularly  reveals  its  specific  features  and  there  is  no  reason  to  believe 
that  chorioma  is  ever  primary  in  the  liver. 

(d)  Carcinomatous  Cirrhosis.  Multiple  Adenoma,  Carcinoma,  or  Hepatoma 
with  Cirrhosis. — A  more  advanced  stage  of  hyperplasia  with  atypical  mor- 
phology, local  aggressive  properties,  invasion  of  veins,  and  occasionally  with 
metastases  is  described  by  many  authors  as  carcinomatous  cirrhosis 


FIG.  325. — Gross  appearance  of  universal  cancerous  cirrhosis  of  liver. 

(Griesinger,  Hanot  and  Gilbert,  v.  Heukelom,  Thorel,  Rolleston).  Others 
designate  the  condition  as  multiple  adenoma  or  carcinoma  (Marckwald,  Lit., 
Lancereaux). 

No  sharp  division  exists  between  multiple  adenoma  without  cirrhosis, 
multiple  adenoma  with  cirrhosis,  and  carcinoma.  Each  of  these  conditions 
exhibits  progressive,  invasive,  and  malignant  tendencies  (Muir). 

The  distinguishing  feature  of  the  present  group  of  cases  is  the  relation  to 
cirrhosis.  The  tumor  process  appears  to  be  the  direct  sequel  of,  or  essen- 
tially connected  with,  the  cirrhosis.  Hence  the  symptomatology  is  much 
influenced  by  the  history  of  cirrhosis,  and  both  the  clinical  picture  and  patho- 
logical anatomy  are  somewhat  distinctive. 

Cancerous  cirrhosis  develops  in  elderly  subjects  of  40  years  or  more,  and 
often  in  children,  previously  in  good  health,  who  develop  symptoms  of  portal 
stasis  with  ascites  and  slight  jaundice.  A  history  of  cirrhosis  regularly 
precedes  the  development  of  the  tumor,  but  is  not  always  pronounced. 
With  the  onset  of  the  tumor  process  there  are  added  increasing  anemia, 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER  687 

cachexia,  diarrhea  and  hemorrhages,  and  the  disease  progresses  steadily 
to  a  fatal  issue.  After  the  appearance  of  ascites  the  duration  is  seldom  more 
than  a  few  months  and  often  only  a  few  weeks. 

The  liver  is  usually  contracted,  but  in  some  cases  is  normal  or  greatly 
increased  in  size.  The  surface  presents  multiple,  projecting,  yellowish,  or 
bile-stained  nodules  which  on  section  may  be  found  to  represent  a  large  part 
of  the  parenchyma.  The  nodules  may  be  numerous,  small,  and  almost  con- 
fluent, or  larger,  discrete,  and  encapsulated.  One  portion  of  the  organ  may 
be  quite  free,  but  frequently  the  lesion  is  nearly  universal.  A  portal  cirrhosis 
is  usually  present  and  many  of  the  nodules  are  surrounded  by  connective 
tissue.  In  many  cases  the  gross  appearance  of  the  organ  resembles  that  of 
Hanot's  hypertrophic  cirrhosis.  The  spleen  is  diffusely  enlarged.  Borst 
found  in  one  case  much  the  same  process  in  both  liver  and  pancreas. 

Many  authors  describe  a  diffuse  form  of  hepatic  carcinoma  (Eggel,  Rol- 
leston).  Yet  these  cases  commonly  represent  a  very  extensive  development 
of  nodular  carcinoma  in  a  cirrhotic  liver  and  not  a  diffuse  growth  of  tumor- 
cells.  Regressive  changes  in  the  tumor  and  overgrowth  of  hyaline  connective 
tissue  may  also  disturb  the  original  structure  and  produce  areas  of  diffuse 
carcinoma. 

The  microscopical  structure  shows  extensive  replacement  of  parenchyma 
by  adenomatous  and  carcinomatous  nodules.  The  process  begins  with  the 
hypertrophy  and  hyperplasia  of  cell  groups  within  the  acinus  and  apparently 
at  any  point  in  the  lobule.  These  cell  groups  enlarge,  forming  nodules  which 
rapidly  encroach  upon  the  remaining  parenchyma  with  atrophy.  The  tumor- 
cells  are  of  large  size,  forming  thickened  liver  cords  (trabecular  adenoma), 
or  the  nuclei  multiply  actively  and  numerous  smaller  cells  result.  Peculiar 
forms  of  nuclear  division,  chiefly  of  the  amitotic  type,  are  observed.  Giant 
and  syncytial  masses  often  appear.  Fatty  degeneration  may  be  prominent 
and  liquefaction  may  be  added.  The  cells  may  contain  globules  of  bile  and 
many  hyaline  cytoplasmic  bodies.  The  structure  may  vary  in  the  same  or 
different  nodules.  The  cells  may  be  arranged  in  small  regular  alveoli  with 
a  fine  lumen,  or  the  lumen  may  be  wide  and  the  lining  cells  low  cuboidal. 
Many  transitions  from  adenoma  to  adenocarcinoma  and  diffuse  carcinoma 
are  observed,  v.  Heukelom  was  able  to  trace  the  origin  from  the  liver-cells 
and  to  follow  the  growth  of  early  nodules  into  the  central  veins  and  portal 
and  hepatic  radicles.  By  this  route  the  tumor  grows  into  the  larger  veins 
which  may  be  occluded  by  tumor  masses,  although  their  walls  are  intact  and 
no  point  of  penetration  may  be  found.  These  tumor  thrombi  may  fill  the 
hepatic  or  portal  veins  and  enter  the  vena  cava.  Yet  metastatic  growths 
are  often  wanting,  but  in  about  20  per  cent,  secondary  deposits  are  found 
in  lungs  or  peritoneal  nodes  (Kelsch  and  Kiener,  Brissaud,  Hanot  and  Gilbert, 
Frohmann,  Goldzieher,  and  Bokay). 

The  part  played  by  the  bile-ducts  varies.  In  most  cases  they  are  con- 
siderably increased  in  number  in  the  cirrhotic  areas,  but  do  not  contribute 
to  the  tumor  process.  In  other  cases  the  proliferation  of  bile-ducts  is  more 
active  and  they  appear  to  become  transformed  into  tumor-cells  (Birch- 
Hirschfeld,  Thorel,  Marckwald).  The  structure  is  then  apt  to  present  many 
small  groups  of  tumor-cells  lying  chiefly  in  connective  tissue,  as  well  as  the 
typical  hepatic  adenoma.  In  such  cases  Marckwald,  Theodorow,  and 
Parcelier  and  Fromaget  conclude  that  two  separate  tumor  processes  exist, 
one  affecting  the  liver-cells,  the  other  the  bile-duct  cells.  Pure  adenoma  or 
carcinoma  of  the  bile-ducts  presents  a  rather  specific  structure  and  will  be 
separately  considered. 

The  relation  of  the  tumor  process  to  the  associated  cirrhosis  is  not  always 


()HS  NEOPLASTIC  DIXKA.SItf 

identical.    In  many  cases  the  rapid  progress  of  the  disease  and  I  he  moderate 
grade  of  cirrhosis  indicate  Ilial   (lie  latter  is  secondary  l<>  the  former  procesi 
(Lancereaux,    Man  k  u;dd)        Moreover,  extensive    nodular    hypciplasia,   ade 
tioma,  and   piimary  carcinoma   occur   without    cirrhosis.     Since   focal   hyper 
trophy  is  often  observed  in  portal  cirrhosis  and  I  lie  grade  of  cirrhosis  is  ollcn 
extreme,  tin-  liver  being  contracted  and  deformed,  it   is  highly  probable  Ilial 
the  Condition  in  such  cases  represents  a  sequel  of  the  cirrhotic  proce:/;  (Sim- 
monds,  Orth,  Schmieden,  Travis,  IVabody).    In  most  cases  the  two  processes 
are  probably  coordinate  (\Vat/.oldi  I, 

The  many  gradations  presented  by  different  cases  between  simple  nodular 
hyperplasia,  multiple  adenoma,  and  adenocarcinoma,  the  multiple  origin, 
the  peculiar  localization  of  the  disease  to  the  liver,  and  the  frequent  absence 
of  local  aggressive  properties,  have  raised  doubts  regarding  the  genuine  car- 
cinomatous  nature  of  the  disease.  Borst,  while  admitting  its  morphological 
identity  with  carcinoma,  urges  a  distinction  between  secondary  epithelial 
proliferation  after  injury  of  liver  tissue  with  hypertrophy,  hyperplasia  of 
adenomatoid  or  carcinomatoid  structure,  and  true  primary  autonomous 
neoplasms  of  the  liver.  This  point  of  view  may  be  emphasi/ed  by  the  occur- 
rence of  congenital  solitary  hyperplastic  areas,  and  solitary  adenoma  and 
carcinoma  of  this  organ.  Yet  all  the  features  of  t  he  malignant  primary  tumors 
are  observed  in  multiple  adenoma  or  carcinomatous  cirrhosis.  Different 
cases  present  every  gradation  from  nodular  hyperplasia  to  malignant  carci- 
noma, so  that  the  distinction  bet \\een  multiple  adenoma  with  cirrhosis  and 
true  carcinoma  without  cirrhosis  appears  to  be  the  condition  of  origin  and 
intensity  of  the  process  rather  than  in  the  essential  nature. 

Renon  and  Geraudel  contrast  the  biological  features  of  all  the  liver-cell 
tumors  (hepatoma)  with  (other)  true  cancers.  They  point  out  the  multiple 
origin,  the  lack  of  complete  emancipation  of  the  cells  which  do  not  survive 
well  outside  the  environment  of  the  liver  or  frequently  produce  metastases, 
the  preservation  of  functional  capacity  in  secreting  bile,  and  hence  they 
discard  the  term  ''carcinoma"  in  favor  of  "hepatoma."  I  can  only  endorse 
the  employment  of  a  specific  term  for  such  a  peculiar  process,  but  must  still 
regard  the  process  as  essentially  carcinomatous  with  certain  features  which 
are  duplicated  by  some  carcinomas  in  other  organs.  Geraudel  contends 
that  the  hepatic  parenchyma  is  of  mesoblastic  origin.  Yet  the  liver-cells 
are  derived  from  exactly  the  same  endodermal  bud  as  the  bile-ducts,  and  the 
only  part  of  the  parenchyma  which  is  of  mesodermal  origin  is  the  system  of 
blood-vessels. 

CYSTS  AND  TUMORS  OF  BILE-DUCTS.    CHOLANGIOMA 

Cysts  of  the  Bile-ducts. — Biliary  obstruction  is  the  cause  of  a  variety  of 
hepatic  cysts. 

(1)  In  cirrhosis  obstructed  bile-ducts  may  dilate,  giving  rise  to  very 
numerous  small  or  microscopic  cysts  containing  fluid  bile.     Rolleston  de- 
scribes a  case  with  many  subserous  cysts  containing  inspissated  bile.     In 
cirrhosis  with  nodular  hyperplasia  or  adenoma  the  hypertrophic  nodules  may 
break  down  and  yield  small  cysts  in  the  parenchyma. 

(2)  Large  single  or  multiple  cysts  from  retention  of  bile  are  occasionally 
observed.    Bayer  found  a  cyst  containing  13$  pints  of  fluid,  Aldous  12  pints. 
and  North  5  pints,  mostly  clear  or  bloody  fluid  from  which  the  bile  pigment 
had  been  absorbed,     Doran's  cyst  contained  2\  pints  of  colored  bile  and 
was  evidently  more  recent.    In  all  these  cases  the  wall  is  of  fibrous  tissue  in 
which  are  embedded  numerous  bile-ducts.     The  lining  may  be  of  cubical, 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER  689 

cylindrical,  or  flat  cells,  but  the  epithelium  is  much  desquamated.  Zahn 
collected  14  cases  of  cysts  lined  by  ciliated  epithelium.  These  suggest  an 
origin  from  congeni tally  misplaced  aberrant  bile-ducts  (Moschkowitz). 

(3)  Congenital  multiple  cystic  disease  of  the  liver  is  a  not  infrequent 
condition  which  is  nearly  always  associated  with  similar  changes  in  the  kid- 
neys (Bristowe,  Still,  Moschkowitz).  Cystic  kidneys,  however,  are  usually 
found  without  cystic  liver  (73  per  cenf.,  Lejars;  94  per  cent.,  Luzatto).  The 
pancreas  and  spleen  may  also  be  involved. 

The  condition  is  rather  common,  although  not  always  pronounced,  in 
malformed  infants,  especially  females,  and  in  various  ways  leads  to  early 
death.  Another  group  of  cases  is  observed  in  adults  who  escape  the  initial 
dangers  or  in  whom  the  condition  develops  late.  The  chief  symptoms  are 
uremic. 

The  liver  may  be  of  normal  size  or  greatly  enlarged.  MacDonald  records 
a  cystic  liver  weighing  14  pounds.  When  the  cysts  are  very  small  the  organ 
may  appear  fibrosed,  otherwise  a  portion  or  the  whole  of  the  liver  may  be 
the  seat  of  a  large  number  of  cysts  from  ^  mm.  to  several  centimeters 
in  diameter.  The  parenchyma  may  be  reduced  to  a  trace  and  cirrhotic. 
The  kidneys  are  usually  more  altered  than  the  liver.  The  fluid  contents  are 
clear,  albuminous,  mucoid,  bloody  or  inspissated,  and  contain  urea,  salts, 
and  cholesterin,  but  no  bile.  The  earliest  stages  of  the  process  show  a  multi- 
plication of  slightly  dilated  but  otherwise  normal  bile-ducts  in  widened  portal 
canals.  By  progressive  dilatation  and  fusion  of  smaller  cysts  the  larger  develop. 
In  adults  the  lining  cells  are  cylindrical  or  cubical,  occasionally  ciliated  (Lehars) 
and  often  flattened  or  absent. 

The  structure  does  not  favor  the  old  .theory  of  a  fetal  cholangitis,  nor 
the  origin  from  hepatic  degeneration  with  widening  of  new  formed  bile-ducts. 
A  neoplastic  element  was  discerned  by  Rindfleisch  and  designated  as  cystic 
fibrosarcoma.  Any  neoplastic  element  present  is  more  probably  adenomatous, 
as  appeared  in  unusual  distinctness  in  cases  of  Siegmund,  v.-  Kahlden,  and 
Workman,  and  especially  in  the  kidneys  in  the  cases  of  Nauwerck  and  Huf- 
schmidt.  A  congenital  malformation  is  undoubtedly  the  original  factor. 
Shattuck  suggests  that  the  tubules  represent  remains  of  mesonephros  blended 
with  the  metanephros,  and  for  the  liver  Still  traces  the  tubules  to  irregular 
diverticula  from  the  duodenal  invagination  which  develops  along  with  the 
normal  bile-ducts.  Moschkowitz  finds  aberrant  atypical  ducts  along  with 
normal  bile-ducts  in  the  portal  canals  of  cystic  livers,  but  Rolleston  doubts 
this  interpretation  of  these  structures.  I  do  not  find  them  in  my  cases,  in 
which  all  the  bile-ducts  are  alike.  On  the  basis  of  this  congenital  anomaly 
progressive  dilatation  may  occur  or  adenomatous  processes  may  be  estab- 
lished. Some  single  and  multiple  cystic  adenomas  of  the  liver  probably  develop 
in  this  way,  and  in  the  kidney  I  have  seen  highly  cystic  Wilms'  tumors  which 
suggested  a  transition  from  the  congenital  cystic  kidney  to  congenital  sarcoma. 

Tumors  of  the  Bile-ducts.— The  epithelium  of  the  bile-ducts  gives  origin 
to  several  varieties  of  true  tumors.  While  the  congenital  cystic  liver  rarely 
or  never  gives  rise  to  a  progressive  neoplasm,  single  and  multiple  cystic 
adenomas  arise  from  the  bile-ducts  in  cirrhosis ;  multiple  solid  adenomas  of  the 
bile-ducts  are  rather  frequently  observed  (Watzold);  and  a  specific  form  of 
multiple  carcinoma  develops  from  these  structures. 

Cystic  Adenoma  of  Bile-ducts. — Definite  tumors  of  this  origin  are  rare 
and  the  neoplastic  nature  of  some  of  the  recorded  cases,  of  which  Leppman 
collected  9,  is  doubtful.  Thus  Shattuck  removed  a  large  cyst  containing  a 
gallon  of  clear  fluid,  in  the  wall  of  which  were  many  ducts  and  minute  cysts 
interpreted  as  adenomatous.  A  true  multilocular  cystadenoma  was  suc- 
44 


690  NEOPLASTIC  DISEASES 

cessfully  removed  by  Keen.  It  weighed  113  gm.  and  contained  many  cavities 
lined  by  cylindrical  cells  and  supported  by  fibromuscular  tissue.  In  Sieg- 
mund's  case  a  large  part  of  the  liver  formed  an  isolated  cystic  mass  in  which 
were  many  areas  suggesting  active  neoplastic  growth  of  cubical  cells. 

A  remarkable  development  of  multiple  cystic  adenomas  involving  the 
whole  of  a  cirrhotic  liver  is  described  by  Dmochowski  and  Janowski.  The 
organ  weighed  10,850  gr.,  contained  very  numerous  cysts,  minute  and  as 
large  as  a  child's  head,  filled  with  clear  fluid.  There  was  extensive  epithe- 
lial proliferation  filling  some  of  the  smaller  cysts. 

Multiple  Adenoma  of  the  Bile-ducts. — Usually  observed  as  a  secondary 
condition  after  death  from  other  causes  and  of  itself  produces  no  symptoms 
(Watzold,  Hippel).  The  liver  is  usually  the  seat  of  stasis  or  cirrhosis.  In 
Brigidi's  cases  the  liver  weighed  6  pounds,  the  adenomas  were  small  and 
numerous,  and  an  extensive  cirrhosis  was  present.  V.  Hippel  found  very 
little  cirrhosis.  The  tumors  lie  beneath  the  capsule  or  deeper  in  the  paren- 
chyma and  appear  as  grayish-white  nodules  0.5  to  2  or  3  cm.  in  diameter. 
The  gross  appearance  may  resemble  that  of  thyroid  tissue  when  the  alveoli 
are  filled  with  secretion  (v.  Hippel,  Dreschfeld).  Occasionally  there  is  bile 
stasis  in  the  alveoli  and  the  tumors  are  discolored.  The  nodules  are  usually 
incased  in  connective  tissue  and  are  free  from  bile  deposits. 

The  structure  presents  many  small  alveoli  with  definite  lumina  lined  by 
one  or  more  layers  of  small  cubical  or  higher  cylindrical  cells  in  which  the 
nuclei  are  very  prominent,  and  the  cytoplasm  clear.  These  alveoli  resemble 
the  proliferating  bile-ducts  in  cirrhotic  livers.  The  adenomatous  alveoli  are 
usually  confined  to  the  widened  portal  canals,  while  the  hepatic  lobules  are 
pushed  aside,  but  in  some  cases  there  is  more  active  proliferation  and  the 
alveoli  grow  between  or  within  the  lobules.  The  lumina  of  the  alveoli  are 
usually  empty  or  contain  granular  or  hyaline  detritus,  but  dilatation  and 
lateral  outgrowths  may  occur,  polypoid  projections  may  develop,  and  there 
are  many  transitions  to  cystadenoma  and  adenocarcinoma.  Thus  Watzold 
found  30  to  40  nodules  under  the  capsule  of  the  liver  and  showing  many  stages 
of  cystic  dilatation.  Kika  describes  these  cases  as  proliferating  cystadenoma. 
They  develop  chiefly  from  the  larger  ducts. 

Multiple  Carcinoma  of  the  Intrahepatic  Bile-ducts.— Incidence. — Malig- 
nant tumors  of  this  origin  occur  under  much  the  same  conditions  as  multiple 
liver-cell  carcinoma,  but  less  frequently  associated  with  cirrhosis.  Regarding 
their  frequency  opinions  are  widely  at  variance.  Basing  the  diagnosis  on  a 
structure  presenting  alveoli  lined  by  cylindrical  cells,  Eggel  found  that  32 
per  cent,  of  primary  carcinomas  of  the  liver  were  of  this  origin.  Pepere,  on 
much  the  same  data,  reduced  the  proportion  to  14  per  cent.  B.  Fischer,  on 
the  other  hand,  encountered  2  typical  cases  and  hastily  undertook  to  eliminate 
the  entire  group  of  liver-cell  tumors,  assuming  that  practically  all  primary 
carcinomas  of  the  liver  arise  from  the  bile-ducts.  In  the  literature  definite 
reports  of  bile-duct  carcinoma  are  much  less  numerous  than  cases  of  liver- 
cell  carcinoma.  Of  the  53  cases  collected  by  Herxheimer  some  are  of  un- 
certain origin. 

Bile-duct  carcinoma  appears  chiefly  in  adult  or  later  life,  in  subjects  of 
cirrhosis.  A  history  of  severe  disturbance  in  the  evacuation  of  bile,  as  in 
Fischer's  case,  is  relatively  common. 

Gross  Anatomy. — The  liver  is  usually  enlarged  sometimes  to  very  notable 
dimensions,  intensely  jaundiced,  and  often  the  seat  of  advanced  cirrhosis, 
chiefly  of  the  biliary  type.  The  dilated  larger  bile-ducts  may  be  visible  in 
the  gross.  The  tumor  process  affects  most  or  all  of  the  organ,  and  produces 
very  numerous,  usually  small,  firm  nodules  which  may  become  confluent. 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER  691 

Fischer  found  the  most  extensive  tumor  growth  in  the  region  of  the  hilus 
where  it  probably  arose  from  the  larger  bile-ducts.  In  most  cases  it  is  im- 
possible to  locate  any  single  primary  focus  and  the  origin  is  multicentric. 
Massive  forms  of  adenocarcinoma  of  bile-ducts  with  transitions  to  carcinoma 
in  multiple  secondary  nodules  are  described  by  Greenfield  and  Thorel. 

The  extensive  hemorrhages,  necrosis,  the  bulky  soft  tumor  masses,  and 
prominent  invasion  of  large  veins  which  characterize  hepatoma  are  missing. 
A  tendency  toward  cicatricial  fibrosis  of  the  tumors  has  often  been  noted  in 
the  gross. 

The  structural  features  usually  form  a  sharp  contrast  with  those  of  liver- 
cell  carcinoma.  The  prevailing  structure  is  that  of  adenocarcinoma  or 
alveolar  carcinoma.  The  cells  are  cylindrical,  high  or  low,  or  cubical,  re- 
sembling those  of  bile-ducts,  and  the  cytoplasm  is  clear,  lacking  the  granular 
acidophile  character  of  liver-cells.  The  nuclei  are  small  and  vesicular  and 
mitoses  may  be  very  numerous.  Giant-cells  are  rare.  Ciliated  epithelium 
is  described  by  Sokalow  and  Cagnetto  in  otherwise  typical  cases.  In  more 
atypical  malignant  tumors  the  resemblance  to  duct-cells  may  be  lost  (Wal- 
deyer).  Many  observers  describe  the  transformation  of  bile-duct-cells  into 
liver-cells  in  tumors  originating  from  the  former  (Fischer,  Herxheimer). 
Others  reverse  the  order  and  trace  bile-ducts  forming  from  liver-cells  (Rind- 
fleisch,  Muir,  Rolleston).  Tn  many  of  these  cases  it  is  quite  possible  that  the 
tumor  has  a  dual  origin,  as  held  by  Wiegert,  Witwicky,  Beneke,  Marckwald, 
and  others,  or  that  the  tumor  arises  from  cells  which  had  previously  assumed 
the  characters  of  pseudobile-ducts. 

The  stroma  is  abundant  and  reveals  the  desmoplastic  property  of  true 
carcinoma,  while  in  hepatoma  the  stroma  is  composed  only  of  capillaries. 
Elastic  fibers  derived  from  the  thickened  portal  canals  and  formed  anew  are 
demonstrable,  and  there  is  a  strong  tendency  toward  cicatricial  contraction 
of  the  tumor  nodules.  Most  of  the  nodules  are  inclosed  in  capsules  of  con- 
nective tissue  and  the  gradation  into  hepatic  parenchyma  seen  in  hepatoma 
is  usually  missing.  Yet  malignant  tumors  may  widely  infiltrate  the  paren- 
chyma. With  overgrowth  of  fibrous  tissue  a  scirrhous  structure  may  develop 
which  is  not  observed  with  hepatoma. 

The  outlying  portal  canals  commonly  exhibit  marked  proliferation  of 
bile-ducts  as  in  biliary  cirrhosis,  and  these  ducts  may  be  dilated,  lined  by 
one  or  more  layers  of  proliferating  cells  or  filled  with  papillary  projections 
of  epithelium.  From  such  precancerous  overgrowth  every  stage  up  to*  true 
adenocarcinoma  has  been  traced  (Kika). 

The  arrangement  of  the  cells  in  small  alveoli  is  characteristic  and  at  once 
distinguishes  most  of  the  tumors  from  the  coarse  trabecular  tumors  of  liver- 
cells.  In  the  slower  growths  the  alveoli  are  regular  and  adenomatous,  in 
more  malignant  cases  they  become  smaller,  more  numerous  and  irregular,  and 
in  very  active  processes  they  break  up  into  compact  small  groups  of  cells 
which  grow  diffusely,  as  in  mammary  carcinoma.  The  lumina  are  empty  or 
filled  with  hyaline  material  or  inspissated  bile.  When  bile  is  present  in  these 
tumors  it  must  be  referred  to  retained  secretion  derived  from  neighboring 
parenchyma  (Lohlein). 

When  small  cubical  or  indifferent  cells  form  compact  anastomosing 
groups,  Goldzieher  and  Bokay  liken  the  structure  to  basal-cell  carcinoma. 
They  recall  the  basal-cell  carcinoma  of  the  ductus  choledochus  described  by 
Burkhardt  and  suggest  that  these  hepatic  tumors  may  arise  from  the  larger 
bile-ducts.  The  liver  tissue  undergoes  passive  atrophy  or  degeneration,  but 
in  rare  cases  hypertrophy  of  cords  and  cells  is  observed. 

Although  the  small  veins  may  often  be  invaded  by  carcinoma  of  the  bile- 


692  NEOPLASTIC  DISEASES 

ducts,  metastases  are  not  commonly  observed  except  with  the  very  active 
tumors.  The  portal  and  mediastinal  lymph-nodes  may  be  involved.  In 
Dresclifeld's  and  Lohlein's  cases,  probably  derived  from  the  bile-ducts,  the 
metastases  were  general.  The  structure  of  the  secondary  tumors  may  re- 
produce the  original  or  appear  much  more  atypical.  Bile  formation  is  absent. 
Bonnet  describes  the  production  of  mucoid  material  in  secondary  tumors, 
and  Baschko  saw  a  cystic  growth  with  watery  secretion  reproduced  in  metas- 
tatic  tumors  of  lymph-nodes  and  rib. 

'       SARCOMA  OF  LIVER 

The  possible  sources  of  true  sarcoma  of  the  liver  and  the  probability  of 
their  occurrence  are  suggested  from  the  embryology  of  the  organ.  The 
hepatic  parenchyma,  liver  cords  and  bile-ducts,  and  gall-bladder  develop 
from  a  single  endodermal  bud,  from  which  an  early  subdivision  goes  to  form 
•the  gall-bladder.'  The  remainder  branches  out  into  a  mesodermal  matrix 
which  supplies,  blood-vessels  to  the  growing  parenchyma  and  connective 
tissue  in  the  portal  canals.  The  primitive  liver  is  a  hemopoietic  organ,  with 
marked  activity  of  the  endothelial  cells,  but  later  this  function  is  replaced  by 
metabolic  and  secretory  activities. 

•  '  The  presence  of  superfluous  mesodermal  material  in  the  liver  is  indicated 
in  the  cases  of  hepatoma  in  which  mucous  tissue  and  cartilage  of  metaplastic 
origin  have  been  found.  Great  proliferative  capacity  of  hepatic  endothelium 
is  exhibited  in  hepatoma,  in  which  the  growth  of  capillaries  keeps  pace  with 
that  of  the  liver-cells,  or  in  some  cases  of  perivascular  type  seems  almost  to 
outstrip  the  epithelial  growth.  Dominici  has  described  a  true  sarcomatous 
proliferation  of  the  endothelial  cells  in  a  case  of  multiple  hepatoma,  and  one 
nodule  seemed  to  be  composed  exclusively  of  endothelial  overgrowth. 

There  is,  therefore,  somewhat  scanty  but  direct  evidence  that  both  the 
stroma-cells  and  the  endothelium  of  the  capillaries  are  susceptible  of  tumor 
growth.  In  the  early  embryonal  liver  there  are  collections  of  blood-forming 
cells  which  might  be  drawn  into  possible  sources  of  round-cell  sarcoma,  but 
in  the  normal  liver  at  birth  there  is  no  structure  which  might  reasonably 
be  expected  to  give  rise  to  round-cell  or  lymphosarcoma.  Arnold's  lymph- 
nodules  are  islands  of  normoblasts. 

The  supposed  origin  of  sarcomas  suggested  by  the  observers  who  have 
repotted  cases  of  this  disease  is  extremely  varied.  Arnold  thought  of  the 
connective  tissue  about  blood-vessels  or  acini.  Delepine  argued  in  favor 
of  the  cellular  elements  of  the  vessels.  Byrom  suggested  the  perilymphatic 
connective  tissue.  Demel  derived  the  tumors  from  the  normal  connective 
tissue.  De  Vecchi  and  Guerrini  concluded  that  the  new  connective  tissue  in 
cirrhosis  was  the  source  of  the  polymorphous  and  angiosarcomas.  Marx 
derived  his  angiosarcoma  from  a  cavernoma.  Rolleston  and  Trevor  called 
their  case  malignant  hemangio-endothelioma.  It  is  obvious  that  the  source 
of  these  tumors  has  never  been  actually  traced. 

Considering  the  structures  accepted  as  indicating  a  mesoblastic  origin 
there  is  again  direct  conflict  of  opinion.  Arnold  included  in  his  table  of  26 
cases  of  sarcoma  several  reported  as  carcinoma.  De  Vecchi  and  Guerrini 
discard  20  and  accept  21  reported  cases.  Marx  questions  the  majority  of 
cases  on  various  grounds,  as  incomplete  autopsies  and  the  presence  of  other 
and  possibly  primary  tumors.  Several  reported  cases  were  probably  leuke- 
mic.  Rolleston  warns  against  mistaking  syphilitic  lesions  for  sarcoma  in 
infants. 

The  clinical  history  of  sarcoma  fails  to  show  any  distinguishing  features 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER  693 

from  carcinoma  (Rolleston).  The  disease  occurs  as  a  congenital  or  very 
early  tumor  in  infants,  in  children,  and  also  in  old  age.  Its  course  is  usually 
very  rapid  and  the  symptoms  are  those  of  malignant  carcinoma.  The  gross 
appearance  of  the  organ  recalls  various  forms,  chiefly  of  hepatoma,  as  massive, 
multiple,  hemorrhagic,  and  necrotic  tumors,  usually  in  much  enlarged  organs. 
Rolleston  and  Trevor  collected  7  cases  in  cirrhotic  livers. 

According  to  histological  structures  the  sarcomas  may  be  grouped  as 
angiosarcoma,  alveolar  sarcoma,  spindle-  and  round-cell  sarcoma. 

Angiosarcoma  is  much  the  most  frequent  variety  (Arnold,  v.  Kahlden, 
De  Vecchi,  Marx,  Nazari).  Yet  in  the  descriptions  of  the  cases  one  finds 
the  prominence  of  blood-vessels,  the  polymorphous  granular  cells,  the  giant- 
cells,  as  well  as  the  necrosis  and  hemorrhage  so  prominent  in  atypical  car- 
cinoma. The  structure  in  Marx'  case  is  exactly  duplicated  by  areas  of 
L'Esperance's  hepatoma.  I  do  not  believe,  therefore,  that  the  existence  of 
a  true  angiosarcoma  arising  from  blood-vessels  of  the  liver  has  been  satis- 
factorily demonstrated.  The  sole  direct  observation  pointing  to  such  an 
origin  is  that  of  Dominici  in  a  mixed  spindle-cell  sarcoma  and  embryonal 
hepatoma. 

The  alveolar  sarcomas  also  fail  to  commend  themselves  as  true  meso- 
blastic  tumors.  Typical  cases  are  those  of  Theodorow,  Holm,  and  de  Haan. 
Rolleston  and  Trevor  mention  an  alveolar  arrangement  of  polymorphic,  round, 
polygonal  and  giant-cells,  with  perithelial  structures  resembling  the  angio- 
epithelioma  of  Renon. 

Some  of  the  spindle-cell  sarcomas  seem  more  probably  of  mesoblastic 
origin,  but  a  pure  spindle-cell  tumor  with  uniform  structure  has  yet  to  be 
reported.  Ford's  tumor  in  a  cirrhotic  liver  was  largely  necrotic,  but  a  metas- 
tatic  tumor  was  composed  exclusively  of  spindle-cells.  Bramwell  and  Leith 
mention  areas  of  spindle-cells  with  long  oval  nuclei,  gelatinous  foci,  and 
multinuclear  giant-cells  in  a  large  cystic  hemorrhagic  tumor  replacing  the 
right  lobe.  Steinhaus  describes  eight  large  hemorrhagic  and -necrotic  tumors 
in  a  much  enlarged  liver,  the  edges  of  which  contained  large  spindle-  and 
giant-cells.  The  condition  recalls  atypical  hepatoma.  Some  of  the  polypoid 
and  spongy  spindle-cell  tumors  of  Pepere's  collection  were  probably  meso- 
blastic. Myxosarcomas  in  infants  are  reported  by  Meissenbach  and  Bernhinz. 

Primary  melanoma  of  the  liver  is  a  very  difficult  diagnosis  to  establish. 
Rolleston  in  referring  to  9  reported  cases  points  out  that  no  case  can  be  ac- 
cepted unless  the  uveal  tract  has  been  examined  after  death.  This  precau- 
tion has  usually  been  omitted.  In  2  cases  very  small  uveal  melanomas 
were  discovered  only  at  autopsy.  Marx  refers  to  other  reports  and  accepts 
the  occurrence  of  primary  melanoma  on  somewhat  uncertain  grounds. 

CARCINOMA  OF  GALL-BLADDER 

On  account  of  its  clinical  interest  carcinoma  of  the  gall-bladder  has  been 
very  fully  studied:  by  Frerichs  (1861);  Musser,  in  100  cases,  1889;  Courvois- 
sier,  103  cases,  1890;  and  Futterer,  268  cases,  1901.  A  very  full  analysis 
of  the  disease  is  given  by  Rolleston  (Lit.). 

It  forms  5  to  6  per  cent,  of  all  carcinomas  (Kaufmann),  affects  women  in 
the  ratio  of  4  or  5  to  one  man,  and  occurs  almost  always  after  40  years,  the 
average  in  both  sexes  being  58  years.  Maxon  reported  a  villous  carcinoma 
in  a  child  of  4  years,  while  Thomas  and  Noica  observed  the  disease  at  90 
years.  A  remarkable  etiological  relation  with  cholelithiasis  is  one  of  the 
most  interesting  features  of  this  disease.  Gall-stones  were  present  in  69  per 
cent,  of  Musser's  cases,  70  per  cent,  with  Futterer,  85  per  cent.  Zenker,  91 


694  NEOPLASTIC  DISEASES 

per  cent.  Courvoisier,  95  per  cent.  Siegert,  and  100  per  cent.  Janowski.  In 
some  cases  gall-stones  may  have  been  passed  earlier  or  they  may  have  been 
small  and  overlooked,  or  the  catarrhal  inflammation  which  commonly  leads 
to  gall-stones  excites  a  cellular  overgrowth  without  the  mechanical  irritation 
of  the  formed  stone.  The  proportion  of  cases  of  cholelithiasis  which  develop 
cancer  is  estimated  from  4  to  18  per  cent.  (Rolleston,  Slade).  Candler,  find- 
ing only  2  cases  of  carcinoma  in  315  cases  of  gall-stones  among  the  insane, 
argues  that  hospital  statistics  show  an  unduly  high  proportion.  Yet  Slade 
found  microscopical  cancer  in  10  of  17  (59  per  cent.)  gall-bladders  with  calculi. 
Since  secondary  cancers  rarely  produce  gall-stones  these  calculi  cannot  be 
regarded  as  the  result  of  the  tumor  (Siegert). 

Mechanical  irritation  of  calculi,  the  relation  to  a  peculiar  form  of  lipoid 
metabolism   (cholesterin),   and   the  irritative   and   digestive   action  of   bile 


FIG.  326. — Adenocarcinoma  with  columnar  cells  diffused  through  the  wall  of  the  gall- 
bladder. 

seem  to  combine  in  producing  the  remarkable  susceptibility  of  this  mucous 
membrane  to  cancer. 

Gross  Anatomy. — The  chronic  inflammation  associated  with  gall-stones 
produces  either  a  papillomatous  outgrowth  or  an  original  downward  growth 
with  metaplasia.  These  initial  tendencies  or  precancerous  conditions  deter- 
mine the  later  course  of  the  tumor,  yielding  three  main  forms:  (i)  Villous, 
papillomatous  or  fungating,  (2)  gelatinous,  and  (3)  diffuse,  flat,  infiltrating 
carcinoma. 

The  disease  first  appears  as  a  papilloma  or  as  a  flat  induration,  or  as  an 
eroded  ulcer.  The  location  is  usually  at  the  fundus,  or  the  neck,  or  at  the 
cystic  duct. 

(i)  The  papillary  form  grows  out  into  the  bladder  as  a  coarse  villous  or 
solid  fungating  mass  which  eventually  distends  and  obliterates  the  bladder 
and  forms  a  bulky,  well-circumscribed  tumor  (Michaux).  Early  papillary 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER  695 

tumors  are  rarely  seen,  but  may  appear  as  fragile,  villous,  or  warty  growths 
in  a  distended  cavity.  These  may  grow  along  the  cystic  duct  into  the  bile- 
ducts  or  the  common  duct  (Devic,  Gallavardin). 

Secondary  incrustations  with  bile-salts  and  tissue  detritus  may  form. 
Villous  tumors  gave  rise  to  hemorrhage  in  7  of  Musser's  cases.  Most  or  all 
of  the  bulky  tumors  appear  to  originate  as  papillary  adenocarcinomas  which 
reach  considerable  size  before  infiltrating  the  liver.  The  thickened  and  dis- 
tended wall  of  the  bladder  may  become  adherent  to  adjoining  tissues.  The 
gall-stones  may  be  found  embedded  in  the  mass.  In  advanced  stages  the 
infiltration  and  adhesions  render  it  difficult  to  determine  the  origin  and  early 
type  of  the  tumor. 

(2)  The  gelatinous  carcinomas  form  bulky  tumors  which  infiltrate  the 
wall  and  fill  the  cavity  of  the  bladder  and  early  extend  to  liver,  lymph-nodes, 
and  peritoneum.     After  the  stomach  the  gall-bladder  is  the  most  frequent 
source  of  gelatinous  carcinoma  of  the  peritoneum  (Kaufmann).    Yet  reports 
of  such  cases  distinctly  traced  to  the  gall-bladder  are  not  numerous.    Musser 
found  6. 

(3)  The  infiltrating  tumors  begin  as  a  submucous  growth  or  as  a  localized 
thickening  or  ulceration  in  a  mucosa  which  has  been  the  seat  of  chronic  in- 
flammation.   It  early  infiltrates  the  wall  of  the  bladder  which  becomes  uni- 
versally thickened  and  contracted.     Extensions  to  the  liver  and  adjoining 
lymph-nodes  are  soon  formed  and  the  disease  may  run  its  course  chiefly  as  a 
secondary  hepatic  carcinoma.    This  event  is  particularly  common  when  the 
tumor  originates  on  the  hepatic  aspect  of  the  bladder  wall. 

The  majority  of  infiltrating  tumors  follow  the  scirrhous  type,  converting 
the  bladder  into  a  hard  contracted  mass  without  increase  in  bulk,  or  constrict- 
ing it  in  hour-glass  form  (Rolleston),  and  fusing  the  organ  to  adjacent  viscera. 

Extensions  of  the  tumor  to  neighboring  tissues  are  observed  in  all  but 
early  cases,  and  metastases  are  frequent.  The  tumor  is  usually  adherent 
to  the  liver,  stomach,  duodenum,  or  colon,  and  bound  do,wn  by  adhesions 
which  inclose  tumor-cells  and  along  which  further  extensions  are  wont  to 
travel  (Courvoisier).  Extension  along  the  walls  of  the  bile-ducts  into  the 
liver  has  several  times  been  traced  (Willigk).  In  my  cases  the  sheaths  of 
nerve-trunks  have  formed  a  prominent  channel  of  dissemination.  Peritoneal 
extensions  may  constrict  the  cystic  or  common  ducts,  the  colon,  duodenum, 
or  pylorus.  Metastases  are  usually  located  in  liver,  abdominal  nodes,  and 
peritoneum.  Musser  in  100  cases  found  55  with  secondary  tumors,  besides 
cases  with  direct  extensions  to  colon,  duodenum,  and  stomach.  The  liver 
was  involved  in  54,  abdominal  nodes  in  16,  lungs  or  pleura  10,  and  pancreas 
and  adrenals  occasionally.  Mediastinal  and  supraclavicular  nodes  may  be 
extensively  enlarged  (Beadles,  West).  Tumors  have  also  been  found  in  ribs, 
navel,  rectum,  uterus,  ovary,  and  kidney.  Adrenal  metastases  may  give 
rise  to  cutaneous  pigmentation  suggesting  Addison's  disease  (Warthin). 
Eistulous  tracts  form  in  much  the  same  manner  as  with  migrating  gall-stones 
and  are  especially  common  when  the  carcinoma  begins  in  the  fundus.  The 
fistulous  openings  lead  chiefly  to  the  colon,  duodenum,  and  stomach,  rarely 
into  the  peritoneum  or  externally  (Riedel,  Moutier). 

Suppuration,  lateral  sacculation,  thrombosis  of  the  portal  veins,  angio- 
cholitis,  and  peritonitis  are  frequent  complications. 

Structure .— Precancerous  changes  are  often  pronounced  in  cases  of  chole- 
lithiasis. Janowski  mentions  the  frequency  of  papillary  outgrowths  and 
disorder  of  glands,  without  attributing  to  them  any  special  significance. 
Zenker  describes  elongation  of  glands,  overgrowth  of  epithelium,  fibrosis  of 
submucosa,  and  round-cell  infiltration  as  preliminaries  of  cancer.  Slade 


696  NEOPLASTIC  DISEASES 

found  a  high  proportion  of  microscopical  carcinomas  in  cases  of  cholelithiasis, 
but  the  details  of  these  lesions  are  not  given.  McCarthy  in  a  considerable 
series  found  only  3  cases  of  chronic  catarrhal  cystitis  with  carcinomatous 
changes. 

It  is  probable  that  the  markedly  scirrhous  character  of  many  cases  of  early 
carcinoma  of  the  gall-bladder  results  from  the  chronic  productive  inflamma- 
tion preceding  the  new  growth.  In  some  cases  there  are  no  precancerous 
changes  in  the  mucosa.  In  an  early  carcinoma  at  the  neck  I  found  a  submucous 
nodule  as  large  as  a  pea  lying  beneath  practically  unaltered  mucosa  and 
suggesting  an  origin  from  aberrant  gland  tissue.  Other  probable  modes 
of  origin  are  suggested  by  the  rare  cases  of  cholesterin  cysts  of  the  mucosa 
and  of  cystic  adenomas  which  may  project  internally  or  externally  and  may 
contain  cholesterin  concretions  (Rolleston,  Kaufmann) . 

In  a  case  of  cholelithiasis  of  long  standing  the  enlarged  and  thickened 
gall-bladder  I  found  to  present  over  its  eroded  mucosa  very  numerous  flat 
or  nodular  opaque  plaques,  2  to  5  mm.  in  diameter.  On  section  these  proved 
to  be  foci  of  cellular  connective  tissue  surrounding  groups  of  atypical  glandu- 
lar epithelium  showing  numerous  mitoses.  Here  was  evidently  the  begin- 
ning of  a  carcinoma  arising  from  multiple  foci  and  destined  to  produce 
a  diffuse  carcinoma  of  the  organ. 

The  natural  course  of  papilloma  appears  to  be  that  of  the  benign  growth 
or  of  the  rare  villous  carcinoma.  Sand  and  Mayer  and  Chappet  describe 
advanced  cases  without  loss  of  villous  type.  M.  Dominici  describes  diffuse 
papilloma  of  the  entire  mucosa  without  a  trace  of  atypical  growth.  Pels- 
Leusden,  however,  finds  atypical  downward  as  well  as  outward  growth  of 
epithelium  in  early  papillomas. 

Luschka's  glands  consist  of  epithelial  invaginations  of  the  mucosa  which 
extend  into  the  muscular  layer  and  often  to  the  serous  surface  of  the  gall- 
bladder. Aschoff  and  others  find  very  marked  proliferation  of  these  canals 
in  cholelithiasis,  and  Pels-Leusden  believes  that  the  irritation  of  cholesterin 
granules  and  bacteria  in  these  crypts  is  an  important  source  of  carcinoma 
following  gall-stones. 

Aside  from  minor  variations  the  established  disease  presents  two  main 
structural  types:  (i)  Adenocarcinoma  and  (2)  alveolar  carcinoma. 

Adenocarcinoma  is  the  most  frequent  form,  and  it  produces  papillary, 
gelatinous,  and  scirrhous  tumors.  The  growths  present  elongated  vascular 
papillae  of  connective  tissue  covered  by  cylindrical  cells  and  infiltrated  with 
secondary  alveoli  lined  by  cuboidal  cells.  Mucous  oversecretion  and  degenera- 
tion is  a  very  common  feature  of  all  the  adenocarcinomas.  It  may  appear 
in  isolated  foci  in  the  papillary  and  scirrhous  growths  and  become  universal 
in  certain  cases  which  run  the  course  of  bulky  and  wide-spread  gelatinous 
carcinoma.  They  early  tend  to  perforate  the  wall  and  extend  to  the  peritoneum. 

In  the  scirrhous  type  extensive  new  growth  of  fibrous  tissue  surrounds 
the  isolated  adenomatous  alveoli  in  the  bladder,  but  in  the  lymph-nodes  and 
liver  the  cells  grow  more  rapidly  and  fibrosis  is  wanting.  The  extent  of  the 
fibrosis  is  often  remarkable,  and  only  pyloric  cancers  show  such  desmoplastic 
quality  in  ordinary  adenomatous  alveoli. 

Alveolar  carcinoma  presents  in  the  gall-bladder  the  usual  features  of  this 
neoplastic  process.  The  most  malignant  growths  are  composed  largely  of 
pseudo-alveoli  of  small  cuboidal  or  rounded  cells.  Others  show  many  traces 
of  adenocarcinomatous  structure,  and  the  frequent  transition  of  one  type 
into  the  other  indicates  that  both  arise  from  the  same  glandular  structures 
in  the  mucosa. 

Squamous-cell  carcinomas,  pure  or  associated  with  cylindrical  cell  carci- 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER  697 

noma,  are  not  infrequently  observed  (Rolleston,  Lit.)-  Deetz  reports  several 
cases  in  some  of  which  the  squamous  characters  with  pearls  and  spine -cells 
were  highly  developed.  In  Monckberg's  case  the  two-cell  types  were  inti- 
mately mingled  in  the  original  tumor,  but  grew  in  greater  isolation  in  the 
lymph-nodes.  These  tumors  probably  arise  in  lesions  which  have  previously 
developed  a  squamous  metaplasia.  Thus  Lubarsch  found  a  vesical  papil- 
loma  the  size  of  a  bean  resembling  an  acuminate  condyloma.  Or  they  signify 
a  progressive  tendency,  illustrated  in  Monckberg's  case,  toward  squamous 
metaplasia  of  the  cylindrical  cells  of  an  adenocarcinoma. 

A  primary  melanoma  of  the  gall-bladder  is  described  by  Wieting  and 
Hamdi. 

Clinical  Features. — The  symptoms  of  cancer  of  the  gall-bladder  may  be 
referred  to  (i)  the  preexisting  cholelithiasis,  (2)  the  local  effects  of  the  tumor, 
and  to  (3)  extensions  and  metastases  (Rolleston). 

Symptoms  of  gall-stones  are  absent  in  the  majority  of  cases  (Kehr),  but 
have  preceded  the  tumor  for  25  years  (Jourdan).  Initial  symptoms  may  be 
local  pain,  dyspepsia,  or  (50  per  cent.)  a  local  tumor.  Jaundice  suddenly 
established  and  persistent  occurs  in  most  cases.  Many  cases  simulate  hepatic 
carcinoma.  Ascites  is  usually  added  from  thrombosis  of  large  veins  or  peri- 
toneal extensions,  and  the  effusion  may  be  chylous.  The  cachetic  stages  are 
marked  by  fever  from  infections,  cholemia,  hemorrhages,  and  emaciation. 
The  total  duration  is  extremely  variable,  but  after  the  appearance  of  jaundice 
few  cases  last  more  than  6  months. 

SARCOMA  OF  GALL-BLADDER 

Considerable  uncertainty  as  well  as  theoretical  interest  surround  the 
interpretation  of  certain  tumors  recorded  as  primary  sarcoma  of  the  gall- 
bladder (Bayer,  Rolleston,  Lit.).  All  of  these  cases  appear  to  have  occurred 
in  adults  who  long  suffered  from  gall-stones  and  usually  from  suppurative 
cholecystitis.  The  organ  was  much  enlarged,  once  to  the  size  of  a  man's  head 
(Bayer),  and  the  cystic  central  cavity  contained  fluid.  One  or  many  gall- 
stones appeared  in  the  cavity  or  wall.  The  course  of  the  disease  was  pro- 
longed. It  is  evident  that  a  long  period  of  chronic  inflammation  had  pre- 
ceded any  neoplastic  process  which  may  have  developed  by  the  time  the 
tumor  came  under  observation.  Therefore  in  the  interpretation  of  these 
cases  a  wide  range  of  productive  inflammatory  changes  must  be  taken  into 
account.  Iwasaki's  very  large  tumor  appears  to  have  been  composed  largely 
of  inflammatory  tissue,  and  in  the  case  of  Carson  and  Smith,  a  localized  large 
round-cell  growth  8  cm.  in  diameter,  the  bladder  wall  was  the  seat  of  a  pro- 
nounced productive  and  exudative  inflammation. 

It  appears,  however,  that  two  forms  of  sarcoma  arise  on  such  an  inflam- 
matory basis,  one  derived  from  an  overgrowth  of  smooth  muscle-cells,  the  other 
from  the  inflammatory  new  growth  of  connective  tissue  and  blood-vessels. 

Myosarcoma  with  the  above  general  characters  was  described  by  Land- 
steiner.  The  wall  of  the  much  enlarged  bladder  was  3  cm.  in  thickness. 
There  was  beginning  infiltration  of  the  liver.  The  tissue  was  composed  of 
areas  of  spindle-cells  arranged  in  parallel  bands,  and  presenting  the  char- 
acters of  smooth  muscle.  Other  areas  presented  larger  rounded  atypical  cells 
apparently  derived  from  the  spindle-cells.  The  liver  nodules  contained 
spindle-cells.  Other  spindle-cell  sarcomas  are  recorded  by  Griffon  and  Segall 
and  Rolleston,  and  in  the  latter 's  case  there  were  metastases  in  aortic  and 
inguinal  glands.  In  connection  with  these  cases  Sutherland's  adenomyoma 
is  of  interest. 


698 


NEOPLASTIC  DISEASES 


Sarcomas  of  fibroblastic  type  are  of  somewhat  less  definite  nature.  Par- 
lavecchio  evacuated  2  liters  of  purulent  fluid  from  a  thickened  gall-bladder 
the  wall  of  which  contained  sarcomatous  tissue  with  polymorphous  cells. 

Bayer  describes  two  very  large  gall-bladders  containing  many  stones, 
one  8  cm.  in  diameter,  with  fluid  detritus.  The  wall  was  composed  of  sar- 


FIG.  327. — Sarcoma  of  gall-bladder.     (After  Carson  and  Smith,  A.  S.,  62.) 

comatous  tissue  containing  vascular  connective  tissue  and  areas  of  spindle-, 
rounded  and  giant-cells,  and  epithelial  remnants.  One  of  the  tumors  had 
invaded  the  liver  and  gave  peritoneal  nodules.  In  the  other,  areas  of  cartilage 
and  bone  were  found.  An  angiosarcomatous  structure  was  described  by 
Klingel,  the  neoplastic  nature  of  which  is  doubted  by  Landsteiner.  Seibert 


FIG.  328. — Structure  of  tumor  in  Fig.  327.     Sarcoma  of  gall-bladder. 

described  a  very  large  cystic  and  necrotic  tumor  as  a  degenerating  lympho- 
sarcoma.    Becker's  endothelioma  seems  of  uncertain  nature. 

CARCINOMA  OF  THE  LARGER  BILE-DUCTS 

Epithelial  tumors  of  the  large  bile-ducts  present  much  the  same  etiolog- 
ical,  gross  anatomical,  and  microscopical  features  as  carcinoma  of  the  gall- 
bladder, but  their  location  favors  early  mechanical  obstruction  of  important 
channels,  which  promptly  declares  itself  in  the  form  of  severe  jaundice  and  a 
rapidly  fatal  course  of  the  disease.  The  fatal  effects  of  such  comparatively 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER  699 

miniature  and  relatively  benign  tumors  render  these  growths  of  much 
surgical  interest. 

The  chief  locations  of  these  tumors  are:  (i)  Ductus  choledochus,  (2) 
ductus  cysticus,  (3)  ductus  hepaticus.  A  common  seat  of  carcinoma  is  the 
point  of  junction  of  the  three  ducts,  of  which  Donati  collected  33  cases. 
Rolleston  finds  the  following  distribution  in  go  cases:  Common  bile-duct, 
44;  junction  of  three  ducts,  27;  hepatic  duct,  22;  cystic  duct,  7.  Lapointe  and 
Raymond  collected  32  cases  in  the  hepatic  duct  and  37  at  the  junction. 
Miodowski  analyzed  41  cases. 

Etiology. — The  relative  infrequency  of  gall-stones  (22  per  cent,  in  264 
cases)  and  the  predominance  of  the  disease  in  males  (50  to  35)  contrast  car- 
cinoma of  the  larger  bile  passages  with  that  of  the  gall-bladder.  Possibly  the 
trauma  of  migrating  calculi  may  be  a  factor. 

Gross  Anatomy. — Chiefly  because  of  the  early  appearance  of  mechanical 
obstruction  carcinoma  of  the  bile-ducts  is  encountered  when  the  tumor  is 
small.  These  early  tumors  are  villous,  nodular,  or  diffuse: 

(1)  Villous  growths  may  be  single  or  multiple,  and  may  fill  and  distend 
the  duct.     Extensions  may  form  while  the  original  tumor  remains  small 
(Lamble,  Schmidt). 

(2)  Nodular  masses  appear  in  the  submucosa  and  muscular  wall  and  the 
very  small  size  of  some  of  these  tumors  is  notable.    They  tend  early  to  encircle 
and  constrict  the  passage,  and  may  appear  merely  as  a  cicatricial  stenosis, 
the  cancerous  nature  of  which  can  be  determined  only  by  the  microscope 
(Devic,  Gallavardin,  Lit.). 

(3)  A  more  diffuse  growth  may  extend  along  the  duct  converting  it  into  a 
smooth  rigid  tube  from  the  inner  surface  of  which  project  minute  carcinoma- 
tous  vegetations  (Jenner,  Chapper).     Bulky  tumors  rarely  develop  from  the 
bile-ducts. 

The  extensions  are  usually  limited  to  the  walls  of  the  ducts,  but  in  later 
stages  adjoining  viscera  are  involved  by  various  channels.  In  12  cases  of 
carcinoma  of  the  hepatic  ducts  Lecene  and  Pagniez  found  the  tumor  limited 
to  the  ducts.  Beginning  at  one  point  the  growth  infiltrates  the  wall  until  it 
involves  a  large  portion  of  several  ducts  or  the  gall-bladder.  Extensions  of 
papillary  tumors  through  the  hepatic  ducts  may  invade  the  liver.  More 
frequently  the  liver  is  invaded  through  the  lymphatics  of  the  duct.  In  either 
case  the  condition  may  simulate  hepatic  carcinoma.  Extending  to  the  pan- 
creas the  head  of  this  organ  may  be  infiltrated,  simulating  pancreatic  car- 
cinoma. Carcinoma  of  the  cystic  duct  is  rarely  demonstrated,  but  in  not  a 
few  cases  the  tumor  involves  both  cystic  duct  and  bladder  so  that  its  original 
source  cannot  be  determined.  The  gastrohepatic  and  other  nodes  are  fre- 
quently involved. 

The  condition  of  the  gall-bladder  varies  with  the  location  of  the  tumor. 
Carcinoma  of  the  hepatic  ducts  leads  to  contraction  of  the  bladder  or  per- 
mits its  moderate  distention  by  mucus  or  calculi.  The  intrahepatic  ducts 
may  then  become  the  seat  of  catarrhal,  suppurative,  or  gangrenous  cholan- 
gitis,  and  the  liver  parenchyma  may  undergo  focal  icteric  necrosis  (Futterer). 
Similar  results  follow  when  the  tumor  is  lower  down  in  the  common  duct. 
Tumors  involving  the  junction  usually  lead  to  distention  of  the  bladder, 
but  when  the  cystic  duct  is  occluded  the  bladder  remains  small  (Lapointe, 
Raymond).  Tumors  of  the  common  duct  regularly  permit  filling  and  dis- 
tention of  the  gall-bladder. 

Courvoisier  stated  the  principle  that  the  gall-bladder  is  usually  distended 
with  cancer  and  contracted  with  calculi  of  the  ductus  choledochus.  Very 
moderate  compression  is  capable  of  bringing  about  bile-stasis,  so  that  the 


700  NEOPLASTIC  DISEASES 

stenosed  duct  may  readily  admit  a  probe  or  become  pervious  on  manual 
compression  of  the  bladder. 

The  structure  of  carcinoma  of  the  bile-ducts  presents  the  same  types  as 
in  the  gall-bladder,  differing  chiefly  in  the  greater  tendency  to  fibrosis.  In 
some  cases  it  is  remarkable  to  find  such  extensive  areas  of  fibrous  tissue  about 
the  hilus  of  the  liver  or  head  of  the  pancreas  with  so  little  epithelial  tissue, 
so  that  small  carcinomas  in  these  regions  frequently  require  microscopical 
detection. 

The  usual  structure  is  that  of  adenocarcinoma  with  cylindrical  cells  and 
mucus  production.  Occasionally  the  alveoli  are  small,  the  lining  cells  cuboidal 
or  spherical.  Leith  describes  a  colloid  carcinoma.  Squamous  metaplasia 
is  occasionally  observed. 

According  to  their  chief  clinical  features  Devic  and  Gallavardin  divide 
the  cases  as  follows:  (i)  Enlargement  of  the  liver  with  distended  gall- 
bladder. This  form  is  regularly  associated  with  tumors  of  the  lower  segments 
(supraduodenal),  rarely  with  tumors  of  the  upper  subhepatic  segments  of 
the  ducts.  (2)  The  liver  varies  in  size  and  the  gall-bladder  is  not  enlarged, 
with  most  tumors  limited  to  the  hepatic  ducts.  (3)  Hypertrophic  biliary 
cirrhosis  may  be  simulated  by  tumors  in  various  locations.  Persistent 
jaundice  and  local  pain  are  nearly  constant.  The  duration  has  varied  from 
3  to  19  months. 

Carcinoma  of  the  Ampulla  of  Vater. — The  duct  formed  by  the  junction 
of  the  common  bile-duct  and  the  pancreatic  duct  (Wirsung)  and  opening 
into  the  duodenum  at  the  papilla  is  called  the  ampulla  of  Vater.  Carcinoma 
arises  in  the  corrugated  mucosa  of  this  structure  and  at  the  duodenal  papilla. 
Cases  have  been  collected  by  Busson  (i)  Georges  (20),  and  Rolleston  (19) 
(Lit.).  Exc^)t  in  very  early  cases  it  is  difficult  to  determine  the  exact  origin 
of  these  tumors.  Some  arise  at  the  termination  of  the  common  bile-duct, 
others  in  the  mucosa  of  the  pancreatic  duct,  still  others  in  the  ampulla  proper 
or  at  the  papilla.  The  etiological  factors  are  similar  to  those  of  carcinoma  of 
the  bile-ducts. 

Gross  Anatomy. — The  tumors  are  small  villous  or  papillary  growths  or 
diffuse  infiltrations  of  the  wall.  McCarthy  found  the  papilla  excavated  by  a 
cancerous  ulcer.  They  early  cause  stenosis  of  the  duct  with  cholemia. 
Aynoud  found  that  20  per  cent,  of  the  cases  progress  far  enough  to  produce 
secondary  extensions  and  metastases,  chiefly  in  the  adjacent  lymph-nodes. 
The  structurally  benign  growths  are  almost  equally  effective  with  the  malig- 
nant in  producing  obstruction,  and  the  anatomical  relations  are  so  intimate 
that  the  mechanical  effects  are  very  similar  in  all  the  various  locations.  The 
gall-bladder  and  the  bile-ducts  from  the  point  of  the  tumor  to  the  intra- 
hepatic  radicles  are  usually  dilated.  Jaundice,  at  first  intermittent,  later  per- 
sistent, is  a  nearly  constant  symptom,  but  is  often  absent  with  tumors  of  the 
papilla.  Suppurative  cholangitis  with  fever  may  result  especially  with  tumors 
of  the  papilla.  The  pancreatic  duct  becomes  widely  dilated,  usually  with- 
out secondary  changes  in  the  pancreas  (Dieulafoy). 

Structure. — Columnar-cell  adenocarcinoma  is  the  type  almost  always 
observed.  The  architecture  is  villous,  fungoid,  or  infiltrating,  without  much 
variation  in  structure.  Alveoli  lined  by  smaller  cubical  or  rounded  cells 
appear  in  tumors  of  Wirsung's  duct  (Letulle),  and  have  been  described  in  a 
growth  traced  to  the  duodenal  mucosa  or  Brunner's  glands  by  Klotz.  In  a 
small  villous  growth  at  the  termination  of  Wirsung's  duct  Carnot  and  Harvier 
found  all  transitions  from  finely  villous  papilloma  with  cylindrical  cells  to 
infiltrating  alveolar  carcinoma.  Tumors  of  the  duodenal  papilla  arise  chiefly 
from  the  duct  mucosa  and  contain  columnar  cells  (Schuller).  A  highly  pig- 


EPITHELIAL  HYPERPLASIA  AND  TUMORS  OF  LIVER  701 

mented  but  otherwise  typical  villous  adenocarcinoma  of  the  ampulla  was 
described  by  Duval,  an  observation  which  speaks  strongly  in  favor  of  the 
local  origin  of  certain  melanotic  tumors. 

The  results  of  surgical  treatment  of  carcinoma  of  the  gall-bladder  and 
ducts  is  highly  unsatisfactory.  In  93  cholecystectomies  collected  by  Quenu 
the  operative  mortality,  chiefly  from  hemorrhage,  was  18  per  cent.,  and  only 
14  of  52  cases  were  known  to  be  living  after  one  year.  Quenu  mentions  9 
excisions  of  tumors  of  the  bile-ducts,  and  Mayo  2.  The  final  results  were 
unfavorable.  For  carcinoma  of  the  ampulla  Quenu  in  9  cases  found  6  deaths, 
and  Oehler  the  same  proportion.  Borelius  reports  several  fatal  operations 
from  Sweden.  The  early  stage  of  growth  at  which  these  tumors  declare  them- 
selves encourages  surgical  interference.  L'Esperance,  in  this  laboratory,  has 
observed  just  within  the  papilla  a  papillary  carcinoma  5  mm.  in  diameter 
which  had  caused  a  single  fatal  hemorrhage. 


CHAPTER  XXXIV 


TUMORS  OF  PANCREAS 

Adenoma  of  Pancreas. — Adenomas  are  very  rarely  observed  in  the  pan- 
creas.    Borst  states  that  he  has  seen  nodular  hyperplasia  of  the  pancreas 

associated  with  a  similar  condition  in 
•   "  the  liver. 

Cystadenomas  may  be  separated 
from  retention  cysts  by  the  abundant 
growth  of  epithelial  papillae.  Lazarus 
describes  many  stages  in  the  develop- 
ment of  cystadenomas  from  dilated 
ducts.  Edling  collected  13  cases  from 
the  literature,  which  illustrate  single 
and  multiple  cystadenomas,  lined  by 
single  layers  of  cubical  or  cylindrical 
cells,  or  partly  or  completely  filled  by 
epithelial  papillae.  Atypical  overgrowth 
and  signs  of  malignancy  appear  in  some 
cases.  Kaufmann  saw  malignant 
changes  in  a  portion  of  a  large  cystad- 
enoma  of  the  cauda,  and  Sotti's  tumor 
gave  papillary  metastases. 

Solitary  adenomas  appear  as  small 
solid  tumors  well  circumscribed  from 
the  parenchyma.  Neve's  scirrhous  ade- 
noma measured  2\  X  2  inches  and 
constricted  the  duodenum.  Thierfelder 
shelled  out  of  the  pancreas  a  small  tumor 
composed  of  alveoli  of  cylindrical  cells. 
Other  cases  are  reported  by  Biondi  and 
Chauffard.  All  of  them  appeared  to 
arise  from  the  ducts.  Cesaris-Demel 
describes  an  adenoma  which  suggested 
an  origin  from  the  glandular  acini. 

Adenoma  of  island  tissue  has  been 
described  by  Nicholls,  Helmholtz,  and 
Cecil.  They  were  single  small  yellowish 
nodules  as  large  as  a  pea  and  presented 
a  structure  strongly  resembling  that  of 
island  tissue.  Cecil,  in  describing  such 
a  structure,  traces  the  transition  from 
the  hypertrophic  islands  of  various  con- 
ditions and  concludes  that  the  small 
tumors  are  more  properly  to  be  re- 
garded as  markedly  hypertrophic  islands 
rather  than  neoplasms. 

Carcinoma  of  Pancreas. — Cancer  of  the  pancreas  has  long  been  a  subject 
of  much  clinical  interest.     It  was  extensively  discussed  by  Classen  in  1842 

702 


FIG.  329. — Cystadenoma  of  pancreas. 

(After  Roman.) 


TUMORS  OF  PANCREAS  703 

(older  Lit.),  by  Ancelet,  who  analyzed  200  cases  in  1860,  and  by  Miraillie 
in  1893. 

Bard  and  Pic  (1888)  emphasized  certain  features  of  the  disease  as  con- 
stituting a  specific  syndrome,  viz.:  distention  of  the  gall-bladder,  absence  of 
hepatic  enlargement,  jaundice,  and  rapid  cachexia. 

General  Etiology. — Cancer  of  the  pancreas  formed  1.76  per  cent,  of  Kauf- 
mann's  autopsies  on  malignant  tumors.  Of  2943  autopsies  on  cancer  referred 
to  by  Korte  there  were  59  pancreatic  cases,  2  per  cent.  Bashford  collected 
1000  cases  of  primary  malignant  tumors  of  the  pancreas  among  84,000  can- 
cers. Owing  to  the  difficulty  of  accurate  diagnosis  the  value  of  miscella- 
neous statistics  may  be  doubted.  Ollivier  has  pointed  out  the  necessity  of 
very  careful  histological  study  in  order  to  avoid  confusion  with  cancer  of  the 
duodenum  and  bile-ducts.  The  disease  occurs  between  30  and  50  years,  but 
often  in  younger  subjects.  A.  Kuhn  describes  a  cylindrical-cell  carcinoma 
in  a  cirrhotic  pancreas  with  pulmonary  metastases  in  a  child  of  2  years  and 
refers  to  other  cases  at  an  early  age.  I  have  observed  one  case  associated 
with  a  large  pancreatic  cyst. 

Many  cases  occur  in  cirrhotic  organs  and  a  parallel  may  here  be  drawn 
between  the  liver  and  the  pancreas  since  it  appears  that  carcinoma  of  the 
ducts  follows  periductal  fibrosis,  carcinoma  of  the  parenchyma  appearing 
after  interstitial  fibrosis  (Hulst).  Only  rarely  are  there  preliminary  symp- 
toms, as  in  Leriche's  case  of  transient  jaundice,  pointing  to  a  cholelithiasis 
or  pancreatic  calculus.  Lazarus  mentions  5  cases  of  adenocystoma  with 
pancreatic  calculi.  The  gall-bladder  is  usually  free  of  calculi  and  contains 
thick  bile  and  mucus.  Reasoning  from  analogy  with  the  liver,  carcinoma  of 
the  pancreatic  parenchyma  may  be  regarded  as  beginning  in  a  functional 
hyperplasia  following  cirrhosis,  and  carcinoma  of  the  ducts  from  chronic 
irritation  and  stasis  in  these  canals. 

The  occurrence  of  aberrant  pancreatic  tissue  in  the  duodenal  mucosa 
and  about  the  head  of  the  pancreas  suggests  that  certain  turriors,  especially 
those  involving  both  duodenal  wall  and  pancreas,  may  arise  from  such  aber- 
rant tissue  (Heinrich,  Lit.).  In  some  of  these  accessory  glands  there  is  exten- 
sive multiplication  of  ducts  from  which  a  cylindrical-cell  tumor  might  arise. 

Gross  Anatomy. — The  location  of  the  tumor  is  usually  in  the  head  or 
extending  diffusely  over  most  of  the  organ.  Tumors  limited  to  the  body  are 
much  less  common  and  the  tail  is  rarely  affected.  Of  386  cases  collected 
from  the  literature,  158  were  diffuse,  156  limited  to  the  head,  28  in  body,  12 
in  tail.  The  organ  is  regularly  enlarged,  but  in  scirrhous  tumors  the  gland 
may  be  small  but  very  hard. 

While  small  tumors  may  be  limited  to  the  pancreas  (12  of  127  cases, 
Segre),  more  advanced  growths  early  infiltrate  the  surrounding  tissues  and 
cause  compression.  The  common  duct  is  occluded  with  bile-stasis,  dila- 
tation of  the  bladder,  and  varicosities  of  the  bile-ducts  up  to  and  into  the 
liver.  The  pancreatic  duct  may  be  distended  and  tortuous  and  filled  with 
mucinous  fluid.  Lachmann  reported  rupture  of  the  gall-bladder.  Muller 
observed  displacement  of  the  stomach  with  hour-glass  contraction.  The  duo- 
denum was  stenosed  in  8  scirrhous  cases  collected  by  Hagenbach.  Stenosis 
of  the  aorta  is  reported  by  Boldt.  Portal  thrombosis  has  been  recorded  in 
5  cases  (Korte) .  The  soft  tumors  may  necrose  and  perforate  the  stomach 
or  the  large  veins  with  fatal  hemorrhage. 

Metastases  are  very  commonly  observed  and  appear  first  in  adjacent 
lymph-nodes  and  liver.  Bard  and  Pic  emphasize  the  occurrence  of  very 
numerous  minute  nodules  in  the  liver  without  enlargement  of  the  organ, 
whereas  secondary  gastric  carcinoma  causes  bulky  growths  in  the  liver.  Very 


704 


NEOPLASTIC  DISEASES 


numerous  nodules  may  appear  over  the  peritoneum  and  in  the  peripancreatic 
fat  tissue.  Extensive  invasion  of  the  pancreas  and  adjoining  tissues  may  be 
complicated  by  hemorrhages  and  fat  necrosis.  General  metastases  are  not 
common,  probably  because  the  disease  is  rapidly  fatal. 

Structure. — Two  main  types  of  pancreatic  carcinoma  are  observed:  (i) 
Cylindrical-cell  adenocarcinoma,  arising  from  the  ducts,  and  (2)  carcinoma 
simplex  arising  from  the  parenchyma.  The  former  may  rarely  show  exten- 
sive gelatinous  changes,  and  most  cases  of  the  latter  are  scirrhous  (Kaufmann, 
Miraillie). 

(i)  Carcinoma  of  the  ducts  may  be  associated  with  proliferation  of  lining 
cells  in  the  outlying  regions,  which  Hulst  observed  in  a  case  of  periductal 
fibrosis  and  interpreted  as  precancerous.  Ollivier  also  traced  his  case  of 
cylindrical-cell  tumor  from  such  preliminary  changes.  Muckenbeck,  how- 


xgvt..jiiff/&r?.J/  :3 


FIG.  330.  —  Structure  of  an  infiltrating  and  fibrosing  adenocarcinoma  of  the  head  of  the 

pancreas. 


ever,  found  reason  to  believe  that  cylindrical-cell  tumors  might  develop  from 
the  parenchyma. 

The  tumors  are  regularly  located  in  the  head  or  corpus  and  form  some- 
what massive  growths  which  are  imperfectly  separated  from  the  parenchyma. 
They  are  firm  from  fibrosis  or  contain  many  small  cysts,  or  the  central  mass 
is  broken  down,  suggesting  an  origin  from  cystadenomas. 

The  structure  is  composed  of  papillary  outgrowths  and  alveoli  lined  by 
cylindrical  or  cuboidal  cells.  In  atypical  areas  the  cells  may  lose  their  cyl- 
indrical form  and  grow  more  diffusely.  Yet  Kulst  found  the  cylindrical 
type  preserved  in  secondary  tumors  of  lymph-nodes  and  liver,  and  Satti 
reports  a  cystadenoma  papilliferum  with  typical  metastases  in  lymph-nodes, 
lungs,  and  peritoneum. 

The  local  extensions  of  the  tumor  have  been  traced  by  Ollivier  through 


TUMORS  OF  PANCREAS 


705 


ducts,  lymphatics,  and  nerve-trunks.    Kaufmann  found  the  large  and  small 
veins  invaded,  but  without  metastases. 

(2)  Carcinoma  of  the  parenchyma  produces  a  more  diffuse,  rapidly  grow- 
ing tumor  which  is  firm  or  soft  according  to  the  proportion  of  fibrous  tissue. 
The  cells  are  small  or  large,  granular,  hydropic,  or  fatty,  resembling  those 
of  the  pancreatic  alveoli.  The  cell  borders  are  often  indistinct,  and  the 
vesicular  nuclei  occupy  much  of  the  cell.  Nucleoli  are  poorly  developed. 
The  relatively  large  size  of  the  nuclei  is  often  a  notable  feature.  The  cells 
are  arranged  in  small  or  large  alveoli  separated  by  a  fine  stroma  and  in  some 
cases  the  appearance  suggests  a  simple  cirrhosis  in  an  otherwise  unaltered 
pancreas  (Bard,  Pic).  In  the  larger  alveoli  the  outer  cells  may  be  cubical. 
In  some  cases  there  is  a  definite  lumen  in  the  cell  groups,  filled  with  coagulum. 
These  spaces  may  then  be  lined  by  high  cuboidal  or  low  cylindrical  cells. 
Large  mononuclear  giant-cells  may  appear  in  numbers  and  persist  in  metastases. 


FIG.  331. — Structure  of  a  carcinoma  of  pancreas. 


In  more  atypical  and  malignant  tumors  the  cells  are  smaller  and  embry- 
onal in  type  and  the  arrangement  may  be  irregular  and  diffuse.  Such  cases 
may  resemble  lymphosarcoma  with  a  faint  alveolar  tendency.  In  one  of 
my  cases  the  original  tumor  recalled  lymphosarcoma,  while  the  pulmonary 
metastases  contained  small  cuboidal  or  spindle-cells. 

The  origin  of  this  tumor  has  been  traced  by  Ollivier,  in  an  early  case,  to 
the  pancreatic  alveoli  and  the  transformation  of  gland-cells  into  tumor-cells 
he  has  sketched  in  detail.  Usually  all  early  stages  of  such  origin  are  lost. 

The  desmoplastic  properties  of  pancreatic  carcinoma  are  somewhat  un- 
usual and  probably  account  for  the  large  proportion  of  scirrhous  cases.  A 
preexisting  cirrhosis  is  also  a  factor.  Extensions  throughout  the  pancreas 
occur  early  and  travel  by  ducts,  lymphatics,  blood-vessels,  nerve-trunks, 
and  alveolar  spaces.  In  one  of  my  cases  the  organ  was  diffusely  infiltrated  and 
the  seat  of  very  numerous  small  cysts,  dilated  ducts  containing  minute  calculi. 

The  parenchyma  shows  interesting  changes.  There  may  be  a  collateral 
45 


706  NEOPLASTIC  DISEASES 

or  preexisting  hyperplasia  of  the  gland  tissue  which  is  difficult  to  distinguish 
from  invading  carcinoma.  The  islands  of  Langerhans  are  usually  hyper- 
trophied  and  may  be  much  increased  in  number,  showing  many  transitions 
from  secreting  to  island  tissue.  The  islands  may  also  exhibit  a  peculiar  hyper- 
trophy approaching  the  structure  of  the  tumor.  It  was  apparently  this 
appearance  which  led  Fabozzi  to  conclude  that  all  parenchymatous  cancers 
arise  from  the  islands.  This  interpretation  has  been  discussed  by  Reitmann 
and  Helmholtz.  Another  feature  which  might  suggest  such  an  origin  con- 
sists in  focal  adenocarcinomatous  areas  which  somewhat  resemble  hyper- 
trophic  islands.  In  an  invaded  lymph-node  I  found  such  structures  exclusively 
represented.  These  various  peculiarities  seem  to  justify  the  claim  of  Bard 
and  Pic  that  the  histology  to  pancreatic  cancer  is  specific. 

The  symptoms  frequently  present  the  characteristic  syndrome  of  Bard 
and  Pic,  but  only  when  the  tumor  is  located  in  the  head.  Progressive  jaun- 
dice without  remissions,  great  distention  of  the  ball-bladder,  absence  of 
hepatic  enlargement,  subnormal  temperature,  and  rapid  emaciation  and 
cachexia,  form  a  rather  specific  group  of  clinical  features  observed  in  the 
majority  of  cases.  A  palpable  tumor  is  often  missing,  but  was  detected  in 
about  one-fourth  of  Miraillie's  113  cases.  The  liver  may  be  considerably  en- 
larged (Miraillie,  Eloesser),  and  the  metastases  may  be  bulky  (Oser).  When 
the  growth  involves  only  body  and  cauda,  the  ampulla  of  Vater  may  remain 
pervious,  the  gall-bladder  is  not  distended,  and  jaundice  is  absent.  Such 
clinically  atypical  cases  are  described  by  Pic  and  Tolot.  An  unusual  pre- 
disposition to  hemorrhage  is  emphasized  by  Eloesser.  Pain  is  very  constant. 
The  loss  of  pancreatic  fluid  and  bile  leads  to  acholic  and  fatty  stools.  This 
condition,  however,  is  by  no  means  constant,  and  occurred  in  only  20  cases 
collected  by  Miraillie,  Oser,  and  Fitz.  Imperfectly  digested  bulky  stools 
are  described  by  Oser.  Glycosuria  is  rare.  In  30  cases  of  carcinoma  of  pan- 
creas (13  primary).  Pearce  found  intermittent  glycosuria  in  one,  diabetes 
in  another.  Persistent  glycosuria  occurred  in  2 1  cases  collected  by  Miraillie 
and  Oser. 

Sarcoma  of  Pancreas. — Very  few  satisfactory  reports  of  pancreatic  sar- 
coma are  available.  Schilling  collected  24  cases  and  Kakels  21,  most  of  which 
are  of  uncertain  nature,  but  from  these  data  it  appears  probable  that  spindle- 
cell  sarcoma  and  lymphosarcoma  arise  in  the  pancreas. 

K.  Ehrlich  described  two  large  cystic  tumors  the  walls  of  which  were  com- 
posed, one  of  spindle-cells,  the  other  of  alveoli  of  rounded,  spindle-,  and  giant- 
cells  which  he  regarded  as  of  endothelial  origin.  Each  tumor  gave  local  or 
visceral  metastases.  The  author  concluded  that  they  arose  in  the  walls  of 
primary  cysts.  Weil  also  found  spindle-  and  giant-cells  in  the  wall  of  a  pan- 
creatic cyst.  Kakels  found  a  large  solid  tumor  of  the  tail,  composed  of 
spindle-,  round,  and  giant-cells.  Some  very  vascular  tumors  are  reported  as 
angiosarcomas  (Kronlein).  Michaelson's  case  of  carcinosarcoma  may  signify 
a  participation  of  the  stroma  of  the  gland  or  metaplastic  changes  in  a  carcinoma. 

Of  lymphosarcomas,  L'Huillier  found  a  small  tumor  in  the  head  of  the 
pancreas  of  a  newborn  infant.  It  was  composed  of  lymphocytes  and  giant- 
cells.  Litten's  case  occurred  in  a  child  of  4  years  and  gave  intestinal  metas- 
tases. Schirokogoroff  describes  a  diffuse  tumor  growth  in  the  pancreas 
of  a  man  of  54  years,  with  extensive  visceral  metastases.  The  cells  were 
embryonal  in  type  and  of  quite  uncertain  origin.  Some  of  the  difficulties  in 
the  diagnosis  of  pancreatic  sarcoma  are  illustrated  in  Piccoli's  cases,  which 
differ  from  most  of  the  reports  in  being  so  fully  described  that  several  critics 
have  recognized  them  as  carcinomas  (Borrmann,  v.  Kahlden). 


CHAPTER  XXXV 


MAXILLARY  TUMORS  OF  DENTAL  ORIGIN 


•  The  dental  origin  of  cer- 
tain cystic  and  dentigerous 
tumors  of  the  maxillae  has 
been  recognized  for  at  least 
a  century,  and  the  struc- 
tural details  and  probable 
histogenesis  were  rather 
clearly  conceived  by  several 
writers  since  about  1850 
(Barnes,  Guzack,  Delpech, 
Dupuytren,  Forget,  Nela- 
ton).  At  this  time  it  was 
generally  supposed  that  all 
the  cystic  tumors  arose 
from  dilated  dental  follicles, 
and  in  1872  Magitot  classi- 
fied the  series  upon  this 
basis,  excluding  certain 
cysts  which  he  thought  to 
develop  between  the  perios- 
teum and  the  tooth.  In 
several  solid  tumors  also 
some  authors  detected  epi- 
thelial structures  which 
they  interpreted  as  deriva- 
tives of  the  enamel  organ 
(Robin,  Wedl).  The  odon- 
tomas  were  systematically 
classified  by  Broca  in  1868. 
The  entire  subject  was 
greatly  simplified  in  1885 
by  the  classic  study  of  Ma- 
lassez,  who  referred  most  of 
the  tumors  to  embryonal 
remnants  of  the  enamel 
organ. 

Debris  epitheliaux  par- 
adentaires. — Under  this 
term  Malassex  (1885)  de- 
scribed numerous  cell 
groups  which  he  found  in 
the  fetus  scattered  along 
the  borders  of  the  teeth 
from  apex  to  crown.  They 
are  divisible  into  three 
groups:  (i)  Superficial  cells 
lying  just  beneath  the  gin- 


708 


NEOPLASTIC  DISEASES 


gival  epithelium;  (2)  intermediate,  lying  along  the  sides  of  the  tooth;  and  (3) 
deep,  connected  with  the  enamel  organ.  The  structure  of  the  cells  varies 
considerably.  Some  are  round  and  of  indifferent  character  and  are  found 
in  all  three  situations.  The  superficial  groups  also  include  round  cells  en- 
circled by  cylindrical,  and  canals  lined  by  one  layer  of  cylindrical  cells.  About 
the  enamel  organ  lie  groups  of  cells,  which  show  transitions  between  cylin- 
drical enameloblasts,  round  cells,  and  stellate  cells.  Many  of  these  groups 
he  was  able  to  show  persist  in  the  adult.  Malassez  interpreted  the  cell  groups, 
not  as  accidental  offshoots  or  misplacements  of  the  enamel  organ,  but  as 
analogues  of  the  very  rich  dental  apparatus  of  some  lower  vertebrates  and 
as  giving  rise  to  the  supernumerary  teeth  of  the  so-called  third  dentitions. 
They  are  derived  from  the  invaginations  of  gingival  epithelium  which  go 
to  form  the  enamel  organs. 


IB 


FIG.  333. — Section  of  inferior  maxilla  of  fetus  of  5  months,  showing  epithelial  cell  groups 
beneath  gum.      (After  Malassez.) 

These  observations  of  Malassez  have  formed  the  basis  of  our  knowledge 
of  many  inflammatory  and  neoplastic  processes  connected  with  the  teeth. 
About  inflamed  and  carious  teeth  the  cells  multiply,  hypertrophy,  wander 
out  into  the  tissues,  become  infiltrated  with  leukocytes,  and  participate  in 
the  expulsion  of  the  teeth  in  pyorrhea  alveolaris.  They  are  concerned  with 
various  fibrous  or  myxomatoid  outgrowths  attached  to  the  borders  of  the 
teeth  (fungosites  radiculo-dentaires).  Dilatation  of  the  lumina  of  these 
vestigial  alveoli  gives  rise  to  various  simple  cysts  found  in  contact  with  or  in 
the  neighborhood  of  the  roots.  In  many  epulides  atrophic  or  proliferating 
groups  of  epithelial  cells  are  found  which  are  derived  from  the  original  para- 
dental  structures.  The  numerous  cysts  of  the  maxillae  with  single  or  multiple 
chambers  and  containing  walls  or  cavities  and  imperfect  or  well-formed 
teeth  appear  to  be  derived  from  these  paradental  structures  and  from  the 
specialized  mesodermal  elements  over  which  the  enamel  organ  exerts  a  forma- 
tive control.  In  the  various  forms  of  odontoma  enameloblasts  and  enamel 
are  usually  more  or  less  prominent,  and  these  elements  Malassez  derives 


MAXILLARY  TUMORS  OF  DENTAL  ORIGIN 


709 


from  the  paradental  structures.     Finally,  in  the  entire  group  of  cystic  and 
solid,  malignant,  epithelial    growths   aris- 
ing in  the  maxillae  the  sole  source  is  to 
be  found  in  the  paradental  epithelium. 

The  views  of  Malassez  regarding  the 
importance  of  the  paradental  structures 
have  received  general  acceptance.  Galippe 
has  recently  reviewed  the  entire  subject, 
tracing  in  greater  detail  the  natural  history 
of  the  paradental  structures  and  illustrat- 
ing by  selected  cases  their  pathological 
relations. 

It  still  remains  uncertain  to  what  ex- 
tent the  dental  follicle  itself  is  concerned 
in  the  formation  of  dentiferous  and  dentig- 
erous  cysts.  Many  believe  that  the  com- 
plex odontomas  and  dentiferous  cysts  arise 
from  original  or  supernumerary  dental 
follicles  and  Malassez  and  Galippe  admit 
such  an  origin  for  certain  cases.  It  is 
reasonable  to  suppose  that  all  transitions 
exist  between  simple  groups  of  para- 
dental epithelium  and  true  supernumerary 
enamel  organs  and  that  the  structure  and 
contents  of  maxillary  cysts  will  vary  ac- 
cordingly. In  the  very  complex  processes 
located  in  the  maxillae  in  connection  with 
the  formation  of  two  sets  of  teeth  abundant 
opportunity  is  presented  for  abnormal 
overgrowths  of  several  structures  in  various 
stages  of  evolution.  It  is,  therefore,  un- 
likely that  any  single  embryonal  event 
such  as  gives  rise  to  the  ordinary  para- 
dental debris  is  responsible  for  all  the  very 
numerous  clinical  forms  which  these  abnor- 
malities present. 

Adamantinoma. — Tumors  of  this  group 
arise  from  the  paradental  epithelial  debris. 
They  are  solid  or  cystic  growths  located 
within  the  alveolar  borders,  excavating  a 
cavity  within  the  maxilla,  distending  the 
tissues  until  they  become  surrounded  by  a 
thin  parchment-like  bony  capsule  which 
crepitates  on  pressure.  Eventually  the 
capsule  may  rupture  and  the  disease  ex- 
tends further  by  continuity  into  antrum, 
orbit,  or  other  tissues  and  cavities.  The 
cystic  tumors  may  reach  a  large  size, 
Bryck's  tumor  weighing  1.5  kg.  I  found 
at  autopsy  a  solid  tumor  of  tjie  upper  jaw 


FIG.  334. — Groups  of  superfluous 


as  la'nrp  as  a   child's  head    nrmVrtinP  ex-    epithelial  cells  found  in  five  successive 
as  large  as  a  cnna  s  neaa,  projecting  ex-   fi__t;_ns  nf  thp  a]vpniar  H^ntai  in- 


ternally into  the  nasopharynx,  with  dys- 
phagia,  and  into  the  orbit  with,  extreme 
exophthalmos. 


sections  of  the  alveolar  dental  liga- 


ment   of    an 

Malassez.) 


adult    man.       (After 


710 


N  EOF  LA  STIC  DISEASES 


FIG.  335. — Adamantinoma  of  inferior  maxilla. 


FIG.  336. — Relations  of  a  cystic  adamantinoma  of  inferior  maxilla.     (After  Fritsch.) 


MAXILLARY  TUMORS  OF  DENTAL  ORIGIN  711 

The  cystic  tumors  are  unilocular  or  multilocular  and  the  small  cystic 
ramifications  may  penetrate  extensively  into  the  cancellous  tissue  (Beneke). 
The  cysts  contain  serous  fluid  or  mucous  or  inspissated  fatty  and  scaly  ma- 
terial. Calcific  particles,  probably  remnants  of  imperfect  enamel,  may  be 
mingled  with  the  fluid.  The  cavity  may  be  smooth  walled  or  lined  by  pap- 
illary projections  of  epithelium.  In  the  cyst  wall  one  finds  cellular  or  fibrous 
connective  tissue,  calcified  areas,  or  masses  of  bone  or  cementum.  Cellular 
overgrowth  may  give  the  structure  of  spindle-cell  or  myxosarcoma  (Albar- 
ran),  and  it  is  probable  that  by  exaggeration  of  this  process  apparently  pure 
sarcomas  may  arise.  Bilateral  cystic  tumors  were  observed  by  Flaubert. 

The  tumors  composed  of  small  cysts  are  often  traversed  by  fibrous  tra- 
becula  which  constitute  the  bulk  of  the  tumor.  In  such  a  case  Chibret  found 


FIG.  337. — Glandular  adamantinoma.     Many  small  cysts  lined  by  columnar  enamelo- 

blasts. 

areas  of  well-formed  enamel  lying  on  shallow  beds  of  dentine.  Smaller  de- 
posits of  enamel  were  observed  by  Bernays  and  by  others. 

The  solid  tumors  present  every  gradation  from  the  small  cystic  variety. 
As  a  rule,  they  are  more  cellular  and  malignant.  On  section  they  usually 
present  a  papillary  appearance  and  many  fine  cysts  may  be  detected.  Or  by 
overgrowth  of  the  stroma  they  may  appear  firm,  solid,  and  sarcomatous. 
Some  of  the  solid  tumors  from  their  early  stages  project  from  the  alveolar 
border  as  a  form  of  epulis,  and  when  the  vessels  are  overabundant  their  gross 
appearance  may  closely  resemble  that  of  a  vascular  epulis  of  sarcomatous 
type.  The  ordinary  epulis,  however,  fails  to  distend  the  ramus  of  the  jaw. 

That  all  these  tumors  are  essentially  of  one  nature  is  indicated  by  the 


712 


NEOPLASTIC  DISEASES 


numerous  intermediate  forms  described  in  the  literature  and  by  the  occasional 
transformation  of  unilocular  into  multilocular,  cystic,  or  solid  tumors  in 
recurring  cases  (Guibout,  d' Amiens,  Malassez). 

Structure. — The  epithelial  cells  of  adamantinoma  exhibit  all  variations  in 
form  between  stratified  squamous  epithelium  and  specialized  adult  enamelo- 
blasts,  thus  recalling  the  changes  traversed  in  the  normal  development  of 
the  enamel  organ. 

Superficial  adamantionomas  of  the  alveolar  border  present  many  of  the 
characters  of  acanthoma,  but  the  central  cells  in  the  epithelial  columns  usu- 
ally exhibit  the  peculiar  reticulated  structure  of  the  central  portion  of  the 
enamel  organ.  In  some  cases  there  is  a  direct  connection  between  the  gin- 
gival  epithelium  and  the  deeper  groups  of  characteristic  reticulated  enamelo- 
blasts,  so  that  Buchteman  and  Eve  assumed  that  such  tumors  arise  from  the 
gingival  lining.  Malassez  is  probably  correct  in  referring  these  appearances  to 
secondary  union  by  upward  growth  of  the  tumor,  or  to  supernumerary  invag- 


FIG.  338. — Structure  of  adamantinoma  resembling  epidermoid  carcinoma. 

inations  of  epithelium,  but  it  is  sometimes  difficult  to  distinguish  between 
primary  acanthoma  of  the  gum  and  squamous-cell  adamantinoma.  Galippe 
holds  that  the  adult  gingival  epithelium  has  lost  all  capacity  to  differentiate 
toward  enameloblasts  and  that  the  squamous  cells  of  superficial  tumors  arise 
from  the  superficial  debris  paradentaire,  which  may  be  regarded  as  the  atrophic 
duct  of  the  enamel  gland. 

The  epulis  of  adamantinoma  presents  a  fibrous  or  mucoid  or  giant-cell, 
sarcomatous  stroma,  supporting  cords  and  groups  of  epithelium  of  the  enamel 
type.  The  cells  vary  as  usual  from  squamous-cell  to  columnar  and  vesicular 
forms  and  the  origin  of  the  squamous  cells  presents  the  same  problems  as  in 
the  case  of  other  superficial  tumors  of  the  gums.  In  various  cases  described 
by  Malassez,  Heath,  and  Eve,  the  features  of  adamantinoma  were  prominent. 
Haasler  finds  that  the  common  epulis  is  usually  connected  with  a  granuloma 
of  the  dental  root. 

The  solid  intramaxillary  or  projecting  tumors  present  a  variable  structure, 
the  cells  exhibiting  many  gradations  from  enameloblasts  to  squamous  epithe- 


MAXILLARY  TUMORS  OF  DENTAL  ORIGIN 


713 


Hum.  Three  main  types  of  structure  may  be  recognized:  (i)  Acanthoma; 
(2)  plexiform  epithelioma;  (3)  glandular  adamantinoma  (L'Esperance). 
Malassez's  classification  included  squamous,  cylindrical,  and  carcinomatous 
cell  types.  All  the  growths  are  locally  aggressive  and  fall  in  the  general  class 
of  carcinoma.  The  glandular  tumors  are  adenocarcinomas.  Some  tumors 
present  chiefly  one  structure,  others  show  sharp  and  extreme  variations  in  the 
cell  type,  and  the  arrangement  of  the  cells  is  very  diverse.  Acanthoma  presents 
anastomosing  cords  of  squamous  epithelium  in  which  are  spine  cells  and  many 
pearls,  but  the  characters  of  the  enamel  organ  appear  in  isolated  foci  of  large 
vesicular  cells. 

Plexiform  epithelioma  presents  broad  convoluted  columns  of  epithelium 
without  marked  squamous  character,  lying  in  dense  or  cellular  connective 
tissue.  Many  small  cystic  tumors  present  this  structure. 


FIG.  339. — Adamantinoma.      Large  cell  groups  composed  of  very  small  epithelial  cells 
surrounded  by  compact  columnar  enameloblasts. 

Glandular  adamantinoma  (adenocarcinoma)  covers  a  variety  of  struc- 
tures in  which  the  columnar  enameloblasts  predominate.  The  tumors  may 
be  composed  exclusively  of  such  cells  arranged  in  long  columns  or  alveoli. 
Or  the  columnar  cells  may  inclose  islands  of  reticulated  cells.  Or  numerous 
pearls  may  be  surrounded  by  reticulated  cells  with  a  border  of  columnar 
enameloblasts.  Considerable  areas  of  spindle-cells  may  simulate  sarcoma. 
Such  spindle-cells  may  be  extremely  small,  suggesting  round-cell  sarcoma, 
but  a  limiting  border  of  columnar  cells  usually  indicates  the  embryonal  epi- 
thelial character  of  such  areas.  Extensive  metaplasia  and  extreme  anaplasia 
may  be  observed  in  recurring  tumors.  During  a  period  of  4  years  in  five 
recurrences  of  an  original  plexiform  and  squamous  epithelioma  I  observed 
a  continuous  loss  of  specific  characters,  the  tumor  eventually  spreading  widely 
as  a  large  round-cell  perivascular  growth  without  a  trace  of  its  epithelial  origin. 


NEOPLASTIC  DISEASES 


Secretory  products  appear  in  the  form  of  mucous  droplets  in  the  cells  or 
as  small  cysts  with  mucous,  fatty,  or  calcine  elements.  Deposits  of  well- 
formed  enamel  lying  on  beds  of  dentine  have  been  observed. 

The  stroma  may  be  very  dense  and  hyaline  as  in  the  gubernaculum  dentis, 
or  cellular,  myxomatous,  or  sarcomatous.  In  the  stroma  of  some  adaman- 
tinomas  one  may  find  an  exact  reproduction  of  the  structure  of  the  giant- 
cell  epulis.  Portions  of  cementum  or  bone  may  appear  in  the  capsule.  The 
blood-vessels  may  be  overdeveloped.  In  one  large  tumor  projecting  from  the 
alveolar  border  the  Vessels  became  thrombosed  and  the  stroma  was  every- 
where infiltrated  with  blood. 


FIG.  340. — Glandular  adamantinoma.     Sheets  of  spindle-shaped  epithelial   cells  sur- 
rounded by  columnar  enameloblasts. 

Clinical  Features. — The  tumors  occur  chiefly  in  adults,  but  have  been 
observed  as  early  as  the  sixth  year  (Coate),  and  many  occur  from  60  to  70 
years  (Bornig).  The  duration  of  the  process  is  usually  prolonged,  18  years 
in  Kruse's  case,  23  years  in  one  of  Malassez's,  26  years  in  Bryk's,  and  38 
years  in  Albarran's.  A  history  of  extraction  of  a  carious  tooth  usually  pre- 
cedes by  some  years  the  appearance  of  the  tumor.  Hence  the  age  of  onset 
is  earlier  than  would  appear  in  many  reports  and  probably  begins  shortly 
after  the  full  development  of  the  teeth.  Women  are  more  often  affected  than 
men.  The  lower  jaw  is  the  chief  seat  of  cystic  tumors  (Pincus),  while  the 
upper  yields  most  of  the  solid  and  more  malignant  growths. 

The  course  of  adamantinoma  varies  extremely  with  the  type  and  location 
of  the  tumor.  All  the  cysts  and  tumors  are  of  slow  development  and  their 
natural  history  is  prolonged.  The  superficial  growths  and  small  cysts  may  be 


MAXILLARY  TUMORS  OF  DENTAL  ORIGIN 


715 


readily  extirpated,  but  the  deep-lying  multilocular  cysts  recur  persistently 
and  often  require  the  sacrifice  of  the  maxilla.  Tumors  of  the  upper  jaw  are 
much  the  more  serious,  and  the  solid  adamantinomas  of  all  types  recur  locally 
and  invade  antrum,  orbit,  and  nasopharynx.  In  spite  of  their  relatively  be- 
nign structure  the  prognosis  in  this  group  is  unfavorable.  Yet  the  lymph- 
nodes  are  almost  never  involved,  except  by  malignant  recurrences.  In  one 
very  extensive  nbro-epithelial  tumor  I  found  metastases  in  one  cervical  node 
and  a  small  nodule  in  the  lung.  In  another  very  malignant  case  the  fourth 
recurrence  was  in  the  cervical  nodes  and  loose  tissues  of  the  neck  and  prob- 
ably in  the  lungs. 

Adamantinoma  of  Tibia. — B.  Fischer  describes  a  tumor  involving  the  outer 
portions  of  the  shaft  of  the  tibia,  with  mucoid  stroma  and  many  cell  groups 
presenting  the  typical  structures  of 
adamantinoma.  In  the  origin  of  this 
tumor  he  assumes  a  downward  growth 
of  embryonal  ectoderm  reaching  the 
bone  and  differentiating  as  enamel 
organ,  just  as  the  gingival  epithelium 
penetrates  the  maxilla. 

Radiculodental  Cysts. — The  roots 
of  carious  or  normal  teeth  frequently 
exhibit  small  excrescences  composed  of 
cellular  connective  tissue  in  which  lie 
strands  and  groups  of  epithelial  cells. 
Malassez  showed  that  these  structures 
are  derived  from  the  deeper  debris  para- 
dentaire,  portions  of  which  he  finds 
closely  applied  to  the  apex  of  the  root 
and  even  extending  into  the  pulp  canal. 

Small  radiculodental  cysts  frequently 
develop  by  proliferation  of  these  epi- 
thelial structures  and  dilatation  of  the 
lumina  which  they  surround.  Sup- 
puration may  destroy  or  alter  the  epi- 
thelial lining  of  such  cysts  and  the  lesion 
appears  as  a  small  abscess.  Larger 
radiculodental  cysts  of  this  same  origin 
have  been  described  by  several  authors 
(Sirantoine).  They  inclose  a  portion 
or  the  whole  of  the  root  and  may  reach 
the  size  of  a  robin's  egg,  or  hen's  egg, 
with  considerable  absorption  of  bone. 
Galippe  shows  how  similar  cysts  may 
develop  without  directly  exposing  the  root.  The  lining  of  these  cysts  is  of 
squamous  epithelium,  so  that  they  have  sometimes  been  regarded  as  of  der- 
moid  nature.  Yet  occasionally  the  lining  is  partly  or  wholly  of  columnar  cells 
which  indicates  their  paradental  origin.  Witzel  holds  that  these  cysts  arise 
from  dilatation  of  v.  Brunn's  sheath,  which  is  the  continuation  of  the  enamel 
epithelium  over  the  root  of  the  tooth.  Malassez  includes  this  atrophic  sheath 
with  the  "debris  paradentaire."  The  walls  of  the  cysts  may  be  very  cellular 
or  sarcomatous  and  the  contents  are  serous,  mucous,  fatty,  or  caseous  and 
inspissated  (Galippe,  Mickulicz). 

Multiple  cysts  of  this  character  were  found  by  Wilks,  five  separate  cavi- 
ties surrounding  the  roots  of  as  many  teeth  in  a  child  of  1 2  years.    Or  a  single 


FIG.  341. — Adamantinoma  of  tibia. 


716 


N  EOF  LAST  1C  DISEASES 


cyst  may  surround  several  roots  (Gosselin).  The  cyst  may  lie  at  some  dis- 
tance from  the  root  (Vitalis),  or  project  through  the  absorbed  ramus  of  the 
jaw  externally  (Ancelot,  Sourier),  or  into  the  maxillary  sinuses  (Berger). 
The  radiculodental  cysts  are  much  more  frequent  in  the  upper  than  in  the 
lower  jaw  (76  to  29,  Witzel). 

Coronodental  Cysts.  Dentigerous  Cysts. — All  the  dental  anomalies  thus 
far  considered  relate  to  already  erupted  teeth.  The  remaining  cysts  and 
tumors  affect  the  tooth  before  its  eruption  and  usually  prevent  its  full  develop- 
ment. 

Coronodental  cysts  present  small  intra-alveolar  cavities  into  which  project 
one  or  more  imperfectly  formed  teeth.  The  wall  is  fibrous  and  the  lining  is 
composed  of  squamous  or  cylindrical  epithelium  or  both  types.  The  tooth  is 
usually  misplaced,  lying  horizontally,  a  position  which  prevents  its  eruption. 


FlG.  342. — Atypical  structure  of  adamantinoma  in  late  recurrence. 

The  root  is  imperfectly  formed  owing  to  fibrosis  of  the  pulp,  the  cementum 
may  be  hyper trophied,  and  the  dentine  may  be  eroded  (Albarran).  Heath 
observed  a  cyst  in  each  maxillary  sinus,  one  containing  a  canine,  the  other  a 
molar,  while  in  another  case  the  tooth  lay  loose  in  the  cyst  cavity.  Legouest 
found  two  teeth  in  the  same  cyst,  and  Broca  saw  three.  Bayer  identified  a 
milk  canine  and  a  permanent  canine,  indicating  the  fusion  of  two  original 
cysts.  Nelaton  found  one  well-formed  tooth  projecting  into  the  cavity  and 
numerous  rudimentary  teeth  in  the  wall.  Grosse  saw  eight  well-formed  teeth 
in  the  same  cyst  in  the  middle  of  the  upper  jaw.  These  2  cases  indicate  that 
the  hypertrophic  dilated  enamel  organ  is  still  capable  of  inciting  the  forma- 
tion of  nearly  complete  teeth.  In  several  cases  the  tooth  was  completely 
inclosed  in  the  cyst  wall,  or  in  a  secondary  cyst  in  the  wall  (Nelaton,  Remy- 
Duret).  Haasler  describes  cases  in  which  separate  cysts  seem  to  have  formed 


MAXILLARY  TUMORS  OF  DENTAL  ORIGIN 


717 


about  crown  and  root.  Finally  Allgayer  found  a  small  solid  fibrous  tumor 
involving  four  teeth  and  containing  groups  of  epithelium.  This  tumor  prob- 
ably originated  in  the  gubernaculum  of  one  or  more  teeth,  but  without  the 
usual  formation  of  cysts. 

The  origin  of  these  coronodental  cysts  is  referred  by  Galippe  to  the  stimulus 
exerted  upon  the  debris  paradentaires  of  the  gubernaculum  by  an  imperfectly 
formed  tooth  which  becomes  arrested  in  the  course  of  its  eruption.  Fibrosis 
of  the  gubernaculum,  opposing  the  eruption  of  the  tooth,  with  dilatation 
of  the  paradental  alveoli  extending  to  the  original  enamel  organ,  would  also 
account  for  most  of  the  relations  observed.  Others  regard  them  as  true 
follicular  cysts  arising  by  hypertrophy  and  dilatation  of  the  enamel  organ 
(M.  B.  Schmidt). 


FIG.  343. — Topography  of  a  radiculodental  cyst.  (After  Malassez.)  i,  2,  Connec- 
tive tissue  of  wall.  3,  4,  5,  Cellular  connective  tissue  of  inner  layer  of  cyst,  infiltrated 
with  lymphocytes.  6,  7,  Epithelial  lining  of  cyst.  8,  Cyst  cavity. 

Dentigerous  Cysts  and  Odontoma.— In  this  group  of  anomalies  are 
included  cysts  and  solid  tumors  caused  by  an  increase  in  number  of  more  or 
less  well-formed  teeth.  The  most  striking  illustration  of  dental  overgrowth 
is  seen  in  the  rare  case  of  third  dentition  described  by  F.  J.  Hunter. 

The  extensive  hypertrophy  of  a  single  tooth  is  described  by  Virchow, 
Wedl,  and  Billroth. 

A  unique  case  of  remarkable  multiplication  of  teeth  is  described  by  Hilde- 
brandt.  In  a  boy  of  9  years  whose  erupted  teeth  were  normal  in  number 
but  misplaced,  both  upper  and  lower  jaws  were  swollen  and  contained  150 
to  200  teeth  lying  singly  or  variously  fused,  most  of  them  being  well  formed. 
After  two  thorough  extirpations  the  condition  recurred  and  again  about  the 
same  number  of  new  teeth  were  removed,  leaving  a  thin  shell  of  bone.  In 


718  NEOPLASTIC  DISEASES 

this  case  it  is  clear  that  there  had  been  an  enormous  overproduction  of  dental 
follicles  and  that  the  dentigerous  cells  remaining  after  the  first  two  operations 
were  capable  of  reproducing  well-formed  teeth.  In  the  curetted  tissues  Hilde- 
brand  found  many  rudimentary  teeth,  enamel  organs,  and  tubules  resembling 
the  debris  paradentaires.  Somewhat  similar  cases  are  recorded  by  Coleman, 
Bland  Sutton,  and  Matthias. 

Dentigerous  cysts  appear  in  several  forms.  Supernumerary  teeth  are  some- 
times inclosed  in  a  cyst  formed  probably  from  the  dilated  gubernaculum  or 
follicle,  containing  one  or  more  well-formed  teeth,  and  serous  or  mucinous 
fluid.  They  lie  in  the  alveolar  ramus  or  at  considerable  distances,  especially 
below  the  orbit. 

In  many  cases  the  tooth  is  very  imperfectly  formed  or  appears  in  rudi- 
ments only,  but  these  rudiments  are  multiple.  Thus  Annandale  found  a 
large  cyst  with  bony  and  fibrous  wall  in  which  were  areas  of  enamel.  Broca 
described  a  cyst  containing  three  irregular  masses  chiefly  composed  of  dentine, 
and  fused  in  a  mass  of  tissue  containing  islands  of  dentine,  imperfect  enamel, 
and  pulp  tissues.  Broca  cites  a  very  similar  case  in  which  a  large  central 
mass  of  dentine,  with  several  roots  and  crowns,  was  covered  with  enamel. 


FIG.  344. — Composite  odontoma.     (After  Gilmer,  J.  A.  M.  A.,  56.) 

Odontoma. — The  typical  odontoma  is  composed  of  a  congeries  of  more  or 
less  perfectly  formed  teeth  usually  surrounded  by  an  epithelial  membrane 
and  fibrous  capsule.  Since  there  are  many  grades  of  development  of  the 
teeth  and  these  may  incompletely  fill  the  inclosing  cysts,  there  is  no  sharp 
dividing  line  between  dentigerous  cysts  and  odontomas.  The  coronodental 
cysts  are  also  closely  related  to  odontoma,  since  they  present  one  or  more 
imperfect  tooth  crowns  in  a  roomy  cavity.  In  Chibret's  case  the  dentigerous 
cyst  contained  irregular  masses  of  dentine  and  enamel.  When  the  enamel 
and  dentine  exhibit  an  orderly  arrangement  and  pulp  tissue  and  canals  appear, 
the  tumor  becomes  a  true  odontoma. 

Localized  hypertrophies  of  portions  of  the  teeth  are  also  conditions  related 
to  odontoma.  Enamel  pearls  are  small  nodules  of  enamel  which  form  along 
the  borders  of  the  teeth  as  a  result  of  overactivity  of  a  group  of  enamelo- 
blasts.  The  verucous  crowns  of  Satler  consist  of  overgrowth  of  enamel  which 
may  at  times  reach  considerable  dimensions.  These  overgrowths  may  con- 
sist of  both  dentine  and  enamel  and  may  even  contain  a  diverticulum  of  the 
pulp  canal,  producing  a  form  radicular  odontoma. 

The  typical  odontoma  occurs  chiefly  in  young  subjects  and  almost  in- 
variably in  the  lower  jaw.  Lloyd's  mixed  odontoma  occurred  in  the  upper 


MAXILLARY  TUMORS  OF  DENTAL  ORIGIN  719 

jaw.  It  forms  a  solid  tumor  in  the  maxilla  and  is  sharply  separated  from 
the  adjacent  bone  by  an  inclosing  cyst  wall.  There  is  usually  an  absence 
of  one  or  more  teeth,  usually  wisdom  teeth,  whose  eruption  is  obstructed 
or  whose  structure  is  included  in  the  tumor.  Incision  may  evacuate  serous 
fluid  or  pus  from  the  cavity  in  which  the  tumor  lies.  Looking  into  this  cavity 
may  often  be  found  the  crown  of  an  obstructed  tooth  which,  after  removal 
of  the  tumor,  may  assume  its  normal  position  in  the  alveolar  border  (Krogius). 
On  gross  section  the  tumor  is  composed  of  fused  teeth  in  which  enamel,  den- 
tine, and  pulp  tissue  reproduce  the  form  of  the  teeth  which  lie  in  disorderly 
arrangement.  The  surface  is  nodular  from  the  projecting  ends  of  the  teeth. 
Well-formed  teeth  may  not  be  discernible  and  the  tumor  may  be  composed 
of  irregular  masses  of  dentin,  enamel,  and  pulp  canals,  all  covered  by  a  layer 
of  enamel  (Forget).  Enamel  may  be  missing  and  the  tumor  be  composed 
of  masses  of  dentin  and  bone  (Uskoff).  Or  enamel  is  reduced  to  traces  and 
the  tumor  composed  of  dentin  and  cementum  (Krogius).  Such  tumors 
may  be  designated  as  amorphous  odontomas. 

A  complex  cystic  odontoma  is  described  by  Robin.  It  contained  three 
well-formed  molars  in  adjoining  cysts,  two  rudimentary  teeth  rooted  in  bone, 
and  projecting  into  small  cysts,  and  three  small  pedunculated  fibromas. 

Tapie  describes  a  cyst  in  the  angle  of  lower  jaw,  of  5  years'  standing. 
A  thick  fetid  sebaceous  discharge  drained  from  two  sinuses.  The  wisdom 
tooth  on  that  side  was  missing.  A  molar  crown  projected  into  the  cyst,  its 
root  embedded  in  the  wall,  which  presented  also  a  large  number  of  small  con- 
ical teeth  and  calcareous  points.  Free  in  the  cyst  lay  a  composite  odontoma 
with  several  teeth  fused  by  cementum.  The  cyst  was  lined  by  stratified  epi- 
thelium. Tapie  interpreted  the  case  as  a«  invagination  of  dentigerous  gingival 
mucosa.  Galippe  thinks  the  cyst  arose  from  paradental  debris  and  that  the 
odontoma  arising  outside  penetrated  the  wall. 

Soft  Odontomas. — In  some  cases  the  odontoma  is  composed  chiefly  of 
connective  tissue  in  which  lie  many  rudimentary  teeth  (Perthes,  Partich). 
In  Schlossmann's  case,  in  a  boy  of  10  years,  the  last  molar  and  wisdom  teeth 
were  missing  from  the  lower  jaw  which  presented  a  tumor  3.5  to  3.2  cm., 
composed  of  firm  connective  tissue  in  which  lay  many  small  hard  structures 
as  large  as  a  pea  or  bean.  The  structure  presented  numerous  well-formed 
enamel  organs  about  which  were  layers  of  dentin  in  various  stages  of  develop- 
ment. Enamel  was  found  only  where  dentin  came  in  contact  with  the  enamel 
organs.  There  were  no  traces  of  dental  papillae.  Regressive  changes  affected 
the  older  teeth  in  the  center  of  the  tumor,  where  vessels  were  invading  the 
enamel  organ  at  the  expense  of  the  active  cells.  The  authors  concluded  that 
the  tumor  arose  from  the  follicles  of  both  missing  teeth,  which  became  dis- 
placed and  disturbed  in  growth  by  neighboring  teeth  in  the  confined  region 
of  the  angle  of  the  jaw. 

General  Etiology. — Odontoma  almost  always  appears  before  the  age  of 
25  years,  or  before  the  full  development  of  the  teeth  has  been  reached.  In 
this  period  also  most  dentigerous  cysts  are  observed,  while  adamantinoma, 
as  a  rule,  appears  in  later  life.  Odontoma  affects  almost  exclusively  the  lower 
jaw,  adamantinoma  frequently  the  upper.  This  contrast  suggests  a  some- 
what different  mode  of  origin  for  the  two  groups.  The  second  or  the  first 
molar  is  frequently  missing  with  odontoma,  indicating  that  the  tumor  arises 
from  the  structures  which  normally  give  origin  to  the  tooth.  The  factors 
which  initiate  the  abnormal  growth  are  at  present  undetermined.  Trauma 
has  been  only  a  rare  antecedent.  Schlossmann  traces  the  origin  to  misplace- 
ment of  a  dental  follicle  during  the  early  period  of  growth,  which  is  especially 
favored  in  the  confined  quarters  of  the  angle  of  the  lower  jaw.  The  exten- 


720  NEOPLASTIC  DISEASES 

sive  variations  in  the  composition  and  relations  of  odontoma,  as  illus- 
trated in  the  preceding  cases,  renders  quite  difficult  the  task  of  tracing  its 
origin. 

Broca  recognized  four  periods  in  the  development  of  the  tooth:  (a)  em- 
bryoplastic,  before  the  appearance  of  definite  dental  structures;  (6)  odonto- 
plastic;  (c)  coronal,  and  (d)  radicular,  and  he  divided  odontomas  accordingly. 
He  assumed  that  all  the  tumors  arose  from  dental  follicles,  the  formative 
process  residing  chiefly  in  the  pulp  tissue.  By  multiplication  of  pulps  several 
teeth  might  form  as  in  the  composite  odontoma.  But  the  structure  of  our 
tumors  does  not  always  correspond  to  this  direct  plan,  which  is  not  fully  in 
accord  with  the  development  of  the  teeth  (Wedl).  A  purely  anatomical 
classification  was  used  by  Sutton,  who  recognized  cementomas,  dentomas, 
osteodentomas,  and  mixed  dentomas.  Yet  cementum  is  probably  only  a 
secondary  product  added  to  stationary  odontomas  (Schlossman).  Malassez 
and  Galippe  refer  the  majority  of  odontomas  to  proliferation  of  the  "debris 
paradentaire,"  but  it  is  difficult  to  adjust  all  the  types  of  these  tumors,  as 
well  as  of  adamantinoma,  to  this  single  source. 

Several  modes  of  origin  seem  to  be  involved  in  the  different  forms  of 
odontoma  and  of  the  closely  related  dentigerous  cysts.  The  absence  of  a 
normal  tooth  indicates  that  the  odontoma  arises  in  the  follicle  of  this  missing 
organ  and  the  growth  of  several  well-formed  teeth  in  its  place  indicates  that 
all  the  structures,  especially  the  pulp,  are  concerned  in  the  tumor  process. 
Many  of  these  tumors  lie  in  a  cyst  or  are  surrounded  by  a  wall  in  which  are 
proliferating  islands  of  enameloblasts,  showing  that  this  structure  also  partici- 
pates in  the  process.  The  varying  proportions  of  enamel,  dentin,  and  pulp 
tissue  point  directly  to  overgrowth -of  particular  elements,  but  not  to  dis- 
tinctly different  modes  of  origin. 

Where  all  the  normal  teeth  are  present  a  supernumerary  follicle  first  pre- 
sents itself  as  the  most  probable  source  of  the  tumor. 

A  congeries  of  imperfectly  developed  teeth,  as  in  Schlossmann's  case,  sug- 
gests an  extensive  multiplication  of  enamel  organs  and  dental  pulps,  which 
are  as  readily  derived  from  a  single  original  follicle  as  from  multiple  foci  of 
paradental  debris.  Hildebrand's  case  shows  that  practically  all  the  follicles 
of  both  jaws  may  be  incited  to  this  form  of  organ  multiplication.  It  is  difficult 
to  conceive  of  such  orderly  but  active  growth  from  embryonal  paradental 
debris. 

Cystic  dilatation  of  the  original  enamel  organ  in  the  follicle  adequately 
explains  the  dentigerous  cyst  with  a  single  tooth,  and  multiplication  of  pulps 
may  be  assumed  where  multiple  teeth  are  observed.  Since  the  enamel  organ 
almost  completely  surrounds  the  developing  tooth  (v.  Brunn),  the  inclosure 
of  many  odontomas  in  an  epithelial  cyst  is  readily  understood. 

Cementum  is  added  to  many  odontomas  after  the  limit  of  growth  has 
been  reached.  The  extensive  overgrowth  of  bone,  sometimes  observed,  must 
be  referred  to  the  periosteum,  and  it  seems  probable  that  some  nearly  pure 
maxillary  osteomas  may  arise  under  these  conditions. 

This  conception  would,  therefore,  limit  the  domain  of  the  debris  paraden- 
taire to  the  adamantinomas  and  the  cystic  tumors  lined  by  epithelium  and 
containing  only  irregular  rudiments  of  dental  structures,  while  the  cysts  with 
multiple  well-formed  teeth  and  the  various  odontomas  may  be  referred  to  the 
enamel  organ  and  the  pulp  tissue. 

Tumors  of  Maxillary  and  Nasal  Sinuses  (Antrum  of  Highmore). — The 
nasal  passages  and  their  accessory  sinuses  are  the  seat  of  a  series  of  tumors, 
benign  and  malignant,  which  form  one  of  the  most  important  departments  of 
rhinology.  The  complex  embryology  of  this  region  gives  abundant  oppor- 


MAXILLARY  TUMORS  OF  DENTAL  ORIGIN  721 

tunity  for  the  origin  of  tumors  from  developmental  anomalies,  while  the 
peculiar  anatomy  of  the  part  gives  unusual  chances  for  the  growth  of  tumors 
as  a  result  of  inflammatory  processes.  The  frequency  of  these  tumors  is  con- 
siderable. At  the  Memorial  Hospital  during  the  years  1916  to  1917,  out  of 
1892  cases  of  cancer  of  all  types  admitted,  48  (2.53  per  cent.)  were  in  this 
region,  and  of  these,  35  involved  the  maxillary  sinus. 

From  the  diagnostic  standpoint  it  will  be  serviceable  to  review  the  tumors 
occurring  in  this  region : 

Nares.  Polyps.     Mucous,  myxomatous,  fibromatous,  angiomatous. 

Choanal  angioma,  angiomyxoma.     Myxosarcoma. 
Mucosa.          Schneiderian  adenoma,  carcinoma. 

Lymphosarcoma.     Melanoma. 
Antrum.          Mucosa.          Cysts.     (Empyema.)    Mucoid.    Cystic  myxoma.    Fibroma. 

Epithelial  papilloma.     Carcinoma. 

Bones.  Osteoma.    Fibro-osteoma.    Osteosarcoma.    Chondroma. 

Teeth.  Dental  cysts.     Odontoma.     Adamantinoma. 

Ethmoidal  sinuses.  Fibroma.     Osteoma.     Carcinoma. 

Sphenoidal  sinus.  Polypoid  myxoma. 

Frontal  sinuses.  Osteoma.     Carcinoma. 

Pharyngeal  vault.  Angiosarcoma.     Chondroma.     Chondrosarcoma. 

Hypophyseal  duct.  Epidermoid  carcinoma.     Adamantinoma.     Dermoids. 

Epignathi.     Teratoma. 

Any  one  of  this  formidable  array  of  neoplasms  may  present  itself  as  a 
mass  obstructing  the  nares,  with  or  without  purulent  or  bloody  discharge,  and 
requiring  for  its  successful  treatment  an  accurate  identification.  Of  the 
above  list  the  benign  tumors  have  been  briefly  discussed  elsewhere,  but  the 
epithelial  tumors  of  the  nasal  mucosa  and  maxillary  sinus  present  many 
special  features  which  may  be  considered  at  this  point. 

Cysts  of  Antrum. — Chronic  empyema  of  the  antrum  may  become  confined 
by  closure  of  the  orifices,  the  inner  wall  may  yield  to  pressure,  giving  a  pro- 
truding tumor  of  the  nasal  passage,  while  the  contents  may  become  inspis- 
sated and  cheesy.  The  bony  wall  may  undergo  absorption  or  necrosis,  while 
the  lining  may  be  transformed  into  squamous  epithelium.  Chronic  inflam- 
mation and  edema  of  the  mucosa  may  lead  to  filling  of  the  cavity  with  myxo- 
ma-like  tissue  which  has  often  led  to  difficulty  in  diagnosis  from  the  material 
excavated  from  the  antrum.  In  many  cases,  but  by  no  means  in  all,  a  chronic 
empyema  has  preceded  carcinoma  or  papilloma  of  the  antrum.  Certain 
osteomas  of  the  antrnm  have  been  described  as  containing  one  or  more  cysts. 
They  were  probably  of  dental  origin.  Polypoid  fibroma  or  myxoma  fre- 
quently develops  from  the  orifice  or  the  fundus  of  the  antrum.  Those  arising 
from  the  fundus  fill  and  may  considerably  distend  the  antrum,  but  many  pro- 
trude through  the  orifice  by  elongated  pedicles  and  appear  as  ordinary  nasal 
polyps.  They  are  usually  firmly  attached  to  the  periosteum  and  may  require 
opening  the  antrum  for  complete  eradication.  In  fact,  some  rhinologists 
recommend  opening  the  antrum  for  all  antral  polyps  (Moore). 

Epithelial  papilloma  occasionally  arises  in  the  antrum.  It  has  consider- 
able growth  capacity,  recurring  after  operation  and  until  the  base  is  removed. 
I  have  observed  a  case  in  which  the  papilloma  recurred  after  many  operations 
over  a  period  of  10  years  and  eventually  became  carcinomatous. 

Carcinoma  of  Antrum. — There  are  two  separate  sources  of  malignant  epi- 
thelial tumors  of  the  antrum:  (i)  from  the  mucosa,  and  (2)  from  epithelial 
dental  structures,  tumors  of  which  may  first  appear  in  the  antral  cavity. 
In  each  of  these  classes  there  is  a  considerable  variety  of  structure  and  many 
peculiarities  in  course. 
46 


722 


NEOPLASTIC  DISEASES 


From  the  mucosa  arise: 

(1)  Papillary  carcinomas,  some  of  which  represent  malignant  transforma- 
tions of  papillomas,  as  above  described.    These  are  originally  of  slow  growth, 
but  eventually  become  fully  malignant. 

(2)  Carcinomas  of  the  basal-cell  type  arise  within  the  antrum  and  also 
from  the  nasal  mucosa.    They  are  composed  of  anastomosing  cords  of  small 
cells  consisting  chiefly  of  nuclei.    The  stroma  is  scanty  and  undergoes  hyaline 
or  mucoid  degeneration,  (so  that  the  structure  resembles  thyroid  gland,  or  the 
mucous  masses  are  more  abundant  and  the  tumor  is  reported  as  adenoid  cystic 
epithelioma,  or  cylindroma.     Endothelioma  is  also  a  favorite  designation  of 
these  tumors.     They  are  of  relatively  slow  growth,  but  recur  persistently 


FIG.  345. — Carcinoma  of  antrum,  probably  arising  from  the  mucosa,  and  showing  many 

globules  of  mucus. 

after  incomplete  removal,  and  they  may  invade  the  bone  and  eventually  the 
lymph-nodes. 

(3)  Squamous-cell  carcinoma  is  rarely  seen  in  the  antrum  except  as  a 
secondary  invasion,  but  either  from  metaplasia  or  through  origin  from  pre- 
viously altered  lining  epithelium  this  type  of  growth  may  arise.     It  pursues 
the  usual  course  of  acanthoma. 

(4)  Cylindrical-cell  carcinoma  is  a  common  form  of  antrum  cancer.     It 
forms  a  bulky  rapidly  growing  tumor  which  distends  the  cavity,  protrudes 
into  the  nares,  erodes  bone,  ulcerates  and  bleeds,  and  usually  extends  widely 
with  recurrence  after  operation.     The  structure  is  adenocarcinomatous,  or 
the  cells  grow  in  large  sheets  and  in  polyhedral  form.    This  same  structure  is 


MAXILLARY  TUMORS  OF  DENTAL  ORIGIN  723 

seen  in  tumors  arising  from  the  maxillary  sinus,  the  ethmoid  cells,  the  frontal 
sinuses,  and  the  Schneiderian  membrane.  Wisotski  has  collected  3  cases 
of  frontal  sinus  carcinoma  and  i  acanthoma. 

(5)  Round-cell    carcinomas    of    atypical    structure    composed    chiefly    of 
rounded  or  polyhedral  cells  consisting  chiefly  of  nuclei  arise   in    the  nasal 
passages  and  accessory  sinuses.     They  probably  form  the  majority  of  the 
so-called  sarcomas  of  this  region.     On  account  of  the  absence  of  alveolar 
structure  and  definite  epithelial  characters   the   true  origin  is  easily   over- 
looked, while  many  reporters  of  cases  have  assumed  that  the  highly  malignant 
course  indicates  a  sarcomatous  nature.     The  diffuse  growth  of  undifferenti- 
ated  cells  is  facilitated  by  the  recurrence  after  incomplete  operation  to  which 
most  of  these  tumors  are  subjected,  but  if  the  primary  structure  of  the  original 
tumor  is  secured  or  the  tissue  in  recurrences  is  carefully  prepared  and  exam- 
ined, the  epithelial  character  is  sufficiently  revealed.    The  conditions  of  origin 
and  the  course  of  these  tumors  are  those  of  carcinoma,  and  the  existence  of  a 
mesoblastic  tumor  of  this  type  has  not  been  demonstrated.     Lymphosar- 
coma  occurs  in  the  nares  as  a  part  of  a  more  general  disease,  but  I  have  seen 
one  case  of  lymphosarcoma  in  which  the  main  lesions  requiring  attention 
were  nasal  and  laryngeal. 

Melanoma  of  the  nares  is  a  very  rare  tumor,  of  which  I  have  studied  one 
example,  reported  by  Coley,  in  which  the  pigmentation  was  prominent  and 
the  structure  carcinomatous. 

(6)  Dental  tumors  not  infrequently  develop  in  the  antrum.     They  in- 
clude radiculodental  cysts,  dentigerous  cysts,  and  squamous  and  glandular 
types  of  adamantinoma  (q.  ?>.).     They  can  usually  be  recognized  on  their 
peculiar  structure  and  also  by  the  occurrence  of  disorder  in  the  adjacent 
teeth  early  in  the  course  of  the  disease.    Yet  the  antral  growth  may  be  well 
advanced  before  the  teeth  are  disturbed,  so  that  this  group  of  dental  tumors 
is  of  relatively  unfavorable  prognosis. 

(7)  True  sarcomas  of  the  nares  and  antrum  are  chiefly  angiosarcomas 
and  myxosarcomas  arising  from  the  mucosa.     Many  authors  describe  fibro- 
sarcomas  without  reference  to  their  exact  nature  (Richou).    Osteogenic  sar- 
comas of  this  region  are  comparatively  rare  and  are  easily  recognized  by 
their  structure.    From  the  choana  and  vault  of  pharynx  arises  the  chondro- 
myxosarcoma  of  infants  and  children. 

Clinical  Course  of  Malignant  Tumors  of  Antrum. — Since  the  prognosis 
of  established  malignant  tumors  of  this  region  is  extremely  unfavorable 
almost  the  only  real  service  the  physician  can  render  in  these  cases  is  the 
early  recognition  of  the  disease.  At  the  Memorial  Hospital  it  is  found  that 
most  of  these  patients  have  passed  the  period  of  hopeful  therapeutics  un- 
noticed, or  with  nasal  douches,  or  extraction  of  teeth. 

Richou  separates  the  initial  symptoms  into  two  groups,  in  one  of  which 
the  disease  is  preceded  or  accompanied  by  purulent  or  bloody  discharge  from 
the  nares,  while  in  the  other  no  such  signs  are  observed,  but  the  tumor  is 
discovered  only  after  it  has  reached  such  a  size  as  to  produce  pressure  symp- 
toms. It  is  important  to  note  that  many  cases  are  long  regarded  as  pyorrhea, 
toothache,  neuralgia,  or  simple  sinusitis,  only  to  reveal  themselves  later  as 
malignant  tumors.  Occasionally  the  histological  report  on  a  benign  process 
removed  from  the  outskirts  of  a  malignant  tumor  has  obscured  the  true  con- 
dition (Richou).  Thus  the  thorough  exploration  of  every  suspicious  case 
seems  to  be  indicated  as  soon  as  possible.  The  condition  of  the  antrum  should 
be  determined  by  an  #-ray  photograph. 

Among  the  conditions  simulating  the  early  stages  of  malignant  tumors 
Jacques  and  Gaudier  mention  disorders  in  the  development  of  the  teeth, 


724  NEOPLASTIC  DISEASES 

misplaced  molars  and  wisdom  teeth  with  cysts  arising  therefrom,  simple 
osteitis  and  periostitis,  mucocele  of  the  antrum,  empyema  of  antrum,  and 
forms  of  syphilis  and  tuberculosis. 

Three  stages  in  the  course  of  malignant  tumors  are  emphasized  by  Jacques 
and  Gaudier.  In  the  stage  of  latency  the  presence  of  a  tumor  may  be  sus- 
pected from  aching  or  neuralgic  pain  in  the  jaw,  purulent  discharge,  epistaxis, 
polypoid  growths  about  the  orifice  of  the  sinus,  and  in  the  case  of  dental 
tumors  loosening  of  the  teeth.  In  the  stage  of  deformation  of  the  maxilla 
there  is  a  swelling  of  the  walls  of  the  sinus,  projecting  externally,  or  into  the 
nares,  or  into  the  orbit,  together  with  more  definite  symptoms  of  the  earlier 
stage.  In  the  stage  of  invasion  there  is  destruction  of  the  walls  and  adjacent 
structures,  hemorrhage,  ulceration,  and  extension  to  skin,  pharynx,  orbit, 
skull,  or  lymph-nodes.  The  general  duration  of  the  disease  is  from  4  months 
to  2  years,  and  is  closely  related  to  the  degree  of  histological  differentiation 
of  the  tumor-cells.  Recovery  from  the  squamous-cell  or  true  carcinomas  is 
very  rare. 

The  lymph-nodes  were  invaded  in  19  of  64  cases  reported  by  Windmuller, 
and  in  19  of  51  cases  of  Winiwarter.  On  the  whole,  this  invasion  occurs 
rather  late  and  infrequently,  considering  the  activity  of  the  process.  The 
nodes  chiefly  affected  are  those  behind  the  angle  of  the  jaw  and  above  the 
expansion  of  the  aponeurosis  of  the  sternomastoid  (Sebileau).  The  lym- 
phatics of  the  superior  maxillary  region  tend  to  pass  posteriorly,  join  with 
those  from  the  nasal  mucosa  and  vault  of  pharynx,  and  descend  along  the 
deep  cervical  chain.  I  have  observed  bulky  pulmonary  and  hepatic  metas- 
tases  in  2  cases  of  antral  and  Schneiderian  carcinoma  in  which  no  invasion 
of  lymph-nodes  could  be  discovered. 

The  best  results  in  the  treatment  of  carcinoma  in  this  region  are  secured 
by  early  operation  combined  with  or  preceded  by  radium.  The  English 
rhinologists  especially  seem  to  have  developed  considerable  reliance  on  this 
latter  agent. 


CHAPTER  XXXVI 
EPITHELIAL  TUMORS  OF  THE  SALIVARY  GLANDS 

Three  groups  of  epithelial  tumors  are  observed  in  the  salivary  glands: 

(1)  Benign  adenoma, 

(2)  Malignant  adenocarcinoma  or  carcinoma,  and 

(3)  Autochthonous  mixed  tumors. 

The  parotid  is  by  far  the  most  frequently  involved,  but  all  the  above 
growths  occur  in  the  submaxillary,  the  sublingual  is  occasionally  affected, 
while  mixed  tumors  of  the  salivary  gland  type  are  also  found  in  the  lip,  cheek, 
palate,  nares,  and  pharynx.  The  lacrimal  gland  may  also  be  included  with 
the  salivary  organs  in  the  study  of  its  tumors. 

Adenoma  of  the  salivary  glands  is  rare.  In  the  parotid,  Nasse  describes 
4  cases  and  others  are  reported  by  Lecene,  Lexer,  Ribbert,  and  Wood.  In 
the  submaxillary,  Chevassu  analyzed  five  reported  adenomas,  concluding 
that  two  were  cases  of  chronic  inflammation  (Duplay,  Poncet),  one  a  cystic 
dilatation  of  the  ducts  (Bougie),  one  a  carcinoma  (Wolfler),  and  one  a  papillary 
cystic  adenoma  (Talazac). 

Sublingual  adenomas  are  described  by  Duplay,  Zeisel,  Ferreri,  and  Kutt- 
ner.  Of  132  tumors  of  the  lacrimal  glands,  Warthin  found  13  described  as 
adenomas.  In  these  cases  the  tumors  have  exhibited  very  slow  growth,  the 
duration  in  Nasse's  cases  being  from  8  to  12  years.  They  are  encapsulated, 
cystic  or  solid,  and  well  incorporated  in  the  gland  or  attached  to  it.  In  the 
gross  the  tumors  are  lobulated  by  traversing  septa,  or  composed  of  solid  gland 
tissue,  or  of  many  minute  cysts  or  of  one  large  cyst.  The  structure  is  alveolar, 
reproducing  the  acini  of  the  glands,  or  cystic  and  papillary-  The  stroma  is 
of  moderate  development  and  all  traces  of  mucoid  or  cartilaginous  deposits 
are  missing.  In  the  cysts  there  may  be  much  mucous  or  serous  secretion. 
Transitions  to  malignant  adenocarcinoma  are  observed  (Chevassu),  and 
Nasse  describes  in  upper  lip  and  nose  combinations  of  adenoma  with  basal- 
cell  carcinoma.  Several  authors  have  described  transitions  to  myxochondro- 
carcinoma. 

Carcinoma. — Pure  malignant  epithelial  tumors  of  the  salivary  glands  are 
by  no  means  rare.  Most  of  the  parotid  carcinomas  are  reported  in  studies 
of  the  mixed  tumors,  and  appear  in  the  series  of  Paris  theses  (Pailler,  Lit.), 
and  in  the  collections  of  Volkmann,  Ehrich,  Chevassu,  and  others.  Pure 
carcinomas  without  any  trace  of  the  features  of  mixed  tumors  are  described 
in  the  parotid  by  Pailler,  Ehrich,  and  Nasse,  in  the  submaxillary  by  Pren- 
grueber,  Waldeyer,  Volkmann,  Kuttner,  Lowenbach,  Nasse,  and  Chevassu. 
Warthin  collected  six  carcinomas  of  the  lacrimal  gland.  Most  of  the  malig- 
nant tumors  of  this  organ  are  of  the  basal-cell  type.  I  have  studied  three 
pure  carcinomas  of  the  parotid.  It  is  evident  that  many  of  the  pure  endo- 
thelial  tumors  described  by  Volkmann  and  others  are  of  glandular  epithelial 
origin,  but  being  chiefly  of  the  basal-cell  type  they  are  included  with  the 
mixed  tumors. 

Whatever  may  be  their  relation  to  the  mixed  tumors,  pure  carcinomas  of 
the  salivary  glands  are  highly  characteristic  both  clinically  and  histologically. 

The  carcinomas  usually  develop  rapidly,  and  while  at  first  they  may  be 
encapsulated,  they  soon  invade  the  whole  gland,  the  capsule,  and  regional 
nodes.  The  more  adenomatous  tumors  may  contain  cysts,  while  the  more 

725 


726 


NEOPLASTIC  DISEASES 


malignant  growths  are  solid,  firm,  and  opaque  and  in  many  cases  lobulated. 
After  extirpation  prompt  recurrence  is  usually  observed,  even  when  the 
structure  suggests  an  adenomatous  nature  (Chevassu).  In  advanced  cases 
there  are  local  and  general  metastases,  and  in  Nasse's  case  many  bones  were 
involved.  The  clinical  malignancy  of  these  tumors  is,  therefore,  pronounced. 
In  Prengrueber's  case  the  growth  was  accompanied  by  continuous  salivation. 
In  some  cases  there  is  a  history  of  a  quiescent  growth  of  long  standing  which 
eventually  became  active,  indicating  a  change  from  a  benign  to  a  malignant 
structure.  I  have  observed  carcinoma  developing  on  a  granuloma  of  3  years' 
duration  in  the  submaxillary  gland. 

Structurally  there  are  two  main  varieties,  adenocarcinoma  and  alveolar 
carcinoma.  To  these  must  probably  be  added  a  third  group  of  diffusely 
growing  tumors  of  spindle-  or  rounded  cells  which  are  atypical  carcinomas 
(Chevassu). 


FlG.  346. — Structure  of  an  adenocarcinoma  of  submaxillary  gland. 

The  adenocarcinomas  are  alveolar  or  papillary.  The  former  develop 
from  the  acini  and  the  latter  from  the  ducts.  The  alveolar  growths  repro- 
duce more  or  less  exactly  the  acini  of  the  gland.  The  lumina  and  the  cells 
may  contain  hyaline,  mucous,  or  serous  secretion.  Chevassu  describes  a 
dendritic  adenocarcinoma  arising  in  the  ducts,  in  which  very  numerous  papillae 
were  lined  by  multiple  layers  of  cubical  or  cylindrical  cells.  This  tumor 
promptly  recurred  after  operation  and  grew  rapidly. 

Under  the  term  cylindroma  has  been  described  a  rather  frequent  form  of 
adenocarcinoma  of  the  salivary  glands  (Lowenbach,  Lit.).  These  tumors 
are  composed  of  anastomosing  cords  or  broad  masses  of  epithelial  cells,  in- 
closing many  spaces  filled  with  mucus.  There  are  coarse  trabeculae  of  con- 
nective tissue  which  may  undergo  hyaline  or  mucoid  degeneration.  The 
structure  suggests  a  relation  to  basal-cell  carcinoma  of  the  type  of  adenoid 
cystic  epithelioma,  but  Lowenbach  was  able  to  trace  the  origin  in  one  case 
to  the  ducts  and  in  another  to  the  acini  of  the  gland. 

The  fully  developed  carcinomas  of  the  salivary  glands  usually  exhibit 
traces  of  the  acinar  structure  of  the  adenocarcinomas,  but  the  most  anaplastic 


EPITHELIAL  TUMORS  OF  THE  SALIVARY  GLANDS  727 

tumors  grow  in  broad,  cellular  masses  or  diffusely,  while  some  highly  atypical 
growths  take  the  form  of  so-called  round-cell  sarcoma.  Three  structural 
peculiarities  suggesting  an  origin  from  the  salivary  glands  are  often  present, 
in  three  structural  varieties  of  these  tumors. 

(a)  Marked  squamous  metaplasia,  affecting  very  many  small  groups  of 
cells,  appears  in  carcinomas  composed  of  anastomosing  columns  of  opaque 
granular,  cubical,  or  cylindrical  epithelium.  These  features  suggest  an  origin 
from  the  ducts  in  which  squamous  epithelium  may  result  from  inflammatory 
changes. 

(6)  Peculiar  large  mucoid  globules  may  distend  many  cells  in  small  alveo- 
lar carcinomas,  yielding  a  structure  which  is  quite  specific. 

(c)  Collections  of  mucus,  such  as  occur  in  cylindroma,  may  persist  in  more 
cellular  and  malignant  tumors. 

Round-cell  Carcinoma. — Malignant  round-cell  tumors  of  the  salivary 
glands  have  been  described  as  round-cell  sarcomas  by  Kuster,  Nasse,  Koch, 
Degen,  and  Schridde  (Lit.).  Kuttner  collected  6  cases  of  round-cell  sar- 
coma of  the  submaxillary.  Some  of  the  tumors  presented  a  distinctly  alveo- 
lar structure,  while  most  others  exhibited  nests  of  polyhedral  cells  strongly 
resembling  epithelium.  Schafer  found  well-marked  epithelial  characters  in 
portions  of  a  tumor  chiefly  "sarcomatous."  Schridde  describes  among  the 
round  cells  remnants  of  gland  tissue  in  markedly  hypertrophic  condition, 
which  he  interprets  as  collateral  hyperplasia.  As  the  tumors  were  large 
and  rapidly  growing,  none  of  the  authors  was  able  to  trace  the  origin  of  the 
growth.  In  some  cases  there  was  pronounced  perithelial  arrangement  such 
as  is  often  seen  in  the  mixed  tumors  (Dubreuil,  Volkmann).  All  of  these 
features  are  much  more  satisfactorily  explained  as  belonging  to  atypical 
rapidly  growing  carcinomas.  Chevassu  argues  strongly  in  favor  of  this  view. 
Lymphosarcoma  originating  in  the  reticulum  cells  of  the  lymph-follicles  is 
not  infrequently  seen  in  the  salivary  glands,  as  in  Mikulicz's  disease,  and 
may  be  difficult  to  distinguish  from  round-cell  carcinoma,,  but  apart  from 
these  lymphoid  tumors  sarcoma  of  the  salivary  glands  has  not  been  satis- 
factorily demonstrated. 

Mixed  Tumors  of  Salivary  Glands,  etc. — In  the  salivary  glands,  buccal 
mucosa,  palate,  lips,  neck,  orbit,  and  lacrimal  gland  and  face  occurs  a  group 
of  tumors  about  the  origin  of  which  has  long  been  maintained  an  active  con- 
troversy. These  tumors  are  of  complex  structure,  usually  presenting  epithe- 
lial elements  in  the  form  of  cell  strands,  alveoli,  or  diffuse  masses,  and  meso- 
blastic  tissues  chiefly  cartilage,  mucous  tissue,  and  cellular  connective.  Any 
one  of  these  elements  may  predominate,  giving  nearly  pure  chondromas,  sar- 
comas, or  carcinomas,  but  usually  all  the  cell  types  are  represented. 

These  tumors  were  originally  regarded  as  carcinomas,  and  while  Virchow  derived  the 
cartilage  from  the  connective  tissue  by  metaplasia,  Cohnheim  regarded  it  as  a  derivative 
of  remnants  of  the  branchial  arches.  The  epithelial  nature  of  the  tumors  was  undisputed 
until  C.  Kaufmann,  on  the  strength  of  peritheliomatous  and  sarcomatous  features, 
placed  them  among  the  sarcomas. 

In  1879  Wartmann  maintained  'that  the  polyhedral  cells  were  derived  from  the 
lymphatic  endothelium,  and  from  this  time  the  endothelial  theory  gained  general  accept- 
ance in  Germany,  especially  through  the  study  of  Volkmann.  Although  the  main  con- 
clusion of  this  author  has  been  proved  untenable,  his  study  was  of  much  value  in  reveal- 
ing the  extent  to  which  embryonal  epithelial  cells  may  simulate  endothelium,  and  his 
view  that  the  mesoblastic  structures  in  the  tumors  are  derived  by  metaplasia  from 
embryonal  connective  tissue  still  remains  a  matter  of  discussion. 

In  France  the  endothelial  theory  failed  to  receive  much  attention,  and  Collet  in  1896, 
Pitance  (1900),  and  many  later  writers  adhered  consistently  to  the  epithelial  interpreta- 
tion. 

The  first  definite  attack  on  Volkmann's  theory  was  made  by  Hinsberg  (1899)  with 


728  NEOPLASTIC  DISEASES 

Ribbert's  support.  He  strongly  maintained  the  cancerous  nature  of  the  tumors,  demon- 
strating that  the  pearls  observed  in  many  cases  by  himself  and  previously  by  Nasse, 
Volkmann,  Mauclaire,  Cavazzani,  and  others  exhibited  spines,  and  disposing  of  many 
histological  arguments  which  had  been  used  in  favor  of  the  endothelial  theory.  By 
embryological  studies  he  endeavored  to  show  that  the  tumors  are  derived  from  very 
early  invaginations  of  buccal  epithelium  and  inclusion  of  mesoblastic  tissue  connected 
with  the  mandible  arches.  He  found  islands  of  salivary  gland  tissue  included  within 
the  periosteum  of  the  maxilla,  and  concluded  that  the  mixed  tumors  arise  from  the  isola- 
tion of  a  mass  of  tissue  including  both  salivary  gland  and  periosteal  tissue.  His  con- 
clusions have  been  accepted  with  certain  reservations  by  Wilms  and  Landsteiner,  and 
represent  one  of  the  prevailing  opinions  at  the  present  day.  In  America  they  have  been 
endorsed  especially  by  Wood  and  Verhoef.  Yet  Borst  and  Kaufmann  will  not  abandon 
the  possibility  that  some  of  the  tumors  are  of  endothelial  origin,  although  they  do  not 
specify  their  distinctive  features.  Recently  Steinhaus  and  Martini  espouse  the  endo- 
thelial theory,  but  with  arguments  which  appear  to  the  writer  inadequate. 

The  arguments  favoring  the  endothelial  theory  relate  chiefly  to  the  morphology  of 
the  cells  and  their  relation  to  surrounding  structures.  The  cells  are  small,  often  poly- 
hedral, and  under  pressure  readily  assume  a  flat  or  spindle  form.  They  are  often  very 
intimately  adherent  to  the  supporting  connective  tissue  and  may  give  the  appearance 
of  merging  with  that  tissue  in  a  manner  rarely  observed  in  carcinoma.  It  has  repeatedly 
been  pointed  out  that  the  cells  may  be  continuous  with  those  lining  lymph-spaces  and 
capillaries.  In  certain  cases  diffuse  masses  of  these  cells  reproduce  a  structure  closely 
resembling  spindle-cell  sarcoma,  and  in  the  various  forms  of  cylindroma  and  perithelioma 
structures  appear  which  have  commonly  been  recognized  as  sarcomatous. 

Especially  the  relation  of  the  tumor-cells  to  the  growing  masses  of  hyaline,  mucinous, 
or  cartilaginous  material  suggests  their  mesoblastic  nature.  The  early  tumors  may  be 
sharply  separated  from  the  gland  structures,  and  many  observers  have  been  unable  to 
find  any  signs  of  derivation  of  the  tumor-cells  from  gland-cells.  Finally,  in  no  other 
situation  do  any  tumors  of  known  epithelial  origin  exhibit  such  peculiar  relations  to 
mesoblastic  tumor  elements,  whereas  in  known  forms  of  endothelioma,  sprouting  of 
capillary  endothelium,  persistence  of  lumina,  pearl  formation,  phagocytosis  of  blood- 
pigment,  intimate  relation  or  fusion  with  the  stroma,  and  ultimate  transformation  into 
hyaline  connective  tissue,  are  observed. 

While  the  above  arguments  appeared  at  one  time  as  conclusive,  they  must  today  be 
regarded  as  inadequate  or  even  superficial.  The  cells  show  no  minute  characters  which 
permit  their  identification  as  endothelium.  Instead  of  a  clear  cytoplasm,  condensed  cell 
border,  and  small  nuclei  with  indistinct  nucleoli,  their  cytoplasm  is  granular,  the  borders 
ill-defined,  and  the  nucleoli  often  prominent.  The  long  strands  of  cells  resembling  sprout- 
ing vessels  are  reproduced  in  carcinoma,  as  is  also  the  intimate  contact  of  cells  with  sup- 
porting stroma.  In  the  pearls  many  have  found  spines  and  fibrils  connecting  the  cells, 
thus  furnishing  the  strongest  evidence  of  their  squamous  epithelial  nature.  The  struc- 
tures identified  as  lymph-spaces  may  equally  well  represent  lumina  of  gland  alveoli. 
In  fact,  this  latter  origin  has  been  clearly  demonstrated  in  some  cases,  whereas  the 
existence  of  many  dilated  lymph-spaces  in  these  tumors  has  not  been  satisfactorily 
proved.  The  alveoli  often  contain  secretion  similar  to  that  found  in  the  atrophic  sali- 
vary gland  alveolus.  Many  of  the  tumors  are  encapsulated  and  do  not  involve  the 
normal  lobules  of  the  gland,  so  that  the  opportunity  to  trace  the  fate  of  gland-cells  when 
included  in  the  tumor  is  rarely  given.  Yet  this  encapsulation  is  often  incomplete. 
Krompecher,  Pailler,  Ehrich,  and  others  have  clearly  traced  the  derivation  of  the  flat 
cells  lining  narrow  spaces  from  the  glandular  epithelium.  I  have  studied  cases  in  which 
normal  gland  alveoli  were  being  inclosed  in  hyaline  material  on  the  edge  of  the  advancing 
process.  Here  the  epithelial  cells  became  transformed  into  flat  cells  exactly  resembling 
those  lining  supposed  lymph-vessels,  and  giving  the  appearance  of  sprouting  capillaries. 
The  structure  of  cylindroma  or  perithelioma  does  not  indicate  an  endothelial  tumor, 
since  this  structure  is  often  produced  by  carcinoma.  The  mixed  epidermal  and  meso- 
dermal  origin  is  rendered  acceptable  by  embryological  studies,  and  it  is  in  accordance 
with  this  view  that  nearly  pure  chondromas  or  carcinomas  may  occur  when  one  element 
becomes  predominant.  It  is  only  in  the  intermediate  group  of  cases  where  both  ele- 
ments are  commingled  that  the  question  of  endothelioma  arises. 

Hence  it  seems  necessary  to  abandon  the  theory  of  the  endothelial  origin 
of  the  common  tumors  of  the  salivary  glands.  If,  as  Borst,  Kaufmann,  and 
others  assume,  true  endotheliomas  occur  in  these  organs  their  specific  char- 
acters remain  to  be  pointed  out. 

With  the  demonstration  of  the  epithelial  nature  of  the  tumors  the  subject 
of  their  histogenesis  is  by  no  means  completed. 


EPITHELIAL  TUMORS  OF  THE  SALIVARY  GLANDS  729 

In  a  series  of  studies  Krompecher  reaches  the  conclusion  that  the  mixed 
tumors  of  the  salivary  glands  and  many  other  regions  belong  in  the  class 
of  basal-cell  carcinoma,  and  especially  in  the  subgroup  of  adenoid  cystic 
epithelioma.  In  the  soft  pliable  stroma  of  these  growths  he  finds  that  the 
epithelial  cells  readily  split  off,  fibrillate,  and  assume  the  spindle  or  star  shape 
of  mucoid  or  embryonal  connective-tissue  cells.  Under  these  conditions  he 
finds  that  true  connective  tissues,  and  by  further  metaplasia  cartilage,  may 
be  derived  from  basal  epithelium.  Hence,  Krompecher  interprets  the  sali- 
vary growths  as  of  purely  epithelial  origin,  with  peculiar  mucoid  and  car- 
tilaginous metaplasia.  Concerning  the  exact  source  of  the  originating  epithe- 
lium he  does  not  specifically  state  whether  the  cells  are  embryonal  and  mis- 
placed, or  located  in  the  salivary  ducts.  For  many  of  the  tumors  of  salivary 


«. 


N  '?>  '"? l      t? ' «".  '7;       5Vl 


FIG.  347. — Mixed  tumor  of  parotid  gland.    Showing  transformation  of  epithelium  into 

spindle-cells. 

glands  and  mucous  membranes  Krompecher's  interpretation  must,  I  think, 
be  accepted.  Especially  the  encapsulated  growths  consisting  of  anastomos- 
ing cords  of  small  cubical  or  spindle-cells  with  hyaline  stroma  and  cartilag- 
inous areas,  this  mode  of  development  appears  to  be  followed.  Both  the 
structure  and  the  clinical  course  of  these  tumors  are  identical  with  those  of 
adenoid  cystic  epithelioma  of  the  skin.  Misplaced  portions  of  buccal  or 
branchial  epithelium  or  superfluous  duct-cells  may  well  serve  as  origins  of 
such  tumors. 

Not  all  of  the  tumors,  however,  may  be  disposed  of  in  this  manner.  A 
large  portion  of  them,  covering  a  wide  variety  of  structures,  are  probably 
derived  from  the  ducts  and  acini  of  the  salivary  and  mucous  glands.  The 
evidence  in  favor  of  this  view  is  well  presented  by  Ehrich,  and  is  duplicated 


730 


NEOPLASTIC  DISEASES 


in  much  of  my  own  material.  He  finds  that  many  tumors  are  not  encapsu- 
lated, but  uniformly  fuse  with  the  gland  and  reproduce  hypertrophic  lobules 
of  the  gland  bounded  by  regular  septa.  In  several  cases  the  tumors  have 
been  multiple,  indicating  that  the  process  originated  in  several  lobules  of  the 
gland  (Ehrich,  Nasse,  Krieg). 

In  these  tumor  lobules  neoplastic  ducts  and  acini  multiply  and  break  up, 
and  the  cells  become  disseminated  in  the  soft  mucoid  stroma.  Cartilage 
appears  chiefly  in  the  centers  of  such  lobules  where  the  metaplastic  process 
is  oldest  and  most  advanced.  The  cartilage  cells  are  derivatives  of  the  epithe- 
lium. The  part  played  by  the  original  stroma  is  subordinate,  although  in 
fibrous  areas  elastic  fibers  may  be  derived  from  the  stroma  and  blood-vessels. 
Yet  genuine  collagen  and  elastic  fibrils  develop  in  the  mucoid  material  under 
the  influence  of  the  modified  epithelium.  The  mucoid  material  is  a  secretion 
from  the  epithelial  cells  and  its  diffusion  prepares  the  way  for  the  dissemina- 


FIG.  348. — Structure  of  a  portion  of  a  mixed  tumor  of  parotid  gland,  showing  transition 

of  cell  types. 

tion  of  modified  glandular  and  pavement  epithelium.  Squamous  metaplasia 
occurs  readily  in  the  proliferating  cells  of  both  ducts  and  acini,  as  in  pure 
carcinomas. 

According  to  this  view  many  of  the  salivary  tumors  are  pure  adenocarci- 
nomas  with  peculiar  and  exceptional  metaplasia,  and  not  requiring  any  peri- 
osteal  or  other  mesoblastic  derivative  in  their  cells  of  origin.  However 
violently  this  interpretation  may  conflict  with  long-established  views  regard- 
ing tissue  growth,  it  appears  to  be  necessary  to  accept  the  facts  so  well  attested 
by  the  close  study  of  these  tumors.  To  a  considerable  extent  Krompecher's 
studies  have  rendered  the  exclusive  epithelial  origin  more  acceptable.  It  is  not 
necessary  to  assume  that  similar  violations  of  the  ordinary  laws  of  histogene- 
sis  occur  in  other  tumors,  since  the  salivary  gland  tumors,  under  the  influence 
of  mucus  production  and  ptyalin  secretion,  appear  to  form  an  exceptional 
class.  Yet  a  very  similar  inclusion  of  epithelial  cells  in  cartilage  may  some- 


EPITHELIAL  TUMORS  OF  THE  SALIVARY  GLANDS 


731 


times  be  traced  in  chondrocarcinoma  of  the  dog's  breast.  That  the  duct- 
cells  possess  a  notable  capacity  for  multiplication  and  squamous  metaplasia 
is  shown  in  the  results  of  ligation  of  the  ducts  or  partial  extirpation  reported 
by  Ribbert,  Broussis,  and  Carraro.  Lowenstein  describes  notable  hyperplasia 
of  acini  occurring  in  areas  infiltrated  by  lymphocytes  in  chronic  inflammation 
of  the  salivary  glands  and  he  finds  in  this  altered  groundwork  the  cause  of  the 
proliferation  which  leads  to  tumor  growth. 

While  the  above  theory  satisfactorily  explains  the  mode  of  growth  of 
the  established  tumor  it  is  less  convincing  in  regard  to  the  exact  cells  of  origin 
of  the  beginning  growth.  Some  very  small  encapsulated  tumors  do  not  exhibit 
any  relations  to  the  ducts  or  acini  of  the  gland.  The  basal-cell  type  of  growth 


FIG.  349.— Dissemination  of  epithelial  cells  in  mucinous  stroma  of  a  mixed  tumor  of 

parotid. 

is  also  less  clearly  connected  with  the  normal  gland  structures  than  is  the 
adenomatous.  The  theory  of  branchial  origin  seems  to  cover  this  deficiency 
and  deserves  careful  consideration.  The  grounds  of  this  theory  have  been 
stated  by  Hinsberg,  Cuneo  and  Veau,  Chevassu,  and  others,  and  attacked 
by  Forgue,  Vialleton,  and  Massabuau.  Chevassu  has  shown  that  branchial 
cysts  may  contain  pharyngeal  epithelium  and  salivary  glands,  which  furnish 
a  satisfactory  origin  for  some  of  the  salivary  tumors.  An  inclusion  of  frag- 
ments of  the  aural  cartilages  is  strongly  suggested  for  certain  tumors  which 
early  involve  the  ear.  Weisshaupt  thinks  that  the  tumors  which  are  sharply 
separated  from  the  gland  tissue  probably  arise  from  an  embryonal  divertic- 
ulum  of  the  parotid  duct,  which  regularly  exists  in  man. 

The  position  of  some  tumors,  attached  to  rather  than  lying  within  the 


732 


NEOPLASTIC  DISEASES 


gland,  is  readily  explained  by  the  branchial  theory.    The  occurrence  of  much 
striated  muscle  tissue  in  a  mixed  parotid  tumor,  described  by  Prudden,  shows 

that  an  extensive  local  malformation  was 
concerned  in  its  origin.  The  epithelial 
structures  in  this  tumor  were,  however, 
quite  peculiar.  Of  similar  significance  is 
a  congenital  tumor  of  the  usual  type  as- 
sociated with  an  accessory  tragus  and 
auricular  fistula,  described  by  Wood.  On 
the  other  hand,  the  wide  distribution  of  the 
tumors  in  lips,  cheek,  and  palate  is  not 
easily  adjusted  to  an  exclusive  branchial 
origin,  but  suggests  rather  that  the  con- 
ditions of  their  origin  are  fully  provided 
in  salivary  and  mucous  glands. 

The  view  expressed  by  Forgue  and 
Massabuau  that  the  tumors  are  true  em- 
bryomas  is  without  adequate  foundation. 
Teratomas  of  the  neck  are  reported  by 
Weyl,  Poult  (Lit.),  McGregor  and  Work- 
man, Ficheaux,  and  others,  but  these 
tumors  were  quite  different  from  the 
common  mixed  growths. 

The  present  status  of  our  knowledge  of 
the  origin  of  mixed  tumors  of  the  salivary 
glands  may  be  summarized  as  follows: 

(i)  The  endothelial  origin  has  been  dis- 
proved. 

(2)  No  single  source  of  the  mixed  tumors  meets  all  the  requirements. 
Some  are  distinctly  adenomatous  and  probably  arise  from  the  acini  and  ducts 
of  the  gland  in  which  they  are  well  incorporated.  Others  are  encapsulated 


FIG.  350. — Early  encapsulated  mixed 
tumor  of  parotid. 


FIG.  351. — Parotid  tumor  with  congenital  malformations  of  ear  and  face  (accessory 
tragus  and  auricular  fissure).     (After  Wood.) 


or  extraglandular  and  take  the  form  of  basal -cell  or  adenoid  cystic  epithe- 
lioma.     These  probably  arise  from  misplaced  and  occasionally  embryonal 


EPITHELIAL  TUMORS  OF  THE  SALIVARY  GLANDS  733 

portions  of  gland  tissue.  Branchial  remnants  may  possibly  be  connected 
with  this  group. 

(3)  The  derivation  of  mucous  tissue  and  cartilage  from  gland  epithelium 
has  been  satisfactorily  proved  and  there  is  no  necessity  of  including  in  the 
originating  tissue  any  cartilaginous  structures. 

General  Etiology. — Epithelial  mixed  tumors  of  the  salivary  glands  are 
comparatively  common,  and  when  all  the  sub  varieties  occurring  about  the 
pharynx  and  face  are  included  they  become  quite  numerous.  The  literature 
contains  many  reports,  each  covering  from  30  to  60  cases. 

They  occur  at  all  ages,  Pailler  observing  one  case  in  a  girl  at  n  months, 
and  another  at  73  years.  Wood  reports  a  rapidly  growing  mixed  parotid 
tumor  at  7  months  and  Wagner  a  mixed  sublingual  growth  in  an  infant  of 
12  weeks.  While  thus  frequently  observed  in  younger  subjects,  the  majority 
occur  between  20  and  40  years.  Of  50  submaxillary  tumors  Chevassu  found 
14  occurring  between  10  and  19  years  and  14  between  20  and  29  years.  In 
several  cases  a  quiescent  or  slowly  growing  tumor  had  existed  from  birth. 
Both  sides  and  both  sexes  are  about  equally  affected.  According  to  Bohme 
and  Kuttner  the  parotid  furnishes  about  90  per  cent,  of  the  tumors,  the  sub- 
maxillary  10  per  cent.,  and  the  sublingual  i  per  cent.,  but  this  proportion  of 
parotid  growths  is  probably  too  high.  Most  tumors  in  the  floor  of  the  mouth 
are  probably  derived  from  aberrant  portions  of  the  submaxillary  (Ehrich). 
In  the  lacrimal  gland  War  thin  collected  13  cases  reported  as  adenoma  and 
5  as  carcinoma.  Verhoef  records  five  mixed  tumors  of  the  lacrimal  gland. 
If  one  includes  all  the  deep  orbital  tumors  of  basal-cell  and  mixed  types,  this 
group  at  once  becomes  numerous. 

In  the  cheek  and  lips  characteristic  basal-cell  or  mixed  tumors  are  de- 
scribed by  Wood,  Sempnooff,  Krompecher,  Lenormant,  and.  Collet;  in  the 
buccal  mucosa  and  vault  of  palate  by  Laraberie  and  Bergem;  in  the  antrum 
of  Highmore  by  Marchand  and  Gutekunst;  in  the  nares  by  Dembrowski; 
in  the  tonsil  and  alveolar  border  by  Krompecher.  Few  of  these  miscellaneous 
tumors  duplicate  the  complex  structure  of  the  salivary  growths.  Most  of 
them  are  more  simple  and  fall  in  the  group  of  adenoid  cystic  epithelioma  or 
cylindroma. 

Clinical  Course. — In  the  great  majority  of  cases  a  quiescent  tumor  has  long 
preceded  the  development  of  an  active  growth.  Very  often  the  quiescent 
nodule  was  observed  for  8  to  10  years,  Pailler  reporting  an  inactive  period 
of  37  years  and  Wood  53  years.  Trauma  rarely  appears  as  a  possible  factor. 
Once  established,  active  growth  proceeds  slowly,  but  varies  with  the  histolog- 
ical  type.  The  average  duration  of  operative  cases  is  about  8  years.  A  limit- 
less growth  is  by  no  means  a  necessary  attribute.  Thus  in  Martland's  case, 
after  2  years'  active  growth,  the  tumor  remained  stationary  for  13  years, 
the  patient  dying  from  phthisis.  This  fact  has  a  bearing  on  the  therapeutic 
results  of  radium,  which  is  of  much  value  in  this  group  of  tumors,  as  well 
as  on  the  wisdom  of  surgical  removal,  which  is  often  followed  by  recurrences 
of  increasing  malignancy.  On  the  other  hand,  some  old  tumors  becoming 
active  soon  infiltrate  the  capsule  and  gland  and  even  invade  the  lymph- 
nodes  in  a  few  months  (Wood,  Case  IV).  There  are  some  indications  that 
the  addition  of  malignant  properties  may  come  from  some  secondary  neo- 
plastic  process  established  in  the  adjoining  gland,  or  by  perforation  of  the 
tumor  capsule.  There  are  thus  very  wide  variations  in  the  clinical  behavior 
of  the  tumors.  Occasionally  the  growth  is  steadily  progressive  from  the 
first.  After  surgical  interference  encapsulated  growths  do  not,  as  a  rule, 
recur,  but  others  are  very  prone  to  return  at  once  or  after  an  average  interval 
of  25  years  (Ehrich)  or  as  late  as  9  years.  In  Wood's  37  cases  there  is  a  record 


734 


NEOPLASTIC  DISEASES 


of  17  recurrences,  45  per  cent.;  while  12  cases  were  checked  by  a  secondary 
operation,  and  20  (55  per  cent.)  were  permanently  cured.  Successive  recur- 
rences with  many  operations  have  extended  over  a  period  of  20  years  (Wood) 
and  23  years  (Billroth).  In  the  recurrent  tumors  the  structure  may  remain 
constant,  but  more  often  it  becomes  increasingly  cellular,  atypical,  and  malig- 
nant. 

Undisturbed  tumors  rarely  invade  the  lymph-nodes,  but  after  unsuccess- 
ful operation,  while  the  recurrences  are  usually  local,  the  cervical  nodes  may 
be  progressively  involved.  In  the  case  of  Barozzi  and  Lesne  both  cervical 
and  tracheal  nodes  were  invaded  by  an  epithelioma  with  mucous  stroma.  I 
have  observed  soft  cartilage  in  the  supraclavicular  nodes.  In  the  case  of 
Griffini  and  Trombetta  a  chondrocarcinoma  invaded  cervical  and  bronchial 
nodes,  lung,  and  pleura,  with  carcinoma  in  the  nodes  and  cartilage  in  lung 


FIG.  352. — Mixed  tumor  of  parotid  apparently  involving  the  entire  gland. 

and  pleura.  Very  cellular  growths  tending  toward  the  carcinomatous  or 
so-called  sarcomatous  types  may  generalize.  Wide  local  extensions  and 
displacement  of  surrounding  structures  marked  the  natural  history  of  a  pro- 
longed case  of  adenomyxoma  of  parotid,  which  I  studied  at  autopsy.  The 
growth  occluded  the  pharynx,  eroded  the  superior  maxilla  and  orbit,  caused 
extreme  exophthalmos,  and  displaced  the  inferior  maxilla  after  10  years' 
duration  in  a  girl  of  20  years. 

Gross  Anatomy. — Beginning  as  a  small  firm  nodule  in  or  upon  the  salivary 
gland,  the  tumor  usually  grows  within  a  capsule  until  it  reaches  considerable 
size.  Fusion  with  the  septa  of  the  gland  is  commonly  observed  and  in  lobu- 
lated  tumors  the  dividing  trabeculae  seem  to  be  continuous  with  the  inter- 
lobular  septa.  While  small  tumors  may  be  completely  separable,  larger 
growths  show  increasing  fusion  and  some  are  fully  incorporated  with  the 
gland  from  the  first.  It  is  usually  impossible  to  excise  the  tumor  without 


EPITHELIAL  TUMORS  OF  THE  SALIVARY  GLANDS  735 

including  fragments  of  the  gland.  Nasse,  Ehrich,  and  Krieg  found  multiple 
early  tumors  in  the  same  gland.  The  location  of  the  tumors  is  not  always 
in  obvious  connection  with  any  gland.  They  may  first  appear  in  the  retro- 
pharyngeal  region  or  in  any  part  of  the  lateral  wall  of  the  pharynx  or  floor 
of  the  mouth.  Some  develop  along  Steno's  duct,  others  appear  below  or 
behind  the  ear  and  seem  to  involve  the  aural  cartilages,  while  a  few  are  found 
well  below  the  submaxillary.  The  consistence  is  usually  very  firm  or  hard, 
but  cellular  and  mucoid  growths  may  be  soft  and  elastic.  Small  cysts  are 
frequently  seen  and  rarely  the  tumor  consists  of  one  large  cyst.  Cross-section 
reveals  opaque  cellular  areas  which  may  be  vascular,  softened  gelatinous 
masses  exuding  mucus  or  serum,  hard  fibrous  or  hyaline  zones,  or  areas  of 
cartilage  and  rarely  of  bone.  Few  of  the  tumors  are  free  from  the  evidences 
of  mucous  secretion.  Predominance  of  one  element  may  give  nearly  pure 
myxoma,  chondroma,  fibroma,  carcinoma,  or  sarcoma. 

Structure. — While  the  majority  of  the  tumors  are  of  rather  uniform  type, 
the  variety  of  structures  to  be  included  in  this  group  is  very  great.  Although 
the  entire  series  is  connected  by  transitional  cases  a  serviceable  classification 
may  be  given  as  follows : 

(1)  Myxochondrocarcinoma. 

(2)  Basal-cell  carcinoma  with  hyaline  stroma. 

(3)  Adenoid  cystic  epithelioma. 

(i)  Myxochondrocarcinoma. — The  majority  of  the  tumors  present  broad 
areas  or  narrow  zones  of  epithelial  cells  which  surround  and  fade  into  masses 
of  mucoid,  connective,  or  cartilaginous  tissue.  The  epithelium  shows  all 
gradations  from  adenomatous  alveoli  derived  from  the  glandular  acini 
and  duct,  to  solid  masses  or  narrow  strands  of  small  flattened  compact  epi- 
thelium of  basal  type.  The  transformation  of  gland  structures  into  tumor 
tissue  can  at  times  be  fully  traced  and  has  been  described  in  great  detail  by 
Pailler,  Ehrich,  and  others.  As  previously  stated  these  appearances  repre- 
sent the  mode  of  extension  rather  than  the  necessary  mode  of  origin  of  the 
tumor.  Small  alveoli  lined  by  cubical  cells  and  filled  with  dense  acidophile 
secretion  are  frequently  seen,  and  these  tubules  often  become  flattened  so 
as  to  resemble  lymph-spaces  lined  by  endothelium.  It  is  conceivable  that 
such  flattened  tubules  may  actually  fuse  with  capillary  endothelium,  as 
claimed  by  Hansemann.  The  mucoid  tissue  is  in  variable  quantity  and 
usually  most  abundant  in  the  central  portions  of  lobules  walled  by  epithelium. 
Its  source  is  chiefly  from  the  dissemination  of  epithelium  into  the  swollen 
interacinar  and  interlobular  stroma  which  has  been  infiltrated  by  mucous 
secretion  of  the  epithelium.  Into  the  composition  of  this  tissue  all  preexisting 
fibroblasts  and  endothelium  are  entitled  to  enter,  but  appearances  indicate 
that  the  epithelium  plays  the  predominant  part.  The  fully  formed  cartilage 
cells  must  be  regarded  as  derivatives  of  the  epithelium.  In  the  fibrous  or 
mucinous  matrix  many  collagen  and  elastic  fibers  may  form,  but  it  is  difficult 
to  trace  their  origin.  Many  foci  of  lymphocytes  or  areas  of  diffuse  lymphoid 
tissue  may  be  found  in  the  stroma.  Collections  of  fat-cells  are  rather  fre- 
quently included  in  the  tumor,  but  fail  to  show  neoplastic  growth. 

Squamous  cells  appear  in  many  tumors,  and  exhibit  fibrillation,  inter- 
cellular bridges,  pearl  formation,  and  keratohyaline  granules.  They  were 
found  in  14  of  Ehrich's  26  cases.  Glandular  acini  may  predominate  and 
several  authors  have  found  chondro-adenoma  in  one  portion,  with  pure 
adenoma  in  other  parts  of  the  same  tumor.  In  slowly  growing  tumors  the 
epithelium  may  almost  entirely  disappear,  leaving  nearly  pure  myxoma  or 
chondroma.  Peritheliomatous  structures  may  be  found  in  the  original  tumor 
or  develop  in  recurrences,  and  it  is  probable  that  many  angiosarcomas  of 


736 


NEOPLASTIC  DISEASES 


the  salivary  glands  develop  in  this  way,  since  some  myxocarcinomas  are 
vascular. 

Yet  v.  Haberer  has  described  a  large  hemangioma  simplex  of  the  parotid,  and  more 
cellular  or  slightly  sarcomatous  growths  of  this  type  are  reported  by  Hartmann,  Herx- 
heimer,  and  others.  In  true  angiosarcomas  of  the  salivary  glands  there  is  an  obvious 
circulation  of  blood  through  the  tumor  units.  Lymphangiomas  of  the  parotid  or  sub- 
maxillary,  usually  congenital  and  once  symmetrical,  have  been  described  by  Lanne- 
longue  and  Achard,  Robinson,  Fuhr,  and  Hagenbach,  but  they  suggest  no  relation  to 
the  atypical  mixed  tumors. 

In  recurrences  the  original  structure  may  be  retained,  but  the  secondary 
growth  is  often  more  cellular  and  malignant.  Thus  spindle-cell,  round-cell, 
and  perithelial  sarcomas  have  been  observed  after  extirpation  of  chondro- 


Fic.  353. — Adenocarcinoma  of  parotid  infiltrating  sternomastoid  muscle. 

carcinoma,  and  it  seems  probable  that  most  of  the  so-called  sarcomas  of  the 
salivary  glands  are  atypical  epithelial  growths  (Menetrier,  Chevassu,  Wood). 
Rarely  these  large  cell  sarcomas  are  pigmented,  but  they  lack  the  malignancy 
of  true  melanoma.  The  more  cellular  structures  of  the  original  tumor  may 
exclusively  appear  in  the  recurrence.  Forster  reports  a  tumor  containing 
mucoid  tissue  and  cartilage  in  one  area,  and  sarcomatous  tissue  in  another, 
the  latter  alone  appearing  in  the  recurrence.  In  several  cases  only  carcinoma- 
tous  portions  of  the  original  tumor  appeared  in  the  recurrence  (Landsteiner, 
Volkmann,  Case  XVII).  In  some  cases  the  recurrence  probably  represents 
the  development  of  a  new  tumor  in  the  remaining  portions  of  the  gland. 

(2)  Basal-cell  carcinoma  with  hyaline  stroma  is  the  type  observed  in  many 
small  early  tumors,  it  forms  the  bulk  of  a  minority  of  the  larger  growths, 


EPITHELIAL  TUMORS  OF  THE  SALIVARY  GLANDS  737 

and  it  appears  frequently  in  tumors  outside  the  salivary  glands.  This  struc- 
ture may  be  uniform  throughout,  or  associated  with  chondrocarcinoma  or 
adenoid  cystic  structures,  but  squamous  changes  are  rarely  added. 

The  cells  are  small,  cubical  or  spindle,  darkly  staining,  with  hyperchromatic 
nuclei,  and  arranged  in  narrow  anastomosing  cords,  or  thin  flattened  strands. 
They  are  often  intimately  fused  with  the  hyaline  stroma  and  appear  to  in- 
close spaces  like  the  endothelium  of  lymph-spaces  (Krompecher,  /.  c.,  Figs. 
12,  13,  1 6).  The  hyaline  stroma  appears  in  narrow  strands  or  large  cords 
or  rings  inclosing  the  cells,  and  is  quite  variable  in  bulk. 

(3)  Adenoid  cystic  epithelioma  observes  the  same  distribution  as  the 
other  basal-cell  types.  It  usually  presents  a  specific  structure  which  has 
long  been  passed  as  cylindroma.  Throughout  broad  coherent  masses  of 
darkly  staining  cubical  or  polygonal  cells  appear  small  droplets  or  globules 
or  larger  rounded  masses  of  mucus  which  are  sharply  outlined  against  the 
surrounding  epithelium.  This  material  may  contain  much  or  little  mucin. 
Its  sources  are  two,  first,  a  secretion  of  the  epithelial  cells,  when  it  appears 
in  broad  rounded  cellular  areas  inclosed  in  dense  connective;  and,  second, 
from  mucous  degeneration  of  fine  strands  of  stroma  originally  supporting 
the  epithelial  cords.  When  these  tumors  are  entirely  free  from  myxomatous 
and  chondromatous  areas  they  are  properly  classed  with  the  pure  adeno- 
carcinomas  (q.  ».). 

In  the  submaxillary  gland  simple  benign  epithelial  tumors  are  extremely 
rare. 

Malignant  dendritic  adenocarcinoma  arises  from  the  ducts  and  produces 
a  firm  circumscribed  tumor  which,  in  the  case  of  Prengrueber,  involved  only 
a  portion  of  the  gland.  In  Chevassu's  case  the  tumor,  although  encapsu- 
lated, recurred  promptly  after  two  operations. 

Infiltrating  carcinomas  of  tubular  or  alveolar  structure  arising  from  the 
acini,  and  proving  quite  malignant,  are  described  by  Waldeyer,  Volkmann, 
and  Chevassu. 
47 


CHAPTER  XXXVII 
TUMORS  OF  KIDNEY 

EPITHELIAL  TUMORS  OF  KIDNEY 

While  indications  of  the  structure  of  epithelial  tumors  of  the  kidney  appear 
in  the  early  descriptions  of  J.  Konig,  Rayer,  and  Cruveilhier,  the  first  definite 
success  in  tracing  the  epithelial  origin  of  these  tumors  was  accomplished  by 
Robin  in  1855,  who  showed  that  the  tubular  epithelium  proliferated,  de- 
stroyed the  membrana  propria,  and  produced  cancerous  nodules.  Waldeyer 
in  1867  also  traced  the  beginnings  of  renal  cancer  to  proliferating  cells  of  the 
renal  tubules.  The  validity  of  these  observations,  which  today  may  be  ques- 
tioned, was  accepted  by  Klebs,  Recklinghausen,  Lancereaux,  and  by  writers 
generally,  who  classified  the  tumors  as  circumscribed  benign  adenoma  and 
malignant  infiltrating  carcinoma.  Ebstein  as  late  as  1877  evidently  identified 
the  sarcomas  of  infants  with  the  carcinomas  of  adults.  More  specific  details 
of  the  origin  of  renal  tumors  were  obtained  by  Sturm,  1875,  who  distinguished 
between  solitary  adenoma  of  normal  kidneys  and  multiple  adenoma  of  sclerotic 
organs,  and  recognized  the  slow  transformation  of  adenoma  into  carcinoma. 
Sabourin  described  two  forms  of  multiple  adenoma,  with  lining  of  cubical 
or  cylindrical  cells,  and  compared  these  small  tumors  with  multiple  adenomas 
of  the  liver.  In  1883  Weichselbaum  and  Greenish  designated  the  two  forms 
of  adenomas  as  papillary  and  alveolar. 

Up  to  this  time  the  epithelial  origin  of  the  small  tumors  was  regarded 
as  proved  and  their  transformation  into  the  common  malignant  tumors 
appears  to  have  been  accepted,  while  the  existence  of  a  separate  group  of 
yellowish  tumors  of  the  cortex,  of  fatty  nature,  was  recognized.  In  1883 
Grawitz  contested  the  lipomatous  nature  of  the  small  yellowish  tumors, 
showed  that  their  structure  was  often  identical  with  that  of  the  cortical  hyper- 
plasia  of  the  adrenal  (Virchow's  "struma  suprarenalis"),  proposed  for  the 
renal  tumors  the  term  "strumae  suprarenales  aberratae  renalis,"  established 
the  occurrence  of  adrenal  rests  in  the  capsule  and  cortex  of  the  kidney,  and 
traced  the  origin  of  an  important  group  of  malignant  renal  tumors  to  these 
rests.  Grawitz's  interpretation  was  supported  and  elaborated  by  many  later 
authorities. 

Beneke  traced  the  origin  of  certain  sarcomas  of  the  kidney  to  adrenal 
cells.  In  1892  Birch-Hirschfeld  introduced  the  term  "hypernephroma"  for 
the  adrenal  tumor  of  the  kidney.  By  some  the  scope  of  this  group  has  been 
regarded  as  including  the  majority  of  renal  tumors  and  structures  of  various 
types,  and  even  the  papillary  growths  (Horn).  Sudeck  in  1893  contested 
the  adrenal  theory,  holding  that  the  papillary  and  alveolar  tumors  are 
essentially  the  same  and  that  the  majority  of  the  hypernephromas  are  renal 
adenomas.  Stoerk  has  adduced  considerable  evidence  to  show  that  the 
identification  of  adrenal  rests  from  fatty  renal  epithelium  may  be  difficult 
and  has  been  too  hastily  undertaken;  that  renal  epithelium  may  undergo 
marked  fatty  changes,  especially  in  the  adenomas  of  sclerotic  kidneys;  that 
papillary  structures  and  lumina  so  common  in  hypernephroma  are  rare  in 
tumors  of  the  adrenal  itself;  and  that  many  of  the  features  regarded  as  typical 
of  hypernephroma  are  reproduced  in  renal  adenocarcinomas. 

738 


TUMORS  OF  KIDNEY  739 

The  discussion  of  the  adrenal  theory  has  also  been  carried  through  phases 
of  chemistry,  comparative  pathology,  and  embryology  without  reaching  a 
final  solution,  but  tending,  on  the  whole,  to  restrict  the  Grawitz  tumors  to  a 
relatively  small  group  in  which  the  structure  is  exactly  duplicated  by  tumors 
of  the  adrenal  gland  itself. 

Epithelial  tumors  in  which  the  cells  are  grouped  about  blood-vessels  have 
been  erroneously  interpreted  by  Paoli  as  angiosarcoma,  and  by  Driessen, 
Hildebrandt,  Hansemann,  and  others  as  endothelioma.  Manasse,  in  a  com- 
prehensive study,  recognized  many  varieties  of  renal  growths,  including 
renal  adenomas  and  carcinomas,  adrenal  tumors  of  various  types,  endothe- 
liomas  from  both  blood-  and  lymph-vessels,  and  various  sarcomas  of  meso- 
blastic  origin.  Birch-Hirschfeld's  group  of  adeno-angiosarcoma,  derived 
from  Wolman  remnants,  and  the  lipomyosarcomas  remain,  however,  the 
only  well-defined  varieties  of  renal  sarcoma  which  have  been  fully  divorced 
from  a  probable  epithelial  origin. 

Classification. — Four  groups  of  epithelial  tumors  of  the  kidney  require 
recognition: 

1.  Adenoma,  single  and  multiple,  essentially  benign,  and  arising  from 
renal  tubules. 

2.  Adenocarcinoma  and  carcinoma,  arising  from  renal  tubules,  and  often 
from  adenomas. 

3.  Papilloma  and  papillary  carcinoma  of  the  pelvis. 

4.  Adrenal  tumors.    Hypernephroma. 

ADENOMA 

Renal  adenomas  appear  first  as  single  or  multiple  tumors  as  large  as  a 
pea  or  bean  in  the  cortex  or  capsule  of  the  kidney,  where  they  are  easily  de- 
tected as  gray,  white,  or  yellowish  nodules.  The  multiple  tumors  are  usually 
seen  in  sclerotic  kidneys  in  which  they  may  be  very  numerous,  while  in  normal 
kidneys  the  nodules  are  usually  single.  The  great  majority  never  pass  be- 
yond a  small  size,  but  tumors  as  large  as  an  egg  and  of  cystic  character  are 
occasionally  observed,  and  some  becoming  malignant  progressively  increase 
in  size.  Nobiling  refers  to  a  case  in  which  one  kidney  was  the  seat  of  miliary 
cystadenomas,  while  the  other  presented  a  Grawitz  tumor.  The  frequency 
of  these  tumors  is  variously  estimated.  Zehbe  collected  250  small  tumors, 
of  which  40.5  per  cent,  were  solid,  59.5  per  cent,  papillary  or  alveolar.  They 
are  more  frequent  in  elderly  subjects  and  Weichselbaum  and  Greenish  found 
them  in  10  per  cent,  of  all  persons  over  70  years  of  age. 

The  structure  of  small  adenomas  presents  several  distinct  varieties,  some 
of  which  appear  to  be  very  similar  to  adrenal  rests. 

A  papillary  structure,  occurring  in  a  small  cyst  and  exhibiting  papillary 
characters  from  the  first,  has  been  generally  accepted  as  indicating  a  renal 
origin.  The  papillae  are  composed  of  thick  branching  strands  of  connective 
tissue  lined  by  one  layer  of  cubical  or  cylindrical  epithelium.  Or  the  connec- 
tive-tissue strands  are  thin  and  vascular  and  the  epithelium  more  abundant. 
Sabourin  pictures  papillary  adenomas  consisting  chiefly  of  convoluted  layers 
of  granular  epithelium  with  very  little  stroma. 

This  group  of  tumors  represents  the  renal  form  of  cystadenoma  arising 
in  organs  which  are  the  seat  of  chronic  inflammation  with  the  production  of 
cysts.  Along  with  the  tumors  cysts  without  papillary  ingrowths  are  often 
seen.  The  small  growths  usually  present  a  single  cavity,  while  the  larger 
ones  may  be  multilocular,  as  in  Edmund's  case.  The  tumors  may  reach  the 
size  of  a  child's  head  while  retaining  a  benign  papillary  structure  (Scudder). 


740 


NEOPLASTIC  DISEASES 


There  is  every  reason  to  believe  that  the  cells  of  origin  are  the  adult  epithe- 
lium of  the  affected  tubules.  While  the  lining  cells  are  often  granular  and 
opaque,  it  is  important  to  note  that  very  early  papillary  tumors  may  contain 
large  clear  cells  containing  fat  and  doubly  refractive  lipoid  material  (Stoerk, 
Zehbe).  Progressive  growth  and  malignant  transformation  of  these  papillary 
cystadenomas  has  repeatedly  been  observed,  and  it  is  probable  that  some 
papillary  adenocarciriomas  of  the  kidney  arise  from  such  benign  lesions 
(Sturm,  Beneke). 

An  alveolar  structure  in  early  renal  adenomas  has  been  described  by 
Klebs,  Sabourin,  Weichselbaum  and  Greenish,  Sturm,  Stoerk,  Zehbe,  and 
others,  and  there  is  little  doubt  that  true  renal  adenomas  may  follow  this 
type.  The  cells  are  cubical  or  cylindrical  and  of  large  size.  They  are  often 
very  fatty  and  fail  to  stain  with  eosin.  Yet  in  a  group  of  solid  nodules, 
described  by  Zehbe,  the  cells  are  granular  and  free  from  fat.  When  the  cells 


FIG.  354. — Group  of  isolated  embryonal  tubules  in  cortex  of  a  normal  kidney.    A  prob- 
able source  of  renal  carcinoma. 

contain  much  fat  it  becomes  very  difficult  to  distinguish  such  small  tumors 
from  adrenal  rests,  so  that  there  has  been  much  conflict  of  opinion  regarding 
the  nature  of  this  tumor.  Stoerk  traces  the  development  of  the  alveoli 
from  convoluted  tubules  with  coincident  transformation  of  opaque  granular 
epithelium  into  swollen  fatty  cells.  Since  the  typical  adrenal  rest  fails  to 
show  lumina  surrounded  by  cells,  the  uniform  presence  of  such  spaces  in  the 
cell  groups  of  small  renal  tumors  must  stand  strongly  in  favor  of  their  renal 
origin. 

The  fate  of  the  alveolar  adenomas  has  not  been  satisfactorily  determined. 
Many  long  remain  of  small  size.  The  development  of  a  progressive  and 
malignant  process  would  produce  a  tumor  of  adenocarcinomatous  and  alveo- 
lar or  papillary  type  with  clear  cells,  resembling  certain  hypernephromas. 
This  relation  is  claimed  by  many,  but  still  remains  to  be  definitely  proved. 

Some  of  the  large  congenital  adenomas  of  children  described  by  Weigert, 


TUMORS  OF  KIDNEY 


741 


Targett,  Kelynack,  and  others  presented  a  purely  alveolar  arrangement, 
suggesting  a  relation  to  the  small  alveolar  adenomas  of  the  adult. 

Tubular  adenoma  is  a  form  of  renal  tumor  described  by  Ricker,  and 
composed  of  elongated  and  irregular  canals  lined  by  small  cells  free  from  fat 
and  consisting  chiefly  of  nuclei.  Similar  structures  appear  in  some  of  Sa- 
bourin's  cases.  The  stroma  is  abundant  and  vascular.  The  peripheral 
alveoli  may  pass  gradually  into  the  surrounding  renal  tubules,  while  in  the 
central  portions  the  tubules  are  wider  and  may  become  cystic. 

In  the  histogenesis  of  renal  adenoma  two  conditions  appear  to  be  chiefly 
concerned.  In  the  group  of  cystadenomas  in  sclerotic  kidneys  the  tumors 
arise  in  cysts  resulting  from  the  sclerotic  process.  The  character  of  the  cell 
lining  may  be  assumed  to  vary  with  the  location  of  the  cysts,  which  affect 
tubules  of  all  types,  including  especially 
the  convoluted  and  collecting  tubules. 
Single  tumors  in  otherwise  normal 
organs  may  be  attributed  to  localized 
cicatrices. 

Congenital  anomalies  in  the  structure 
of  the  organ  are  probably  connected 
with  the  origin  of  certain  adenomas, 
especially  those  of  embryonal  type  with 
small  cells,  some  cystic  tumors,  and  the 
tubular  adenomas.  The  occurrence  of 
a  variety  of  structural  defects  in  the 
kidney  is  fully  attested,  but  few  of  them 
have  actually  been  traced  into  tumor 
development.  Displacement  and  im- 
perfect development  of  renal  tubules 
has  been  described  by  Albarran  in  the 
renal  cortex  and  capsule.  Luzzato  and 
Antona  have  traced  the  development  of 
adenoma  and  adenocarcinoma  from  such 
pararenal  rests.  In  Antona's  case  the 
tumor  lay  outside  the  kidney.  Beneke 
and  Ulrich  identified  renal  tubules  in 
the  adrenal,  and  Ricker  found  such 
islands  of  renal  tubules  in  adrenal  con- 
nected with  the  kidney  by  strands  of 
connective  tissue.  Since  the  renal  tubule 
is  formed  of  two  originally  separate  portions,  secreting  and  discharging, 
which  later  fuse,  there  is  abundant  opportunity  for  the  miscarriage  of  this 
process,  resulting  not  only  in  the  congenital  cystic  kidney,  but  in  isolated 
cysts  which  give  rise  to  cystadenomas.  Nauwerck  and  Hufschmidt  and 
v.  Kahlden  have  pointed  out  the  probable  relation  between  the  cystic  kidney 
and  some  cystadenomas.  The  case  of  Keyes  in  which  the  entire  kidney 
was  the  seat  of  very  numerous  solid  adenoma tous  nodules  as  large  as  i^ 
cm.  recalls  the  distribution  of  multiple  congenital  cysts.  Microscopic  islands 
of  renal  tubules  lined  by  small  densely  staining  cells  are  not  infrequently 
encountered  in  normal  kidneys. 

Under  the  term  "spotted  kidneys"  Guillebeau  and  Vaerst  have  described  in 
the  cow,  and  Schmey  in  the  horse,  characteristic  wedge-shaped  areas  in  the 
renal  cortex  which  they  attribute  to  imperfect  development  of  the  cortex. 
They  resemble  adenomas,  but  are  properly  interpreted  as  hamartomas,  in 
the  sense  of  Albrecht.  They  are  not  associated  with  nephritis.  E.  Meyer 


FIG.  355. — Congenital  malforma- 
tion of  kidney  of  newborn  infant.  The 
organ  is  enlarged  and  the  cortex  every- 
where the  seat  of  superfluous  undiffer- 
entiated  tubules. 


742  NEOPLASTIC  DISEASES 

describes  a  spotted  kidney  in  a  child,  the  areas  involving  both  cor- 
tical and  medullary  tissue,  with  defect  in  the  convoluted  tubules.  R.  L. 
Thompson  found  in  a  2-year  child  a  hyperplastic  pyramid  adjacent  to 
a  normal  cortical  area.  In  the  intermediate  zone  the  structures  were  greatly 
disarranged.  In  a  well-developed  but  stillborn  infant  with  large  cyst  of 
umbilical  cord  I  found  both  kidneys  much  enlarged.  The  renculi  were  of 
unequal  size  and  irregularly  placed.  The  cortical  tubules  were  deficient  and 
many  glomeruli  immature.  Many  tubules,  probably  the  collecting,  were  of 
embryonal  type  lined,  by  very  large  cells  with  hyperchromatic  nuclei,  and 
appeared  in  numerous  foci  throughout  the  organ,  resembling  miliary  fetal 
adenomas  (Fig.  355). 

CARCINOMA 

Malignant  tumors  of  renal  epithelium  appear  in  two  main  forms:  (i) 
Papillary  adenocarcinoma,  and  (2)  alveolar  carcinoma. 

The  structural  subvarieties  of  these  main  groups  are  rather  numerous  and 
constitute  a  field  still  awaiting  investigation  from  the  histogenetic  and  clin- 
ical standpoint. 

In  general  it  may  be  stated  that  the  two  forms  of  carcinoma  accord  with 
the  two  chief  groups  of  adenoma  from  which  many  of  them  arise.  The 
cysta'denomas  form  a  continuous  series  from  the  simple  benign  growths  up 
to  highly  cellular  and  malignant  tumors.  This  group  includes  many  vascu- 
lar growths  with  clear  cells,  which  are  often  confused  with  hypernephroma. 
The  relation  of  the  true  alveolar  carcinoma  to  alveolar  adenoma  is  less 
distinct.  These  tumors  are  less  frequent  than  the  papillary  type  and  many 
of  them  are  of  embryonal  origin. 

Papillary  Adenocarcinoma. — These  tumors  are  much  the  most  frequent 
of  renal  growths.  They  occur  chiefly  in  adults,  but  occasionally  in  children. 
Most  of  them  are  recorded  in  the  literature  as  hypernephroma,  so  that  sta- 
tistical data  regarding  them  are  scanty  and  unreliable.  For  general  clinical 
information  the  reader  may  refer  to  the  elaborate  monograph  of  Albarran 
and  Imbert.  The  group  includes  two  well-defined  varieties  and  one  small 
subgroup  of  minor  importance:  (a)  Papillary  adenoma  and  carcinoma  with 
clear  or  glassy  cells;  (b)  Papillary  adenocarcinoma  or  carcinoma  with  granu- 
lar cells;  (c)  Malignant  tumors  arising  from  simple  cystadenoma. 

Of  these  tumors  the  first  (a)  produces  large  single,  less  often  multiple, 
yellowish  circumscribed  vascular  or  hemorrhagic  tumors,  composed  of  villous 
or  thin  papillary  strands  of  connective  tissue,  lined  by  one  layer  of  cubical  or 
cylindrical  clear  fatty  epithelium.  These  tumors  are  often  confused  with 
hypernephroma,  but  their  pronounced  papillary  structure  and  the  occasional 
presence  of  areas  containing  characteristic  renal  epithelium  free  from  fat, 
usually  permit  their  recognition.  Characteristic  cases  are  described  by 
Kelynack  under  the  term  "malignant  cystadenoma."  The  necessity  of  dis"- 
tinguishing  this  renal  tumor  from  others  and  of  separating  it  especially  from 
hypernephroma  is  recognized  by  most  recent  writers  (Albarran,  Stoerk, 
Ipsen,  Willson,  and  Willis). 

The  second  form  (b}  appears  as  multiple,  solid  whitish  and  cellular  growths, 
less  distinctly  encapsulated,  commonly  free  from  hemorrhage,  and  composed 
of  numerously  branching  strands  of  connective  tissue,  lined  by  one  or  several 
layers  of  opaque,  granular  epithelium,  free  from  fat. 

The  third  group  (c]  includes  cystadenomas  which  have  become  malignant. 
.  It  must  be  admitted  that  the  character  of  the  cytoplasm  of  the  tumor- 
cells  is  an  uncertain  basis  for  classification.  Stoerk  has  shown  that  fatty 
changes  occur  readily  in  foci  of  small  renal  adenomas  in  which  the  cells  are 


TUMORS  OF  KIDNEY  743 

mainly  granular.  Zehbe  finds  that  several  types  of  renal  adenomas  present, 
indifferently,  clear  or  granular  cells.  In  a  tumor  composed  chiefly  of  small 
alveoli  lined  by  low  opaque  cells  I  have  found  sharp  transitions  to  papillary 
adenoma  with  clear  cells.  It  is  probably  impossible  to  establish  a  markedly 
different  histogenesis  for  the  two  types.  Nevertheless  the  above  cases  are 
exceptions  to  the  rule  that  tumors  with  clear  cells  and  those  with  opaque 
granular  cells  arise  under  different  conditions  and  yield  peculiar  gross  as 
well  as  microscopical  appearances. 

(a)  Papillary  Carcinoma  with  Clear  Cells. — The  gross  appearance  of  the 
papillary  carcinoma  with  clear  cells  is  usually  characteristic.     The  tumor 


FIG.  356. — Circumscribed  papillary  and  cystic  adenocarcinoma  of  kidney. 

begins  as  a  small  circumscribed  cortical  or  medullary  solid  nodule  of  light 
yellow  color  and  considerable  vascularity.  The  growth  commonly  reaches 
considerable  dimensions  and  when  encountered  in  surgical  material  it  is  as 
large  as  a  hen's  egg  or  the  fist  and  lies  within  the  renal  capsule  which  is  dis- 
tended. On  section  portions  of  unaltered  or  thinned  renal  tissue  appear 
at  one  or  several  segments  of  the  mass.  Of  194  renal  tumors  chiefly  of  this 
type,  Kuster  located  80  in  the  middle  segment,  60  in  the  lower  pole,  and  54 
in  the  upper  pole.  Ipsen,  who  recognized  the  renal  origin  of  his  tumors,  found 
13  in  the  upper,  10  in  the  middle,  and  12  in  the  lower  lobe.  The  gross  struc- 
ture is  divided  into  many  small  cysts  containing  clear  or  brownish  or  bloody 


744 


NEOPLASTIC  DISEASES 


or  gelatinous  material.  Areas  of  necrosis  and  hemorrhage  may  be  frequent 
and  these  may  fuse,  yielding  large  cystic  cavities.  There  may  be  considerable 
calcific  deposits.  As  a  rule,  these  tumors  are  not  encapsulated. 

From  the  presence  of  numerous  small  cysts  with  gelatinous  contents, 
gross  evidences  of  a  papillary  architecture,  and  a  greater  tendency  to  invade 
surrounding  renal  tissue,  these  tumors  can  usually  be  distinguished  by  the 
naked  eye  from  tumors  of  adrenal  rests. 

In  advanced  and  fatal  cases  the  tumors  become  very  large,  destroying 
most  of  the  kidney  and  undergoing  further  necrosis,  hemorrhage,  and  cystic 
softening.  They  extend  by  continuity  to  the  kidney,  renal  pelvis  with  hydro- 
nephrosis,  adrenal,  lymph-nodes,  and  abdominal  wall,  and  they  invade  the 
renal  and  other  veins  often  very  early.  In  the  renal  vein  they  produce  tumor 
masses  reaching  through  vena  cava  to  the  right  heart  (Coyne,  Troisier,  Wyler, 
Gardner,  and  Coats).  Yet  invasion  of  the  veins  is  not  always  followed  at 
once  by  metastases,  and  Albrecht  records  recovery  after  extirpation  of  such 
a  tumor.  Stoerk  noted  that  the  histology  is  not  always  a  safe  guide  to  the 


FlG.  357. — Adenocarcinoma  of  kidney  metastatic  in  brain. 

viability  of  the  cells,  some  apparently  simple  structures  proving  exquisitely 
malignant. 

Israel,  in  18  cases  of  "hypernephroma,"  observed  characteristic  fever 
curves,  remittent  and  intermittent,  initial,  intercurrent,  and  terminal.  He 
states  that  fever  occurs  in  all  malignant  tumors  of  the  kidney  without  relation 
to  histological  structure,  size,  rapidity  of  growth,  or  invasion  of  vicinity. 
Cabot  records  high  leukocytosis  in  several  cases. 

Metastases  are  very  frequent.  Albrecht  found  the  lungs  involved  in  all 
his  advanced  cases.  Albarran,  in  249  collected  cases  of  renal  carcinoma,  found 
the  lungs  involved  in  75,  liver  71,  lymph-nodes  60,  renal  vein  and  cava  23, 
pleura  14. 

The  frequency  of  bone  metastases  has  long  been  recognized.  In  most 
reports  it  has  been  assumed  that  the  tumors  arose  from  adrenal  rests,  but  it 
is  probable  that  most  of  these  cases  were  renal  carcinoma  with  clear  cells. 
P.  Albrecht  found  bone  metastases  in  8  of  14  fully  studied  cases  of  hyper- 
nephroma. They  occur  chiefly  in  ribs,  spine,  skull,  scapula,  and  long  bones. 


TUMORS  OF  KIDNEY 


745 


They  are  sometimes  mistaken  for  primary  tumors  or  other  diseases  of  the 
bones,  the  renal  tumor  being  discovered  only  late  in  the  disease  or  at  autopsy. 
In  a  well-known  group  of  cases  a  solitary  bone-tumor  arises  from  a  compara- 
tively small  renal  growth.  Such  tumors  have  been  successfully  extirpated, 
the  patient  succumbing  later  to  the  renal  disease. 

Late  bone  metastases,  occurring  5,  8,  9,  and  even  10  years  after  removal 
of  the  primary  tumor,  are  also  recorded  (Clairmont,  Albrecht).  The  slow 
development  of  the  tumor-cells  may  be  referred  to  the  early  invasion  of  veins 
with  accompanying  phlebitis  which  for  a  time  blocks  their  further  transport. 
The  structure  of  the  bone-tumors  often  reproduces  exactly  that  of  perivascu- 
lar  or  papillary  adenocarcinoma,  but  giant-cells  have  been  found  in  very 
large  numbers  on  the  advancing  edge  of  the  tumor,  while  occasionally  the 
secondary  growth  is  much  more  atypical  and  malignant  than  the  primary. 
Osteoplastic  tendencies  were  noted  by  Albrecht. 


FIG.  358. — Papillary  carcinoma  of  kidney  with  clear  cells. 

The  structure  of  the  primary  tumor  is  usually  papillary.  In  some  cases 
there  are  cross-sections  of  very  numerous  small  blood-vessels  surrounded  by 
one  layer  of  larger  glassy  epithelial  cells.  In  other  cases  the  trabeculae  are 
long  and  thin,  covered  by  one  layer  of  high  cubical  or  cylindrical  epithelium 
resembling  those  of  the  collecting  tubules.  Adjoining  trabeculae  may  seem 
to  inclose  long  sections  of  tubules.  Rarely  an  alveolar  appearance  is  pro- 
duced. In  a  third  group  the  lining  cells  appear  in  several  layers,  the  cells 
are  extremely  large  and  elongated  and  the  layers  of  adjoining  trabeculae 
fuse.  Yet  a  diffuse  carcinoma  of  this  type  probably  does  not  occur.  Even 
in  metastases  the  papillary  character  and  the  glassy  appearance  of  the  cells 
are  retained.  Albarran  has  described  this  tumor  under  the  term  adenoma 
alveolare  a  cellules  claires.  Sabourin  groups  it  with  the  papillary  growths. 
Sudeck  reported  several  cases,  but  failed  to  distinguish  them  clearly  from 


746  N EOF LA  STIC  DISEASES 

adrenal  growths.  Ipsen  describes  papillary,  alveolar,  and  solid  structures 
and  concludes  that  all  the  tumors  are  essentially  papillary.  The  structure 
often  resembles  some  cases  of  hypernephroma  of  perithelial  type,  but  careful 
study  of  different  sections  reveals  a  predominant  papillary  and  alveolar  type. 
In  hypernephroma  the  cells  form  thick  anastomosing  sheets  or  columns 
between  which  lie  many  dilated  blood-vessels.  The  presence  of  alveoli  filled 
with  mucous  secretion,  or  with  basic  staining  concentrically  striated  globules, 
also  belongs  to  renal  adenoma. 

In  very  cellular  growths  nutrition  is  poor,  the  cells  may  become  widely 
distended  with  fat  and  watery  fluids,  and  giant-cells  may  form.  Appro- 
priate stains  reveal  the  presence  of  much  glycogen,  fat,  and  lipoid  material, 
but  in  very  variable  amounts. 

The  study  of  the  chemistry  of  these  tumors  has  been  pursued  elaborately 
by  Lubarsch,  Sisson,  Stoerk,  Ipsen,  and  others,  but  it  does  not  appear  that  a 
differential  diagnosis  can  be  established  on  the  character  of  the  lipoids.  The 
glassy  cells  may  be  almost  entirely  free  from  fat,  or  very  large  deposits  of 
material  reacting  to  osmic  acid  or  sudan  III  may  be  present.  Glycogen 
is  usually  abundant,  but  sometimes  missing. 

Ipsen  found  that  the  renal  tumors  yield  about  10.7  per  cent,  of  fat  and 
0.2  per  cent,  of  phosphorus,  while  the  horse's  adrenal  contains  30.8  per  cent, 
of  fat  and  i  per  cent,  of  phosphorus.  The  lipoids  are  cholesterin  esters. 

Histogenesis. — Papillary  carcinoma  with  clear  cells  has  been  subject  to 
several  different  interpretations.  The  older  authors  uniformly  regarded 
it  as  of  renal  origin,  and  this  view  is  maintained  perhaps  by  the  majority  of 
recent  authors.  With  the  advent  of  Grawitz's  theory  these  tumors  were  fre- 
quently classed  as  hypernephroma  because  of  the  clear  cytoplasm  of  the 
cells.  The  pronounced  papillary  character  appears  to  the  writer  as  incom- 
patible with  an  adrenal  origin,  although  contrary  to  Stoerk,  it  must  be  ad- 
mitted that  adrenal  tumors  occasionally  present  a  certain  papillary  tendency. 
Strong  evidence  of  the  renal  origin  of  the  growths  is  the  occasional  presence 
of  tubules  reproducing  the  exact  features  of  hypertrophic  renal  tubules, 
which  are  not  observed  in  tumors  of  proved  adrenal  origin.  The  adrenal 
tumors  which  simulate  papillary  carcinoma  most  closely  present  a  pseudo- 
papillary  structure  and  are  composed  of  thin  but  usually  solid  anastomosing 
columns  of  clear  cells  supported  by  thin  vascular  septa. 

Papillary  carcinoma  with  clear  cells  has  also  figured  as  endothelioma 
and  as  angiosarcoma  in  the  reports  of  Driessen,  Hildebrandt,  Manasse,  and 
Hansemann.  Yet  it  is  now  recognized  that  the  close  approximation  of  large 
clear  cells  about  the  walls  of  capillaries,  or  the  presence  of  extravasated  blood 
in  the  lumina  of  vascular  adenocarcinomas,  does  not  indicate  an  angio- 
blastic  tumor.  Many  so-called  peritheliomas  are  true  adrenal  tumors.  It  is 
possible  also  that  the  intravascular  proliferation  of  endothelium  may  give 
rise  to  new  tumors  of  the  kidney,  as  described  by  Hansemann  under  the  term 
"adenoma  endotheliale,"  but  there  is  no  satisfactory  evidence  that  these 
growths  may  reach  the  size  or  follow  the  course  of  renal  adenocarcinoma. 

(V)  Papillary  adenocarcinoma  with  granular  cells,  resembling  those  of  the 
renal  tubules,  occurs  under  several  conditions. 

(i)  Multiple  adenocarcinoma  in  sclerotic  kidneys  is  one  of  the  best  defined 
varieties  of  renal  carcinoma.  It  was  early  recognized  and  fully  described 
by  Sabourin,  Klebs,  Weichselbaum  and  Greenish,  and  Sturm,  who  encoun- 
tered chiefly  simple  adenomas.  One  or  both  kidneys  may  be  involved  by 
very  numerous  small  circumscribed  light  colored  tumor  nodules  which  may 
become  so  abundant  as  to  leave  little  intact  renal  tissue.  The  organ  retains 
its  form  and  may  be  only  slightly  or  not  at  all  enlarged.  In  the  early  stages 


TUMORS  OF  KIDNEY  747 

the  tumors  may  be  small  and  miliary,  later  they  become  as  large  as  peas 
or  beans,  but  bulky  tumors  are  rarely  if  ever  produced. 

The  structure  follows  a  papillary  adenomatous  type  with  thin  strands  of 
vascular  connective  covered  with  one  layer  of  cubical  or  polyhedral,  slightly 
granular  cells.  Fatty  degeneration  is  not  entirely  missing,  but  the  abundant 
large  clear  cells  of  other  adenomas  are  not  found.  In  some  cases  the  cell 
layers  are  multiplied  and  malignant  features  appear.  The  course  of  these 
tumors  is  slow  and  they  seldom  display  malignant  clinical  qualities.  In  a 
case  of  Keyes,  Sr.,  the  patient,  49  years  of  age,  complained  chiefly  of  hema- 
turia.  The  kidney  was  removed  and  the  disease  did  not  recur.  Manasse's 
2  cases  were  found  at  autopsy. 

The  multiple  tumors  have  been  regarded  as  the  sequel  of  inflammatory 
and  regenerative  hyperplasia.  From  this  point  of  view  the  true  neoplastic 


FIG.  359. — Papillary  adenocarcinoma  of  kidney. 

nature  of  the  simple  forms  may  be  doubted,  as  done  by  Sudeck  and  Hanse- 
mann.  Yet  these  growths  pass  insensibly  into  true  and  sometimes  active 
adenomas  or  adenocarcinomas. 

(2)  Papillary  adenomas  and  adenocarcinomas  with  granular  cells  occur 
not  only  in  sclerotic  kidneys,  but  frequently  in  otherwise  normal  organs.  The 
tumors  are  single  or  more  often  multiple,  and  appear  as  solid  white  masses 
in  cortex  or  medulla.  The  solitary  tumors  may  reach  considerable  dimensions, 
but  the  very  large  growths  composed  of  clear  cells  are  not  duplicated  in  this 
variety.  Fatty  changes  and  hemorrhage  are  usually  wanting,  but  many  of 
the  tumors  are  locally  aggressive  and  invade  the  kidney  diffusely,  perforate 
the  pelvis  and  capsule,  and  extend  into  the  lymphatics.  Invasion  of  the 
veins  is  less  prominent  than  with  other  renal  growths. 

On  gross  anatomical  features  this  group  of  tumors  has  often  been  divided 


748  NEOPLASTIC  DISEASES 

into  nodular  and  infiltrating  forms,  the  former  being  adenomatous,  the  latter 
adenocarcinomatous.  Yet  the  transitions  are  frequent  and  occur  in  the 
same  tumors.  With  increasing  malignancy  the  encapsulation,  which  is 
seldom  distinct,  becomes  obliterated.  The  whole  organ  may  thus  be  much 
enlarged  while  retaining  its  form. 

The  structure  presents  several  variations  of  the  papillary  type.  Usually 
the  connective  tissue  appears  in  thin  strands,  frequently  branching,  covered 
by  one  or  more  layers  of  opaque  granular  cells.  The  vascularity  is  much  less 
than  in  most  other  renal  growths,  so  that  the  gross  appearance  has  been 
described  as  snow  white.  The  cells  somewhat  resemble  those  of  the  convo- 
luted tubules,  but  the  resemblance  is  seldom  sufficiently  distinct  to  impress 
such  an  origin.  Nevertheless  not  a  few  observers  claim  to  have  traced  the 
growth  from  renal  tubules  (Waldeyer,  Manasse,  Stoerk). 

In  some  cases  the  cells  are  extremely  small,  the  papillae  minute,  and  the 
resulting  structure  in  section  resembles  in  part  an  alveolar  growth  and  sug- 
gests an  embryonal  origin.  Sudeck  argued  that  all  the  tumors  are  essentially 
alveolar.  Wiecheselbaum  and  Greenish  found  two  distinct  types  with  transi- 
tions. I  have  seen  rare  tumors  with  both  types  of  structure  in  adjoining 
areas,  but  find  that  the  alveolar  growths,  as  a  rule,  differ  markedly  from 
the  papillary,  suggesting  different  conditions  of  origin. 

In  the  malignant  growths  the  cell  layers  multiply,  adjoining  papillae 
fuse,  and  the  renal  tissue  is  invaded  as  papillary,  alveolar,  or  diffuse  carcinoma. 
(3)  The  malignant  transformation  of  cystadenoma  is  described  by  Klebs, 
Ziegler,  Ricker,  and  others.  These  tumors  are  single  or  multiple,  well  en- 
capsulated, and  sometimes  of  large  dimensions.  The  papillary  and  cystic 
character  is  evident  on  gross  inspection,  and  the  cyst  may  contain  consider- 
able fluid  with  blood  and  fatty  detritus.  The  capsule  may  be  invaded  and  the 
parenchyma  may  be  infiltrated  by  secondary  nodules,  or  the  malignancy  may 
be  demonstrated  by  an  unexpected  recurrence.  The  structure  presents 
coarse  trabeculae,  or  vascular  connective  tissue,  covered  by  cubical  or  cylin- 
drical granular  or  clear  epithelium  which  is  usually  in  a  single  layer,  but 
in  many  areas  becomes  multiple,  atypical  in  form,  and  produces  pseudo- 
alveoli.  Characteristic  tumors  of  this  type  are  rare. 

Alveolar  Adenocarcinoma. — Although  the  early  writers  uniformly  rec- 
ognized an  alveolar  adenoma  of  renal  origin,  the  advent  of  Grawitz's  theory 
led  many  to  refer  the  majority  of  alveolar  growths  to  an  adrenal  source. 
Only  a  superficial  acquaintance  with  the  morphology  of  renal  tumors  could 
favor  such  an  interpretation,  since  alveolar  adenomas  form  a  highly  character- 
istic and  important  group  of  renal  growths  which  are  wholly  different  from 
the  adrenal  derivatives.  In  this  group  also  the  derivation  from  preformed 
renal  tubules  has  been  traced  by  Waldeyer,  Manasse,  Stoerk,  and  others. 

The  structure  may  almost  exactly  reproduce  that  of  the  renal  cortex. 
Stoerk  has  shown  that  regenerating  tubules  may  multiply  and  ramify,  pro- 
ducing localized  tumor-like  nodules  resembling  adrenal  rests.  Most  observers 
have  been  unable  to  trace  alveolar  adenomas  to  preformed  tubules  and  be- 
lieve that  these  growths  are  chiefly  of  embryonal  origin.  In  accordance 
with  this  view  is  the  fact  that  the  renal  carcinomas  in  children  are  chiefly 
of  alveolar  type.  Stoerk  found  foci  of  spindle-cells  in  alveolar  adenoma,  sug- 
gesting a  relation  to  adenosarcoma.  Weigert,  in  a  congenital  case,  observed 
abortive  glomeruli  associated  with  alveolar  adenoma.  In  adults  both  embry- 
onal and  adult  types  of  alveolar  adenoma  are  observed,  and  the  resemblance 
to  adult  tubules  is  occasionally  so  striking  as  to  indicate  that  an  embryonal 
origin  is  not  constant.  Finally,  the  islands  of  displaced  renal  cortex  in  the 
capsule  or  cortex  of  the  kidney,  described  by  Albarran,  were  of  alveolar  type 


TUMORS  OF  KIDNEY 


749 


and  are  believed  to  have  given  rise  to  alveolar  tumors.  Several  forms  of 
small  adenomas  previously  described  also  present  themselves  as  possible 
sources  of  larger  adenocarcinomas. 

The  varieties  of  alveolar  adenomas  which  present  sufficiently  distinct  clin- 
ical and  structural  features  to  warrant  recognition  are  somewhat  numerous. 
They  may  be  conveniently  described  in  the  following  classes: 

(a)  Adenocarcinoma  of  infants. 

(b)  Embryonal  adenocarcinoma  of  adults. 

(c)  Tubular  adenocarcinoma  reproducing  renal  tubules. 

(a)  Adenocarcinoma  of  Infants. — Compared  with  the  mixed  tumors  pure 
epithelial  growths  are  rare  in  children.  Of  170  cases,  Albarran  found  four 
adenomas,  seven  carcinomas,  two  adenocarcinomas,  and  four  adrenal  tumors. 
In  the  literature  attention  is  seldom  given  to  the  recognition  of  carcinoma 


FIG.  360. — Adenocarcinoma  of  adult  kidney,  reproducing  convoluted  tubules. 

in  infants  and  many  cases  have  doubtless  been  included  in  the  literature  of 
congenital  sarcoma.  It  is  quite  possible  that  some  of  the  infantile  adeno- 
carcinomas are  related  in  origin  to  the  congenital  mixed  tumors,  as  Weigert's 
cases,  in  which  there  were  abortive  glomeruli,  but  others  appear  to  be  of 
more  adult  type  and  probably  arise  from  portions  of  well-differentiated  renal 
blastema.  A  relation  to  the  congenital  cystic  kidney  is  also  probable.  Von 
Kahlden  has  shown  that  marked  epithelial  overgrowth  may  occur  in  this 
condition.  The  scope  of  the  structure  is  illustrated  in  the  following  cases: 

Weigert  described  small  bilateral  renal  tumors  in  a  stillborn  fetus  which  projected 
slightly  beneath  the  capsule.  They  were  composed  of  well-formed  alveoli  resembling 
renal  tubules,  and  of  vascular  foci  in  which  loose  polyhedral  cells  surrounding  capillaries 
recalled  the  structure  of  imperfect  glomeruli.  A  large  adenocarcinoma,  interpreted  as  a 
later  stage  of  Weigert's  tumors,  is  described  by  Earth.  It  was  as  large  as  a  child's  head, 


750  NEOPLASTIC  DISEASES 

replaced  most  of  the  kidney  in  a  child  of  5  years,  had  caused  hydronephrosis,  and  was 
composed  of  alveoli,  cords  and  diffuse  growth  of  polyhedral  cells.  Perthes  describes 
three  large  tumors  in  children,  of  adenomatous  and  carcinomatous  structure.  The 
resemblance  of  the  acini  to  renal  tubules  was  noted.  In  Malcolm's  case  the  tubules 
were  separated  by  a  delicate  stroma  and  the  tumor,  a  malignant  adenoma,  was  lacking 
in  embryonal  characters.  In  Manasse's  alveolar  carcinoma  (Case  VIII)  the  resemblance 
to  renal  epithelium  was  also  noted.  The  most  malignant  of  the  growths  show  central 
softening. 

Small  cysts  may  appear  in  the  adenomatous  growths,  as  in  the  cases  of  Iliot  described 
by  Kelynack,  in  which  the  structure  resembled  thyroid  gland,  and  in  Edmund's  case. 
Some  of  the  tumors  reach  a  very  large  size,  especially  the  malignant  adenoma  involving 
the  whole  kidney. 

Metastases  are  comparatively  rare.  Even  the  actively  growing  very 
cellular  carcinomas  may  be  free  from  secondary  growths  (Bokai). 


FIG.  361. — Embryonal  tumor  of  renal  blastema  in  the  kidney  of  a  child. 

(b)  Embryonal  adenocarcinoma  of  adults  is  a  rare  but  characteristic  tumor. 
It  is  probably  of  the  same  origin  as  some  of  the  malignant  adenomas  of  chil- 
dren, which  it  resembles  in  structure. 

In  a  case  in  the  New  York  Hospital  the  patient,  a  woman  of  35  years,  complained  of 
pain  for  i  year  and  hematuria  for  3  months  before  operation.  The  tumor,  24  X  14  X  8 
cm.,  was  well  circumscribed  laterally,  but  fused  gradually  with  the  remnant  of  kidney. 
It  was  solid,  lobulated,  cream  colored,  and  moderately  soft.  There  were  no  metastases. 
Section  showed  a  uniform  structure  of  large  alveoli  lined  by  large  granular,  cylindrical, 
or  cubical  cells  with  darkly  staining  large  nuclei.  Many  of  the  alveoli  contained  homo- 
geneous acidophile  material.  In  some  foci  the  alveoli  were  indistinct.  The  embryonal 
character  of  the  cells  and  structures  was  pronounced. 

(c)  Tubular  Adenocarcinoma  and  Carcinoma  of  Adults. — In  this  group  are 
included  the  majority  of  malignant  alveolar  tumors  of  the  renal  epithelium. 
They  are  clearly  separable  from  the  carcinoma  with  clear  cells,  from  papillary 
carcinoma,  and'  from  adrenal  growths.     The  structure  is  uniformly  alveolar 


TUMORS  OF  KIDNEY 


751 


or  tubular,  adult  in  type,  and  resembles  the  renal  parenchyma.  These 
tumors  probably  originate  from  well-differentiated  renal  blastema  or  from 
adult  cortical  tubules.  Waldeyer,  Manasse,  and  others  claim  to  have  traced 
the  development  of  such  tumors  from  the  renal  tubule  cells,  but  most  obser- 
vers have  not  succeeded  in  this  task.  Sharkey  believed  he  could  trace  the 
origin  of  his  tumor  to  the  glomerular  epithelium.  Beneke  also  has  observed 
tumor-like  hyperplasia  of  glomerular  epithelium.  It  seems  more  probable 
that  the  growths  develop  from  misplaced  renal  tissue  or  from  the  well-known 
types  of  tubular  or  alveolar  adenoma,  but  Albarran's  early  case  (166)  was 
as  well  diffused  as  a  tuberculous  lesion,  and  the  outlines  of  the  cortex  were 
unaltered. 

While  there  are  many  records  of  tumors  of  this  group  they  are  distinctly 
less  frequent  than  other  forms  of  renal  carcinoma.     They  arise  from  any 


FIG.  362. — Embryonal  adenocarcinoma  of  renal  blastema. 

portion  of  the  kidney  and  may  be  located  chiefly  in  the  cortex  or  pelvis,  which 
are  widely  distended,  or  beneath  the  capsule,  or  they  may  be  extrarenal. 
Very  early  circumscribed  but  non-encapsulated  tumors  are  described  by 
Albarran.  In  Brault's  case  a  very  small  tumor  was  associated  with  metas- 
tases.  Most  of  the  tumors  reach  considerable  and  sometimes  large  dimen- 
sions. The  adenomatous  tumor  may  long  remain  encapsulated,  but  infil- 
trating growths  may  greatly  enlarge  the  kidney  while  preserving  its  form. 
Fatty  changes,  hemorrhage,  and  necrosis  are  not  prominent,  but  the  solid, 
lobulated,  opaque  texture  serves  to  distinguish  most  of  them  from  adrenal 
growths  and  papillary  carcinoma.  Small  cysts  containing  gelatinous  mate- 
rial are  not  infrequent,  and  in  a  group  of  cases  the  abundance  of  such  material 
has  led  to  the  designation  as  colloid  carcinoma  (Newman,  Dickinson,  Schuep- 
pel).  The  highly  malignant  tumors  infiltrate  the  kidney  diffusely,  perforate 


752 


NEOPLASTIC  DISEASES 


pelvis  and  capsule,  invade  both  veins  and  lymphatics,  and  produce  metas- 
tases  in  many  organs. 

The  structure  presents  many  variations,  but  usually  follows  that  of  certain 
segments  of  the  renal  tubules.  That  they  are  actually  derived  from  such 
portions  of  the  tubules,  while  possible,  cannot  at  present  be  claimed. 

The  convoluted  tubules  were  reproduced  to  a  remarkable  degree  in  a  case 
of  A.  Frazer's,  kindly  placed  at  my  disposal.  The  tumor  was  a  large  solid 
circumscribed  growth  presenting  mainly  large  alveoli  and  tubules  lined  by 
high  cubical  granular  cells  exactly  duplicating  those  of  the  convoluted  tubule 
of  the  adult  organ.  Numerous  variations  from  this  structure  appeared  in 
more  actively  growing  hemorrhagic  and  degenerating  portions  of  the  growth, 
and  in  some  foci  the  growth  was  diffuse. 


FIG.  363. — Embryonal  tumor  of  renal  blastema,  with  production  of  abortive  tubules 

and  glomeruli. 

The  smaller  renal  tubules  are  simulated  by  many  small  alveolar  adeno- 
carcinomas  and  carcinomas,  but  the  size  of  the  alveoli  seems  to  depend  on 
the  tissue  of  origin  (adenomas),  the  rate  of  growth  and  associated  fibrosis, 
rather  than  on  any  inherent  capacity  to  reproduce  normal  renal  structures. 
In  some  tumors  the  alveoli  are  quite  small,  and  lined  by  small  flat  cubical 
epithelium.  Or  the  cells  are  larger  and  form  small  compact  groups  with 
no  definite  lumen.  Invasion  and  replacement  of  preformed  tubules  may 
determine  the  structure  of  infiltrating  growths.  Tumors  composed  of  small 
alveoli  are  relatively  frequent  and  are  depicted  by  Albarran,  Stoerk,  and  many 
others.  Diffuse  growth  derived  from  such  structures  may  simulate  various 
types  of  sarcoma.  Markedly  elongated  tubules  lined  by  high  cylindrical 
cells  of  opaque  granular  type  are  also  encountered.  Striking  variations  in 


TUMORS  OP  KIDNEY  753 

structure  are  frequently  observed  in  the  same  tumors,  including  especially  low 
papillary  projections  into  distended  alveoli,  collections  of  secretion,  giant- 
cell  formation,  and  peculiar  cell  inclusions. 

EMBRYONAL  ADENOMYOSARCOMA 

Whatever  its  origin  and  its  interrelations  with  other  renal  tumors  may 
prove  to  be,  the  embryonal  sarcoma  of  infants  is  one  of  the  most  characteristic 
neoplasms  of  the  kidney.  Its  rather  frequent  occurrence  in  infants,  the  com- 
plex embryonal  structure,  rapid  growth  to  very  large  size,  fatal  course,  and 
obscure  origin,  render  it  a  specific  clinical  disease  and  a  topic  of  much  theo- 
retical interest.  Hedren  has  extracted  many  of  the  case  reports  up  to  1907, 
but  includes  many  simple  embryonal  tumors  which  do  not  certainly  belong 
in  this  group. 

The  great  majority  of  cases  are  observed  in  the  first  3  years  of  life,  it  is 
rarely  found  after  the  loth  year,  but  Hedren  reports  a  bilateral  tumor  at 
54  years,  while  Schaffer  describes  an  early  stage  of  the  disease  in  the  single 
kidney  of  a  deformed  fetus.  This  kidney  was  twice  the  normal  size,  presented 
abortive  renal  structures,  islands  of  cartilage,  and  areas  of  smooth  and  striated 
muscle.  Several  reports  are  of  bilateral  tumors. 

Gross  Anatomy. — The  tumors  lie  within  a  distended  renal  capsule,  their 
position  may  suggest  an  origin  from  any  part  of  the  kidney,  mid-cortex, 
upper  pole,  papillae  (Manasse),  or  pelvis,  and  while  usually  sharply  separated 
from  the  remnant  of  the  organ,  they  may  fuse  insensibly  with  it  (Busse), 
or  a  thin  rim  of  renal  tissue  may  inclose  a  large  segment  of  tumor.  The  growth 
may  be  entirely  extrarenal  (Broch,  Brandt,  Borst). 

The  large  size  of  these  tumors  is  a  notable  feature,  since  at  any  given 
age  they  are  usually  the  largest  of  the  renal  growths,  and  -  this  volume  is 
attained  rapidly.  In  several  cases  the  largest  diameter  has  reached  35  to 
37  cm.  (Hoisholt,  Jenckel),  while  in  a  subject  of  34  years  Muus  found  a  tumor 
of  40  cm.  Heineke's  tumor  weighed  3580  gr. 

The  growth  is  often  solid,  opaque,  and  variously  subdivided  into  lobules 
or  areas  by  preponderance  of  glandular,  fibrous,  muscular,  or  very  cellular 
tissue.  The  larger  tumors  are  usually  cystic  and  some  approach  the  appear- 
ance of  the  congenital  cystic  kidney.  Hemorrhage  and  necrosis  are  late 
complications.  Extensions  and  metastases  are  exceptional,  but  in  Merckel's 
case  a  tumor  thrombus  extended  in  the  vena  cava  to  the  heart.  The  liver 
is  the  most  frequent  seat  of  metastases.  Pulmonary  metastases  have  been 
observed  in  several  cases,  in  Brandt's  5  months  after  extirpation  of  the  tumor. 
Ribbert's  tumor  extended  along  the  spine. 

The  embryonal  structure  is  the  most  distinguishing  feature  and  presents 
a  great  variety  of  tissues  usually  suggesting  abortive  renal  elements.  The 
usual  composition  is  of  isolated  tubules  of  high  cylindrical  or  cubical  cells 
with  indistinct  lumina,  surrounded  by  broad  zones  of  indifferent  spindle- 
cells,  on  which  is  based  the  designation  of  adenosarcoma.  Either  tubules  or 
spindle-cells  may  be  in  excess,  the  tumor  approaching  embryonal  adeno- 
carcinoma  or  sarcoma. 

Occasionally  a  tuft  of  spindle-cells  projects  into  an  invaginated  tubule, 
like  an  abortive  glomerulus.  Both  spindle-  and  cubical  cells  may  be  very  small 
and  numerous,  producing  a  structure  of  round-cell  or  alveolar  sarcoma. 
Multilobed  giant-cells  may  be  prominent.  Cysts  are  usually  lined  by  cubical 
epithelium.  Squamous  epithelial  nests  with  keratohyalin  were  found  by 
Muus,  and  Jenckel  saw  cysts  lined  by  squamous  cells.  Most  of  the  cells 
are  rich  in  glycogen. 
48 


754 


NEOPLASTIC  DISEASES 


Smooth  or  striated  muscle-cells  are  usually  present  in  some  portions  of 
the  tumors  and  either  may  make  up  the  bulk  of  the  growth.  Some  have 
derived  the  latter  from  the  former,  but  Hedren  maintains  that  the  two  types 
are  separate,  the  striated  cells  first  appearing  in  the  usual  tubular  form  of 
the  embryo.  The  cellular  connective  may  be  edematous  or  myxomatous, 
and  often  contains  elastic  fibers.  Fat  tissue  appears  in  single  cells  or  definite 
lobules.  Cartilage  appears  in  the  form  of  small  isolated  islands,  rather  more 
frequently  in  older  subjects.  In  one  case  islands  of  bone  were  observed 
(Hedren).  The  metastases  are  usually  of  round  cells,  but  Blau  reports  striated 
muscle-cells  in  the  lung. 

Histogenesis. — The  interpretation  of  the  origin  of  renal  mixed  tumors 
has  passed  through  several  phases  and  covered  all  apparent  possibilities. 


FIG.  364. — Topography  of  Wilms'  embryonal  tumor  of  kidney.    Epithelial  tubules  lying 
in  masses  of  spindle  and  polyhedral  cells.     Striated  muscle-cells  in  center. 

An  origin  from  an  aberrant  sex  cell  has  been  deemed  necessary  by  Ribbert, 
who  interpreted  some  of  the  epithelial  rosettes  as  neuro-epithelium  and  who 
emphasizes  the  presence  of  all  three  germ  layers. 

Wilms  places  the  period  of  the  embryogenic  disturbance  later,  but  con- 
siders that  the  originating  tissue  must  be  defined  early,  must  involve  ecto- 
derm and  mesoderm,  and  include  nephrotome,  sclerotome,  and  myotome. 

The  earliest  conception  was  that  of  Cohnheim  and  Birch-Hirschfeld 
who  assumed  an  origin  from  the  Wolfnan  body.  Busse  points  out  that  no 
Wolfnan  remnant  has  ever  been  found  in  the  kidney,  so  that  this  interpre- 
tation has  been  generally  abandoned.  Birch-Hirschfeld's  service  was 
chiefly  in  emphasizing  the  existence  of  a  definite  group  of  embryonal  mixed 
tumors. 


TUMORS  OF  KIDNEY  755 

Busse  and  Muus  place  the  origin  at  a  still  later  teratogenic  termination 
period  and  see  no  reason  why  all  the  structures  observed  may  not  be  derived 
from  the  renal  blastema.  This  view  attributes  a  prominent  part  to  meta- 
plasia, thus  accounting  for  adult  squamous  epithelium,  .striated  muscle, 
cartilage,  and  bone.  In  this  respect  it  is  in  accord  with  modern  tendencies, 
which  are  not  in  favor  of  the  rigid  specificity  of  germ  layers.  It  also  serves 
to  explain  why  some  of  the  tumors  approach  the  type  of  simple  embryonal 
adenocarcinomas  of  the  kidney,  of  which  I  have  seen  one  striking  example. 
It  accords  further  with  the  gradual  fusion  of  some  tumors  with  renal  paren- 
chyma, and  permits  considerable  latitude  in  the  exact  period  in  the  differen- 
tiation and  growth  of  the  renal  blastema  at  which  the  tumor  may  arise.  On 
the  whole,  this  view  is  the  most  acceptable,  as  well  as  the  simplest  of  the  pro- 
posed hypotheses.  Hedren  was  much  impressed  by  the  presence  of  bone  in 
his  unique  case,  which  he  could  not  accept  as  of  metaplastic  origin,  and  con- 
cludes that  embryological  data  and  casuistic  studies  are  inadequate  to  estab- 
lish any  single  origin  of  the  renal  mixed  tumors. 

In  addition  to  the  typical  embryonal  sarcomas  and  their  recognizable 
atypical  forms,  there  are  other  renal  tumors  whose  structure  suggests  a  rela- 
tion with  the  main  group. 

Quiescent  masses  of  fat  and  cartilage  are  not  infrequently  observed  in 
the  kidney  (Hansemann,  Borst).  Fibromyomas,  single  or  multiple,  of 
cortex  or  capsule  (Busse,  Larkin),  fibromyo-osteosarcoma  (Hildebrand), 
fibrolipomyoma  (Busse),  and  myxoliposarcoma  are  recorded.  In  all  of  these 
renal  epithelial  elements  are  missing.  Apparently  pure  carcinomas  of  the 
kidney  occur  in  infancy  (Birch-Hirschfeld).  All  of  these  observations 
suggest  that  the  embryonal  kidney  is  subject  to  a  variety  of  developmental 
disturbances  resulting  in  tumor  growth  and  that  no  single  .source  of  these 
anomalies  should  be  assumed  to  exist. 

RENAL  TUMORS  OF  ADRENAL  TISSUE.   HYPERNEPHROMA 

In  1883  P.  Grawitz  formulated  the  conception  that  certain  tumors  of 
the  kidney  were  derived  from  adrenal  rests.  In  this  group  he  included  the 
so-called  lipomas  of  the  cortex,  angioma  cavernosum,  various  myomas,  as 
well  as  the  adenomas  and  adenocarcinomas  of  Klebs,  Sturm,  Sabourin,  and 
(1884)  of  Weichselbaum  and  Greenish.  The  argument  favoring  this  view 
was  quite  ably  prepared.  The  chief  evidence  consisted  in:  (i)  The  location 
of  the  tumors  under  the  capsule  where  adrenal  rests  are  found.  (2)  The 
character  of  the  cells,  which  differed  markedly  from  renal  epithelium  in  their 
high  content  of  fat  without  signs  of  degeneration.  (3)  The  sharp  encapsu- 
lation separating  the  tumors  from  the  renal  parenchyma.  (4)  The  resem- 
blance of  the  structure  to  that  of  the  adrenal.  (5)  The  presence  in  the  small 
tumors  of  a  fibrous  core  and  a  more  cellular  glandular  cortex.  Even  when 
not  encapsulated  the  tumor  was  sharply  separated  from  the  renal  parenchyma. 

Grawitz  theory  was  soon  endorsed  by  Chiari,  Horn,  Lubarsch,  Beneke, 
Ambrosius,  Marchand,  and  many  others,  and  came  to  be  generally  accepted. 
Sudeck  in  1893  first  offered  objections,  and  in  recent  years  other  contrary 
views  have  been  frequently  expressed  by  Stoerk,  Zehbe,  Wilson  and  Willis, 
Ipsen,  Glynn,  and  others.  It  is  now  evident  that  the  scope  of  Grawitz's 
tumors  was  much  too  widely  extended,  and  it  has  become  necessary  to  deter- 
mine anew  whether  adrenal  tumors  of  the  kidney  exist  and  how  they  can  be 
identified. 

On  these  questions  it  may  be  said  that  the  presence  of  adrenal  rests  in 
the  kidney  is  fully  attested,  although  they  are  probably  less  frequent  than 


756 


NEOPLASTIC  DISEASES 


many  have  supposed.  It  also  appears  that  certain  tumors  arise  from  these 
rests,  although  clear  descriptions  of  their  structure  have  not  been  fully  given. 
Finally,  recent  studies  have  demonstrated  that  a  large  proportion  of  the 
reported  hypernephromas  are  renal  adenocarcinomas. 

Occurrence  of  Adrenal  Rests  (Pick,  Goupel,  Lit.).— The  adrenal  cortex  is  developed 
from  the  mesothelium  of  the  Wolffian  ridge,  as  are  also  the  ovary  and  testis,  while  the 
medulla  is  of  neuro-ectodermal  origin  and  belongs  to  the  sympathetic  system,  although 
mingled  with  the  neuro-epithelium  are  derivatives  of  the  cortical  cells.  According  to 
Aichel  the  interrenal  bodies  of  lower  vertebrates  and  the  adrenals  of  higher  vertebrates 
arise  from  the  Wolffian  body  funnels,  which  are  of  mesothelial  origin.  Marchand's 


FIG.  365. — An  adrenal  tumor  of  the  kidney. 

adrenals,  in  the  broad  ligament  of  the  female  and  along  the  spermatic  cord  of  the  male, 
arise  from  segmental  tubules  of  the  Wolffian  body  and  correspond  to  the  suprarenals  of 
lower  vertebrates. 

The  renal  cortex,  on  the  other  hand,  is  formed  from  the  renal  blastema,  a  mass  of 
indifferent  mesothelium  which  lies  some  distance  below  the  adrenal  and  is  separated 
from  it  by  the  Wolffian  body. 

The  adrenal  is  at  first  larger  than  the  kidney  because  of  the  hypertrophy  of  the  fetal 
cortex,  which  atrophies  and  is  replaced  after  birth  by  the  adult  cortex  derived  from  a 
rim  of  small  cells  (Elliott,  Armour).  The  position  of  the  early  adrenal  is  not  at  first 
favorable  to  the  inclusion  of  its  tissue  in  the  kidney,  as  shown  by  Wilson.  Yet  after  the 
second  month  it  is  closely  applied  to  the  kidney  and  surrounds  a  large  portion  of  the 
renal  body  (Peter).  Inclusions  in  the  kidney  may  therefore  reasonably  be  assumed  to 
result.  The  occurrence  of  diffuse  adrenal  tissue  without  encapsulation  is  described  by 


TUMORS  OF  KIDNEY  757 

R.  Meyer.  That  the  adult  peritoneal  epithelium  is  capable  of  developing  foci  of  adrenal 
tissue  is  suggested  by  Pick  and  Poll.  Total  subcapsular  location  of  both  adrenals,  por- 
tions remaining  on  the  kidney  after  decapsulation,  are  recorded  by  Klebs,  Grawitz, 
Weiler,  and  Ulrich.  Fusion  of  adrenal  in  the  renal  capsule  and  intralobular  inclusion 
of  rests  surrounded  by  renal  parenchyma  are  described  by  Grawitz  and  Ulrich.  Inter- 
lobular  rests  connected  with  the  adrenal  by  a  strand  of  fibrous  tissue  are  more  frequent 
conditions.  Most  of  the  adrenal  rests  contain  only  cortical  tissue,  but  medullary  tissue 
also  was  found  by  N.  Pitt,  Grawitz,  and  Manasse. 

Yet  it  appears  clearly  that  adrenal  rests  in  the  kidney  are  much  less  frequent  than 
the  supposed  adrenal  tumors.  Glynn  could  find  only  about  17  in  the  literature  and 
obtained  none  in  1500  kidneys.  Yet  Lubarsch  in  300  autopsies  found  eight  adrenal 
rests  in  the  kidney.  On  the  other  hand,  such  rests  are  relatively  frequent  in  other  situa- 
tions (Marchand);  in  the  neighborhood  of  the  epididymis,  in  76.5  per  cent,  of  newborn 
children  (Wiesel) ;  on  the  under  surface  of  the  liver,  in  92  per  cent,  of  cadavers  (Neusser); 
in  90  per  cent,  of  all  bodies  (Holmes);  on  the  broad  ligament  and  spermatic  veins  of 
24  females  (Aichel).  In  adults  they  are  much  less  common,  and  many  observers  find 
them  in  only  a  small  proportion  of  cases,  as  Schmorl  in  4  of  510  livers;  Hanau,  about 
spermatic  veins,  in  5.9  per  cent,  of  children  under  5  years.  They  are  occasionally 
found  in  the  testis  (Dagonet,  Michael,  Meyer,  Kirkbride);  pancreas  (Ribbert);  trans- 
verse colon  (Nicholson).  The  facility  with  which  different  observers  are  willing  to 
identify  adrenal  rests  doubtless  explains  the  varying  results. 


FIG.  366. — Adrenal  adenoma  in  kidney. 

It  must  be  admitted  also  that  tumors  of  misplaced  adrenal  tissue  outside 
of  the  kidney  are  distinctly  rare,  although  the  diagnosis  of  such  an  origin 
is  frequently  made  on  insufficient  grounds.  The  location  of  adrenal  rests 
in  the  kidney  is  chiefly  in  the  upper  pole,  but  not  exclusively  between  the 
renculi,  as  is  sometimes  claimed.  On  the  other  hand,  the  tumors  commonly 
attributed  to  these  rests  occur  with  about  equal  frequency  in  all  segments 
of  the  organ. 

Notwithstanding  these  discrepancies  it  is  clear  that  adrenal  rests  occur 
with  moderate  frequency  in  the  kidney,  where  they  may  give  rise  to  tumors. 

Gross  Appearance  of  Adrenal  Rest  Tumors.— The  anatomical  features 
commonly  attributed  to  Grawitz's  tumors  apply  to  a  large  group  of  renal 
growths.  They  are  large,  well-circumscribed,  yellowish,  fatty,  and  vascular 
tumors,  prone  to  hemorrhage,  necrosis,  and  cyst  formation.  A  segment  of 
intact  kidney  is  usually  found  connected  with  the  tumor.  Grawitz  empha- 
sized especially  the  presence  of  a  central  fibrous  area  surrounded  by  a  more 
cellular  cortical  portion,  but  in  most  descriptions  of  hypernephroma  these 
features  have  been  absent  or  disregarded.  Yet  the  true  adrenal  tumor  of 
the  kidney,  at  least  in  its  early  stages,  regularly  presents  such  distinguishing 
landmarks  (Fig.  365).  It  also,  as  a  rule,  lacks  the  markedly  lobulated  sub- 


758 


NEOPLASTIC  DISEASES 


divisions,  numerous  small  cysts  filled  with  gelatinous  or  bloody  material, 
and  gradual  merging  with  the  renal  parenchyma,  which  belong  to  renal 
adenocarcinoma  with  clear  cells.  The  adrenal  tumor  is  usually  more  solid, 
although  cysts  form  from  necrosis  and  hemorrhage.  The  malignant  growths 
invade  the  perirenal  tissues,  peritoneum,  and  lymph-nodes  more  readily 
than  renal  carcinoma.^  Both  invade  the  renal  pelvis  and  the  large  veins, 
but  metastases  are  earlier  and  more  wide-spread  with  adrenal  growths. 

Many  so-called  renal  hypernephromas  actually  arise  in  the  adrenal  gland 
and,  invading  the  kidney,  fuse  the  two  organs  in  a  diffuse  mass.  When  the 
adrenal  cannot  be  found  the  renal  origin  of  the  tumor  at  once  becomes  doubtful. 

Structure. — The  scope  of  the  structure  attributed  to  adrenal  hyper- 
nephroma  should  be  controlled  by  the  known  structure  of  tumors  of  the 
adrenal  itself,  as  seen  in  the  human  subject.  Observations  on  tumors  of 
'the  adrenal  in  lower  animals  cannot  safely  be  used  as  criteria. 


FlG.  367. — Adrenal  tumor  of  kidney.     Note  the  broad  sheets  of  cells  without  alveolar 

formation. 


From  this  standpoint  it  is  necessary  to  eliminate  all  tumors  with  distinct 
lumina  and  especially  those  of  papillary  structure.  There  remains  a  con- 
siderable number  of  trabecular,  or  solid,  or  diffusely  growing  or  sarcomatoid 
tumors  which  differ  essentially  from  renal  adenocarcinoma. 

The  simplest  structure  reproduces  one  or  more  zones  of  the  adrenal  cortex. 
Some  resemble  the  hyperplastic  nodules  of  the  adrenal  itself  (struma  supra- 
rgnalis).  The  cells  are  arranged  in  small  circular  groups  separated  by  fine 
strands  of  connective  tissue  (zona  glomerulosa).  This  structure  may  be 
uniform  in  tumors  several  centimeters  in  diameter.  Or  the  elongated  cords 
of  the  zona  fasciculata  may  predominate.  The  characteristic  cytoplasm  is  not 
clear,  but  slightly  granular,  with  numerous  lipoid  globules  and  glycogenic 
granules,  yielding  a  foamy  texture.  Hydropic  degeneration  may  consider- 
ably enlarge  the  cell  borders.  The  attachment  of  the  cells  to  the  stroma  is 
loose  and  the  palisade  arrangement  of  rigid  cylindrical  cells  of  renal  car- 


TUMORS  OF  KIDNEY 


759 


cinoma  is  absent.  Tumors  of  this  type  may  be  designated  as  adrenal  ade- 
noma of  the  kidney. 

A  peritheliomatous  structure  is  presented  by  certain  adrenal  tumors,  but 
this  type  is  extremely  difficult  to  distinguish  from  similar  structures  in  renal 
carcinoma.  Section  of  many  portions  of  the  tumor  and  attention  to  the 
gross  relations  are  then  of  much  value.  Peritheliomatous  structures  are 
more  atypical  and  malignant  than  the  adenomatous.  The  cells  are  loosely 
attached,  lacking  the  clear  mosaic  appearance  of  renal  carcinoma,  and  present- 
ing a  granular  and  vacuolated  texture.  Large  granular  giant-cells  may  form, 
and  some  tumors  are  composed  almost  exclusively  of  giant-cells,  both  in 
the  original  tumor  and  in  metastases. 

A  trabecular  arrangement  is  followed  in  some  adrenal  tumors  of  the  kidney 
in  which  the  granular  and  fatty  cells  appear  in  broad  anastomosing  sheets 


FIG.  368. — Adrenal  medullary  tumor  of  kidney. 

supported  by  vascular  stroma.  These  tumors  also  approach  the  type  of 
some  renal  carcinomas,  but  the  absence  of  lumina  or  papillae,  and  the  smaller 
size  and  granular  characters  of  the  cells  strongly  indicate  their  adrenal  nature. 
The  most  malignant  forms  of  adrenal  tumors  of  the  kidney  present  a 
carcinomatous  or  sarcomatous  structure.  The  cells  appear  in  small  groups 
(alveolar  sarcoma)  or  grow  diffusely.  In  well-nourished  areas  the  tissue 
may  resemble  overcellular  liver  tissue.  Giant-cells  may  be  very  numerous. 
The  form  is  polyhedral  or  round  or  elongated.  In  some  cases  the  mesoblastic 
tendencies,  emphasized  by  Adami,  yield  areas  of  large  spindle-cells  and  the 
appearance  is  distinctly  sarcomatous.  The  cell  borders  are  indistinct  and 
the  cytoplasm  is  still  more  granular  and  opaque  and  less  fatty.  Areas  of 
pigmented  cells,  doubtless  representing  the  chromafnn  substance  of  the 
medulla,  may  be  present,  as  in  cases  described  by  Weichselbaum  and  Greenish, 
Ambrosius,  and  Manasse,  and  in  one  case  of  the  writer's.  Lassagna  describes 


760  NEOPLASTIC  DISEASES 

a  bilateral  carcinosarcoma  presenting  both  ganglion-cells  and  chromaffin 
pigment. 

All  the  above  structures  are  duplicated  by  tumors  of  the  adrenal  gland. 
Whether  other  observed  types  of  malignant  adrenal  tumors  contribute  any 
portion  of  the  so-called  round-cell  or  alveolar  sarcomas  of  the  kidney  remains 
to  be  shown. 

Differentiation  Between  Adrenal  and  Renal  Tumors. — The  debate  over 
the  structure  of  adrenal  tumors  of  the  kidney  has  been  continuous  since 
1893,  when  the  question  was  opened  by  Sudeck,  and  was  accelerated  by 
Stoerk's  publication  in  1908.  It  concerned  chiefly  the  significance  of  lumina, 
the  evidence  of  a  papillary  structure,  and  the  chemistry  of  the  cells. 

The  presence  of  lumina  in  adrenal  tumors  has  been  maintained  by  Grawitz, 
Marchand,  Askanazy,  Dobbertin,  and  Manasse.  In  the  normal  adrenal 
lumina  are  described  by  Kolliker,  Stilling,  and  Eberth.  In  the  adrenal  of 
the  horse  and  cow  lumina  appear  to  be  constant.  Yet  in  the  human  adrenal, 
adrenal  rests,  and  adrenal  tumors  lumina  are  conspicuous  chiefly  by  their 
absence,  while  their  occasional  presence  is  hardly  sufficient  ground  for  as- 
suming that  tumors  of  the  kidney,  in  which  lumina  are  the  predominant 
feature,  are  derived  from  adrenal  tissue.  Pseudolumina  may  form  by  central 
degeneration  of  tumor  cords,  but  this  origin  cannot  explain  the  well-defined 
structure  described  by  Manasse.  Dobbertin's  tumor  was  an  embryonal, 
alveolar,  and  papillary  tumor  of  uncertain  origin  in  a  child.  Winkler  often 
speaks  of  lumina  in  his  adrenal  tumors,  but  depicts  only  pseudolumina  caused 
by  degeneration.  It  is  also  possible  that  certain  adrenal  tumors  are  derived 
from  renal  rests.  Beneke  and  Ulrich  describe  renal  tubules  in  the  adrenal 
cortex.  Ricker  found  groups  of  renal  tubules  in  the  adrenal  joined  to  the 
kidney  by  cords  of  connective  tissue,  and  concludes  that  hypernephroma 
may  have  a  mixed  adrenal  and  renal  origin.  The  presence  of  lumina  therefore 
is  a  somewhat  uncertain  criterion  on  which  to  separate  adrenal  from  renal 
growths,  but  it  cannot  be  questioned  that  a  predominance  of  this  feature 
tells  strongly  against  an  adrenal  origin.  Yet  small  adrenal  adenomas  may 
show  an  irregular  alveolar  structure. 

The  same  considerations  apply  to  the  papillary  structures  of  supposed 
adrenal  rest  tumors.  The  markedly  papillary  character  of  renal  carcinoma 
is  not  approached  in  any  authentic  case  of  human  adrenal  growth.  Never- 
theless a  certain  papillary  structure  which  is  less  pronounced  than  in  renal 
carcinoma,  may  appear  in  adrenal  tumors  which  are  chiefly  of  perivascular 
type.  Winkler  describes  such  a  structure  in  the  pulmonary  metastases  of  a 
bilateral  adrenal  growth.  A  low  papillary  growth  may  be  present  also  in 
small  adrenal  adenomas.  In  and  about  cystic  cavities  which  form  in  ad- 
renal carcinoma  from  hemorrhage  and  softening  localized  papillary  growth 
may  occur. 

The  characters  of  the  cells  in  adrenal  growths  differ  distinctly  from  those  of 
most  renal  tumors.  In  the  former  the  cytoplasm  is  foamy,  granular,  and 
interspersed  with  lipoid  granules.  In  most  tumors  the  granular  character 
increases  and  the  fatty  appearance  diminishes  with  the  increase  in  malig- 
nancy. In  the  renal  tumors  the  cells  are  remarkably  clear  throughout,  re- 
semble vegetable  cells,  and  contain  large  globules  or  crystals  of  fat  with  hy- 
dropic fluid,  and  little  or  no  granular  material.  Lubarsch  thought  the  abun- 
dance of  glycogen  a  strong  diagnostic  point  in  adrenal  growths,  but  it  may 
be  equally  abundant  in  renal  tumors.  Glycogen  is  scanty  hi  the  normal 
adrenal.  Hydropic  degeneration  is  usually  missing  in  adrenal  growths  (Zehbe), 
but  very  marked  in  Grawitz's  tumors. 

Fat  is  present  in  both  renal  and  adrenal  tumors,  and  in  both  the  lipoids 


TUMORS  OF  KIDNEY  761 

consist  chiefly  of  cholesterin  esters  (Panzer)  and  are  doubly  refractive  (Lohlein, 
Stoerk).  The  fat  content  in  Ipsen's  cases  ran  from  4  to  10.7  per  cent.,  while 
that  of  the  horse's  adrenal  was  30.8  per  cent.  Sisson  finds  the  fat  very  un- 
evenly distributed  in  Grawitz's  tumors,  but  quite  uniformly  in  adrenal  growths. 

The  loose  relations  of  the  cells  to  one  another  and  to  the  stroma  in  many 
adrenal  growths  contrasts  with  the  rigid  cell  borders  and  coherence  of  the 
cells  in  renal  papillary  carcinoma.  Areas  of  diffuse  growth,  of  indifferent 
spheroidal  cells,  and  of  spindle-cells  are  practically  unknown  in  the  renal 
tumors,  but  are  frequent  in  adrenal  growths.  Giant-cells  form  in  both  varieties 
of  tumors,  perhaps  to  a  greater  extent  in  those  from  the  adrenal.  Pigmented 
cells  belong  to  adrenal  tumors.  Fraser  points  out  that  the  primary  structure 
differs  markedly  in  adrenal  from  that  of  renal  tumors,  and  that  while  secondary 
structures  due  to  malignant  change  or  degeneration  may  cause  the  renal  to 
resemble  the  adrenal  growths,  the  primary  structures  of  both  types  are  dis- 
tinct. Hence  the  diagnosis  must  be  based  only  on  the  primary  structure  and 
not  on  non-specific  secondary  changes.  Many  sections  from  various  portions 
of  the  tumor  may  be  required  to  detect  the  primary  structure. 

Among  miscellaneous  data  may  be  mentioned"  the  fact,  pointed  out  by 
Stoerk,  that  Grawitz's  tumors  while  very  frequent  in  the  kidney  are  very 
rare  in  the  adrenal.  Ellis  collected  157  in  the  kidney,  3  in  adrenal,  2  in  liver, 
and  i  in  uterus.  Garceau  mentions  176  in  the  kidney,  while  Woolley  could 
find  only  22  in  the  adrenal.  Glynn  points  out  that  abnormal  sex  characters 
are  commonly  present  with  adrenal  growths,  but  invariably  absent  with 
Grawitz's  tumors.  Wells  failed  to  find  adrenalin  in  a  typical  Grawitz  tumor. 

Croftan  observed  that  a  watery  extract  of  the  adrenal  caused  rapid  de- 
colorization  of  starch  blue  from  action  of  iodin,  and  transforms  starch  or 
glycogen  into  maltose  or  dextrose,  while  injection  of  this  ex.tract  into  dogs 
and  rabbits  produces  glycosuria.  He  employed  this  test  for  the  recognition 
of  adrenal  tumors  of  the  kidney.  Results  of  the  test  in  the  hands  of  Korber 
and  Winkler  were  not  uniform.  Ellis  found  the  reaction  in  a  variety  of  tissues. 

Conclusions. — Sufficient  evidence  has  been  adduced  to  prove,  in  the 
writer's  opinion,  that  the  group  of  adrenal  tumors  of  the  kidney  differs,  as 
a  whole,  quite  distinctly  from  the  renal  adenocarcinoma  with  clear  cells. 
The  main  distinctive  features  of  the  adrenal  growths  are  the  central  fibrous 
core  and  exact  reproduction  of  the  adrenal  by  benign  growths,  and  the  gen- 
eral mesoblastic  tendencies  of  the  malignant  forms.  Chromaffin  cells  are 
not  infrequently  present.  For  an  alveolar  or  papillary  structure  it  is  ex- 
tremely difficult  to  establish  an  adrenal  origin  in  man.  Yet  the  opponents 
of  Grawitz's  theory  seem  to  have  gone  too  far  in  practically  eliminating  the 
adrenal  rest  as  a  source  of  renal  tumors.  In  atypical  cases  of  both  varieties 
it  may  be  impossible  to  establish  a  positive  differentiation. 

Tumors  of  Extrarenal  Adrenal  Rests. — The  distribution  of  adrenal 
structures  outside  the  kidney  corresponds  to  the  location  of  groups  of  tumors 
which  present  a  structure  suggesting  an  origin  from  adrenal  tissue.  Three 
main  divisions  of  aberrant  adrenal  tissue  are  found: 

(a)  Along  the  suprarenal  vein,  solar  plexus,  and  inferior  surface  of  the  liver; 

(#)  Along  the  internal  spermatic  vein,  in  the  broad  ligament  and  about 
the  uterus,  ovary,  and  tube  in  the  female; 

(c)  In  the  spermatic  cord  and  corpus  Highmori  in  the  male. 

These  adrenal  rests  are  usually  of  comparatively  simple  structure,  pre- 
senting only  cortical  tissue,  but  in  several  instances  pigmented  medullary 
tissue  is  present.  The  absence  of  pigmented  cells  is  not  a  certain  indication 
of  entire  lack  of  medullary  elements,  since  pigment  is  late  in  appearance 
even  in  the  normal  adrenal.  From  the  usual  construction  of  the  rests  only 


762  NEOPLASTIC  DISEASES 

cortical  tissue  can  be  expected  in  the  tumors.  In  the  rare  cases  of  hyper- 
plasia  of  aberrant  adtenal  tissue  described  by  Marchand,  Gunkel,  and  Pick 
only  cortical  tissue  was  apparent.  Yet  Chiari's  and  Schmorl's  tumors  con- 
tained brownish  or  yellow  pigmented  cells. 

The  tumors  attributed  to  these  rests  have  often  shown  such  striking 
resemblance  to  adrenal  adenoma  as  to  leave  little  doubt  of  their  true  nature. 
In  others  the  structure  has  been  less  specific,  often  peritheliomatous  or  car- 
cinomatous,  and  the  derivation  from  adrenal  tissue  must  remain  doubtful. 
In  some  reported  cases,  especially  in  the  liver,  ovary,  and  testis,  the  adrenal 
origin  is  highly  questionable.  Thus,  Pepere's  hypernephroma  of  the  liver  is 
clearly  an  hepatic  adenoma,  while  some  of  the  supposed  hypernephromas  of 
the  ovary  and  testis  can  equally  well  or  better  be  interpreted  as  atypical  forms 
of  well-known  carcinomas  of  these  organs. 

In  general,  the  tumors  are  well  encapsulated,  of  large  size,  cystic  or  solid, 
of  light  yellow  color,  with  a  tendency  toward  necrosis  and  hemorrhage.  They 
possess  considerable  malignancy  and  local  extensions  and  general  metastases 
are  frequent. 

Hepatic  Adrenal  Tumors. — Schmorl,  who  reported  finding  four  examples 
of  adrenal  rests  in  the  right  lobe  of  the  liver,  also  described  a  small  yellowish 
tumor  in  this  region  presenting  the  structure  of  adrenal  cortical  adenoma. 
Larger  malignant  tumors  probably  of  the  same  nature  are  recorded  by  Vecchi 
and  Noyes. 

Peritheliomatous  structures  in  hepatic  tumors  have  often  been  regarded 
as  of  possible  adrenal  origin.  An  angiosarcoma  of  the  pancreas  was  so  inter- 
preted by  Ribbert  and  Kronlein. 

Lateral  Retroperitoneal  Tumors  of  Adrenal  Rests. — The  retroperitoneal 
tissues  above  and  below  the  kidney  and  extending  into  the  pelvis  are  the 
seat  of  a  wide  variety  of  tumors  of  sarcoma tous  and  carcinomatous  types. 
Goebel  has  tabulated  101  cases,  illustrating  the  wide  scope  of  this  group  of 
tumors.  They  include  benign  connective-tissue  growths,  lipoma,  fibroma, 
fibromyomas,  and  ovarian  cysts,  various  types  of  sarcomas,  rare  carcinomas, 
teratomas  and  cyst,  and  four  adrenal  rest  tumors. 

Chiari's  case,  the  first  reported  definite  extrarenal  hypernephroma,  was 
a  large  tumor  lying  below  the  kidney  on  the  quadratus  lumborum,  reaching 
the  true  pelvis,  and  extending  into  the  mesocolon  and  along  the  crural  ves- 
sels. The  gross  and  microscopical  structure  was  rather  typical  of  adrenal 
adenocarcinoma.  Weiss  described  a  very  similar  case.  Goebel's  tumors 
both  grew  through  the  mesocolon  in  the  peritoneum  or  abdominal  wall. 

Adrenal  Tumors  of  the  Broad  Ligament,  Ovary,  Tube,  and  Uterus. — 
Peham  has  described  two  large  cystic  and  solid  yellowish  tumors  of  the  ovary 
which  presented  a  structure  recalling  that  of  hypernephroma.  Scudder's  case 
of  bilateral  ovarian  tumor,  of  very  similar  structure,  does  not  strengthen  the 
probability  of  an  adrenal  origin.  The  rare  tumors  of  the  corpus  luteum 
offer  a  strong  resemblance  to  hypernephroma,  and  certain  fatty  and  hydropic 
ovarian  carcinomas  closely  resemble  adrenal  growths. 

In  the  broad  ligament  Weiss  and  L.  Pick  have  each  described  large  yellow- 
ish, hemorrhagic,  and  necrotic  tumors,  displacing  uterus  and  ovary,  and 
exhibiting  many  microscopical  features  of  hypernephroma.  In  a  large  tumor 
attached  to  the  fundus  uteri  Eastwood  describes  rather  typical  reproduction 
of  the  zona  glomerulosa  of  the  adrenal,  as  well  as  alveoli  filled  with  colloid, 
as  in  the  thyroid  gland. 

Adrenal  Tumors  of  Spermatic  Cord  and  Testis. — Adrenal  tumors  of  the 
testis  are  described  by  Chevassu  and  Debarnardi,  but  their  exact  nature 
appears  rather  uncertain. 


TUMORS  OF  KIDNEY  763 

EPITHELIAL  TUMORS  OF  RENAL  PELVIS  AND  URETER 

The  renal  pelvis  and  the  ureters  are  the  seat  of  tumors  very  similar  to 
those  of  the  bladder.  They  take  the  form  of: 

(i)  Papilloma. 

(a)  Papillary  epithelioma  (epidermoid  carcinoma). 

(3)  Alveolar  carcinoma. 

Of  54  such  tumors  collected  by  Albarran  and  Imbert,  22  were  benign 
papillomas,  16  epitheliomas,  and  16  carcinomas.  Savory  and  Nash  have 
tabulated  49  cases.  The  tumor  occurs  chiefly  between  the  ages  of  35  and  65 
years,  much  more  frequently  in  males,  and  in  8  of  53  cases  there  were  calculi. 

(1)  Papilloma  is  a  benign  growth  which  affects  any  portion  of  the  renal 
pelvis  or  ureter.     In  7  cases  both  were  involved,  while  in  6  the  ureter  was 
the  primary  seat,  especially  the  upper  or  lower  orifices.     Pelvis  and  ureter 
throughout  were  affected  in  the  cases  of  Lancereaux,  Fen  wick,  and  Hebb. 

The  tumors  are  usually  multiple  and  may  be  extremely  numerous,  covering 
the  entire  mucosa  with  fine  vegetations.  Often  there  is  one  large  composite 
tumor  and  several  small  polyps  scattered  over  pelvis  and  calices  (Kohl- 
hard  t).  Albarran  holds  that  multiple  tumors  are  often  the  result  of  implan- 
tation, but  it  seems  more  probable  that  in  cases  of  very  extensive  distribution 
the  tumors  develop  all  along  the  genito-urinary  tract  as  the  result  of  factors 
affecting  the  entire  mucous  membrane.  In  the  cases  of  Murchison  and  of 
Neelson  the  bladder  was  involved  with  pelvis  or  ureter,  and  Murchison's 
case  was  bilateral.  The  tumors  are  villous  or  wart-like,  attached  by  a  narrow 
pedicle  and  expanding  in  fan  shape.  Very  fine  branching  growths  collapse 
on  removal  and  require  floating  in  water  for  restitution  of  the  original  form. 
The  great  vascularity  is  a  source  of  hemorrhage,  which  is  the  chief  symp- 
tom. Incrustation  with  salts  and  association  with  calculi  is  frequently  ob- 
served, and  the  intervening  mucosa  may  be  the  seat  of  chronic  pyelitis  some- 
times cystic  (Stoerk).  Various  grades  of  hydronephrosis  often  result  from 
partial  occlusion,  chiefly  by  ureteral  tumors.  The  structure  presents  elongated 
branching  blood-vessels  sometimes  accompanied  by  smooth  muscle-cells, 
covered  by  multiple  layers  of  transitional  epithelium.  The  tumor-cells  are 
cubical,  cylindrical  or  much  elongated  and  spindle-shaped,  but  the  form 
and  arrangement  are  orderly  and  typical.  At  the  bases  of  the  tumors  there 
is  round-cell  infiltration. 

While  the  course  of  these  tumors  is  usually  benign,  not  a  few  of  them  have 
recurred  in  malignant  form  after  curettage  or  incomplete  removal.  They 
are  distinctly  capable  of  developing  recurrences  from  implantation  in  the 
wound.  In  Tikhoffs  case  the  recurrence  developed  locally  as  alveolar  car- 
cinoma, 10  years  after  operation.  Very  suggestive  is  the  case  of  Drew — 
villous  papilloma  of  pelvis  invading  the  kidney,  simple  papillary  excrescences 
throughout  the  ureter,  and  a  large  papilloma  at  the  vesical  orifice. 

(2)  Papillary  epithelioma  produces  more  numerous  and  more  compact 
tumors  than  the  benign  papilloma.     They  appear  as  closely  set,  opaque, 
warty  outgrowths  which  are  usually  found  to  cover  a  considerable  area. 
Both  pelvis  and  ureter  may  be  involved,  as  in  the  cases  of  Rayer,  Drew, 
Israel,  and  Poll,  or  a  recurrence  of  a  pelvic  tumor  may  later  appear  in  the 
ureter  (Israel,  Fenwick).    Pelvis,  ureter,  and  bladder  may  be  simultaneously 
involved  (Rayer,  Drew,  Israel).     Even  in  early  stages  of  the  growth  there 
s  a   tendency  toward  encroachment  on  the  submucous  tissues  and  renal 
parenchyma.    In  a  case  pictured  by  Kuster  the  entire  visceral  layer  of  mucosa 
was  involved  by  low  warty  growths  and  the  renal  cortex  was  perforated. 
It  is  sometimes  difficult  to  determine  in  the  gross  whether  the  original  growth 


764 


NEOPLASTIC  DISEASES 


is  renal  or  pelvic  (Graupner).  In  advanced  cases  the  pelvis  may  be  dis- 
tended and  obliterated  and  fused  with  surrounding  tissues,  and  the  kidney 
may  either  be  invaded  and  deformed,  or  multiple  cysts  may  distend  the  cortex 
in  hydronephrosis. 

Finally,  there  is  a  form  of  diffuse  infiltrating  carcinoma  of  the  kidney, 
the  organ  being  mucji  enlarged  but  not  greatly  deformed,  which  probably 
originates  as  papillary  carcinoma  of  the  pelvis  (Graupner,  Hildebrandt, 
Beneke,  Milne).  A  case  of  this  type,  which  first  suggested  a  diagnosis  of 
endothelioma,  is  described  by  Beneke  and  Namba  and  attributed  to  a  trauma. 
Yet  the  neighboring  lymph-nodes  were  tuberculous. 


FIG.  369. — Papillary  epidermoid  carcinoma  of  renal  pelvis. 

Metastases  are  often  observed  in  adjoining  nodes,  adrenal,  peritoneum, 
liver,  lung,  and  in  Kischensky's  case,  in  the  femur.  Mesenteric,  aortic,  and 
perirenal  nodes  may  be  invaded  (Rayer,  Drew,  Volcker).  Along  the  genito- 
urinary tract  extension  occurs  by  (a)  lateral  encroachment  of  the  tumor 
through  the  lumen,  submucosa,  or  mucosa  of  the  ureter;  (b)  by  the  develop- 
ment of  new  tumors  over  increasing  segments  of  the  mucosa,  and  (c)  accord- 
ing to  Albarran,  by  implantation. 

The  structure  presents  two  distinct  types:  (i)  Simple  papillary  epithe- 
lioma,  suggesting  a  relation  to  benign  papilloma,  and  (2)  squamous-cell  car- 
cinoma. 

(i)  Papillary  epithelioma  shows  overgrowth  of  the  cell  layers  of  benign 


TUMORS  OF  KIDNEY 


765 


papilloma,  atypical  cell  forms,  and  infiltrating  qualities.  In  infiltrating 
tumors  the  papillary  structure  is  soon  lost  and  the  growth  is  alveolar  or  diffuse 
or  scirrhous. 

The  transformation  of  benign  into  malignant  papilloma  has  been  made 
clear  by  Albarran.  In  Battle's  case  simple  papilloma  curetted  from  the 
pelvis  soon  recurred  with  malignant  structure.  Pantaloni  observed  a  recur- 
rence in  malignant  form  in  the  scar  after  nephrectomy  for  a  uniformly  be- 
nign papilloma.  In  portions  of  chiefly  benign  papillomas,  especially  at  the 
base,  atypical  overgrowth  is  sometimes  observed.  The  long  duration  of 
symptoms  preceding  the  discovery  of  a  malignant  papilloma  suggests  the 
development  of  a  slowly  growing  benign  tumor  followed  by  malignant  trans- 
formation. Yet  benign  papillomas  appear  to  have  existed  for  6,  12,  and 


FlG.  370. — Epidermoid  carcinoma  distending  the  renal  pelvis.     Alveolar  growth  of 
small  polyhedral  cells  with  abrupt  and  extensive  pearl  formation. 


27  years  (Battle,  Albarran,  Pantaloni)  and  the  malignant  properties  have 
developed  only  after  incomplete  extirpation. 

(2)  Squamdus-cell  carcinoma  of  the  pelvis  was  described  by  Kundrat 
in  1891  and  later  cases  have  been  reported  by  Rundle,  Graupner,  Kischensky, 
Beisenbruch,  and  Scheel.  These  remarkable  tumors  are  usually  of  large 
size  when  discovered,  but  Battle  observed  squamous  changes  in  a  small  vil- 
lous  tumor  of  the  pelvis  and  Rundle  found  the  upper  ureter  invaded  by  a 
squamous  carcinoma  of  moderate  dimensions.  In  other  cases  the  pelvis 
has  been  distended  and  the  wall  infiltrated  by  a  bulky  growth.  The  kidney 
is  either  transformed  into  large  cysts  by  hydronephrosis  or  infiltrated  and 
destroyed. 

The  squamous  changes  are  very  pronounced  and  much  of  the  growth 


/66  NEOPLASTIC  DISEASES 

may  be  composed  of  epithelial  pearls  many  of  which  are  hornified  or  calcined. 
In  Schmorl's  case  distant  metastases  showed  the  same  structure. 

That  the  pelvic  and  ureteral  epithelium  is  capable  of  extensive  epidermi- 
zation  is  well  attested  by  the  reports  of  Wendel  of  numerous  cases  of  leu- 
koplakia,  usually  associated  with  calculi.  Rokitansky  described  a  very 
advanced  condition,  with  much  scaly  desquamation,  as  "cholesteatoma." 
Ziegler  found  marked  epidermization  in  pyelitis  calculosa,  and  Beselin  re- 
ported an  advanced  case  with  tuberculous  pyelitis.  Yet  all  cases  are  not 
associated  with  calculi  or  leukoplakia,  so  that  the  excessive  hornification 
must  be  regarded  as  a  tendency  inherent  in  the  growth. 

In  a  case  studied  by  the  writer  in  a  woman  of  58  years,  the  kidney  and  tumor  meas- 
ured 14  X  19  cm.  The  tumor  involved  chiefly  the  extrapelvic  fat,  but  had  occluded  the 
lower  half  of  the  pelvis,  along  which  it  invaded  the  kidney.  The  renal  cortex  was  thinned 
out  over  several  large  smooth-walled  cysts.  The  ureter  was  destroyed  down  to  the 
bladder.  There  were  metastases  in  aortic  and  mesenteric  nodes  and  in  the  uterus. 
The  main  bulk  of  this  large  tumor  was  composed  of  hornified  and  slightly  calcined 
epithelial  pearls  surrounded  by  a  moderate  number  of  spindle  or  cubical  granular 
epithelium.  The  transition  from  one  to  the  other  type  of  cell  was  very  sharp. 

(3)  Alveolar  carcinoma  of  the  renal  pelvis  is  not  clearly  distinguished 
from  papillary  epithelioma,  which  in  advanced  and  malignant  cases  may  lose 
its  papillary  character  and  present  the  structure  of  alveolar  or  diffuse  or 
scirrhous  carcinoma.  Hildebrandt  describes  a  large  tumor  of  pelvis  and  kid- 
ney, the  pelvic  portions  of  which  were  papillary,  the  renal  being  scirrhous. 
Yet  Albarran  describes  papillary  adenoma  with  cylindrical  cells  in  pelvis 
and  ureter,  and  Giordano  found  chiefly  cylindrical  cells  in  a  pelvic  tumor, 
while  several  others  have  appeared  to  show  no  trace  of  papillary  but  exclu- 
sively glandular  and  alveolar  carcinoma  (Hedenius,  Wirsing,  Hektoen,  Hart- 
mann,  Israel).  In  Grohe's  case  the  structure  resembled  thyroid  gland  and 
he  attributed  its  origin  to  the  tubular  glands  of  the  pelvic  mucosa. 

The  early  pelvic  and  ureteral  tumors  are  described  as  flat  and  infiltrating 
rather  than  papillary.  The  advanced  tumors  are  large,  infiltrating  and  highly 
malignant. 

TUMORS  OF  THE  RENAL  HTLUS 

The  tissue  of  the  renal  hilus  gives  origin  to  several  forms  of  simple  and 
of  complex  tumors,  which  may  be  distinguished  from  tumors  of  renal  paren- 
chyma, or  pelvis,  or  adrenals,  and  for  which  special  embryological  errors 
appear  to  be  responsible.  Tumors  of  the  hilus  develop  about  the  renal  vessels 
and  the  ureter,  which  are  soon  compressed,  and  the  kidney  is  often  found 
stretching  over  the  tumor  mass  as  a  shell  incloses  a  nut.  The  tumors  are 
often  bilateral.  Most  of  them  are  observed  in  children,  but  not  a  few  appear 
in  adults. 

Lipoma  of  the  hilus  is  not  infrequent.  It  may  be  difficult  to  separate 
from  hypertrophy  of  the  fat  tissue  which  follows  atrophic  conditions  of  the 
kidney.  The  hilus  fat  tissue  is  also  the  seat  of  a  chronic  productive  inflam- 
mation in  which  the  fat  is  infiltrated  with  lymphocytes  and  plasma-cells, 
and  thickened  by  new  connective  tissue,  so  that  it  is  much  increased  in  bulk. 
Hollen  described  a  well-circumscribed  lipoma. 

Angiolipoma  surrounding  the  vessels  and  pelves  of  both  kidneys  is  de- 
scribed by  Salomon. 

Myxoma  and  myxosarcoma  of  the  hilus  produce  bulky  masses  which 
infiltrate  the  surrounding  tissues  and  cause  displacement,  stretching,  and 
atrophy  of  the  kidney.  In  four  large  tumors  of  this  type  I  have  found  con- 
siderable admixture  of  actively  growing  fat  tissue. 


TUMORS  OF  KIDNEY  767 

Schluter  reported  a  large  myoma  which  had  caused  nearly  complete  atrophy 
of  the  kidney. 

Diffuse  Sarcoma  of  Hilus  and  Renal  Pelvis. — A  peculiar  form  of  sarcoma 
of  the  hilus  and  pelvic  tissue  has  been  described  by  de  Vecchi  and  by  Salomon. 
The  tumors  were  bilateral  and  occurred  in  infants  under  2  years  of  age.  The 
tumor  tissue  encircled  the  ureter,  great  vessels,  pelvis,  and  papillae,  but 
was  well  demarcated  from  the  renal  parenchyma.  The  structure  was  com- 
plex, presenting  areas  of  round,  spindle,  and  giant-cells,  which  invaded  and 
destroyed  the  fat  and  muscle  tissues,  de  Vecchi  found  areas  of  chromaffin 
cells  which  he  regarded  as  a  portion  of  the  neoplasm  derived  from  misplaced 
chromaffin  tissue,  but  Salomon  interpreted  these  cells  as  remnants  of  the 
normal  paraganglia  or  adrenal  structures  of  this  region  which  had  resisted 
destruction  by  the  tumor.  Both  authors  were  inclined  to  regard  the  tumors 
as  derived  from  remannts  of  the  nephrotome  or  sclerotome  and  therefore  re- 
lated to  the  Wilms'  tumors  of  the  kidney,  but  the  grounds  for  this  interpreta- 
tion are  not  clear. 


CHAPTER  XXXVIII 
TUMORS  OF  THE  ADRENAL 

The  embryology  of  the  gland  and  the  very  variable  histology  of  its  tumors 
render  it  difficult  to  choose  a  satisfactory  terminology  of  adrenal  growths. 
Since  the  adrenal  cortex  is  of  mesothelial  origin,  neoplasms  of  this  tissue  may 
be  designated  as  mesotheliomas.  The  tendency  of  many  of  these  tumors  to 
reveal  mesoblastic  or  sarcomatous  properties  also  supports  the  suggestion 
of  Adami  and  Woolley  that  recognition  of  this  fact  be  granted  by  employing 
the  term  "mesothelioma."  Yet  the  acquired  epithelial  characters  of  the  gland- 
cells  predominate  in  most  of  the  growths,  which  behave  as  adenomas  or 
carcinomas.  In  others  the  structure  of  epithelial  alveoli  is  mingled  with 
areas  of  spindle-cells  as  in  carcinoma-sarcoma.  In  a  well-known  group  the 
cells  are  large,  round,  and  atypical  and  the  structure  presents  itself  as  round- 
cell  sarcoma.  Yet  there  is  very  good  reason  to  believe,  as  pointed  out  by  J. 
H.  Wright,  that  all  the  round-cell  sarcomas  of  children  are  derived  from 
the  nervous  elements  of  the  sympathetic.  Hence  they  may  properly  be  called 
neurocytoma.  Of  these  some  show  definite  ganglion-cells  and  nerve-fibers, 
and  have  been  called  neuroma,  or  glioma  ganglionare.  Finally,  there  are  rare 
tumors  composed  of  chromaffin  cells,  and  although  these  cells  are  originally 
derivatives  of  the  neural  elements,  their  acquired  characters  dominate  the 
neoplastic  process  and  demand  for  them  a  separate  classification. 

The  entire  group  falls  into  two  divisions,  (i)  cortical  and  (2)  medullary, 
in  which  the  following  special  forms  are  observed. 

ADRENAL  TUMORS 

Cortical:        (a)  Hyperplasia,  nodular  or  diffuse. 

(b)  Adenoma. 

(c)  Carcinoma. 
Medullary:    (a)  Focal  hyperplasia  of 

1.  Glia-tissue  or 

2.  Chromaffin  cells. 
(6)  Neuroma  ganglionare. 

(c)  Neurocytoma,  "sarcoma." 

(d)  Suprarenal  chromatophoroma. 

Hyperplasia. — Various  grades  of  focal  hyperplasia  of  cortical  tissue  are 
well  known  but  rather  rare  conditions  in  the  adrenal.  All  gradations  exist 
between  simple  focal  hyperplasia  and  true  adenoma,  and  the  distinctions 
between  them  are  not  always  emphasized.  Letulle  observed  both  conditions 
in  the  same  adrenal.  Virchbw  described  the  group  as  struma  suprarenalis. 

The  nodules  appear  as  pinhead  or  pea-sized  masses  of  light  yellow  or 
brownish  color,  sharply  circumscribed,  but  not  encapsulated.  Larger  masses 
of  apparently  the  same  significance  may  reach  the  size  of  a  cherry  and  form 
a  well-defined  projecting  tumor. 

Diffuse  hyperplasia  of  the  adrenal  is  also  observed.  It  affects  the  cortex 
and  is  usually  associated  with  feminine  pseudohermaphroditism  (Glynn, 
Lit.).  In  these  cases  the  adrenal  may  be  as  large  as  the  kidney  (Marchand, 
Febiger). 

768 


TUMORS  OF  THE  ADRENAL  769 

The  structure  reproduces  that  of  the  cortical  zones.  The  cells  and  cell 
groups  are  often  larger  than  normal  and  may  be  irregularly  arranged.  The 
tumors  are  usually  very  fatty  and  have  been  mistaken  for  lipomas,  but  usually 
they  present  the  structure  of  the  zona  glomerulosa  or  reticularis. 

Letulle  has  shown  that  nodular  hyperplasia  of  the  adrenal  may  be  asso- 
ciated with  a  similar  condition  in  the  liver  and  occurs  in  a  variety  of  diseases. 
Sex  abnormalities,  as  overgrowth  of  hair  and  genital  organs,  are  observed 
occasionally  with  nodular  hyperplasia,  but  especially  with  definite  tumors  of 
the  adrenal. 

Adenoma  of  the  adrenal  is  distinguished  from  nodular  hyperplasia  by  its 
atypical  and  neoplastic  structure.  From  the  presence  of  adenomatous  areas 
in  portions  of  malignant  adrenal  growths  it  is  evident  that  many  of  the  latter 
arise  from  the  former.  Adrenal  adenoma  is  comparatively  rare,  Kelynack 
finding  3  cases  in  1500  autopsies.  In  some  of  the  cases  of  pseudohermaph- 
roditism  the  process  in  the  hyperplastic  adrenals  approaches  adenoma. 

The  tumors  are  usually  single,  but  may  be  multiple  and  bilateral.  They 
form  projecting  masses  of  yellowish  or  reddish  color,  well  circumscribed  from 
the  cortex  of  the  gland,  but  often  deforming  or  destroying  the  organ.  Hemor- 
rhage and  central  softening  may  occur.  They  may  reach  a  considerable  size, 
weighing  2  to  4  ounces  while  retaining  the  adenomatous  structure.  A  fibrous 
stroma  is  nearly  constant  and  may  be  abundant,  rendering  the  tumors  quite 
firm  and  fibrous  (fibro-adenoma).  More  often  the  stroma  is  fine  and  vas- 
cular. Rarely  the  tumors  are  surrounded  by  a  definite  capsule.  The  structure 
may  reproduce  exactly  that  of  the  adrenal  cortex,  with  increase  in  the  size  of 
the  cells,  hyperchromatism  of  nuclei,  and  often  with  marked  fatty  changes. 
Or  the  cells  may  be  smaller,  more  numerous,  granular,  and  free  from  fat. 
Irregular  alveolar  structures  with  lumina  and  low  papillary  growths  are  de- 
scribed by  Kelynack  in  benign  tumors.  Lumina  surrounded  by  cylindrical 
cells  are  also  described  in  Manasse  in  adrenal  adenoma,  and  this  structure 
appears  to  be  very  frequent  in  horses. 

Rolleston  described  a  brownish  fibro-adenoma  as  large  as  a  walnut.  Ex- 
tensive fatty  changes  may  produce  a  structure  resembling  lipoma.  Auvray 
and  Pfeiffel  described  a  large  tumor,  in  a  case  of  pseudohermaphroditism,  as 
adeno-angiolipoma.  In  a  few  reported  cases  the  cells  were  markedly  pigmented, 
but  these  tumors  were  probably  medullary. 

The  limits  of  growth  of  adrenal  adenoma  are  restricted.  In  pure  form 
they  do  not  reach  large  dimensions  or  produce  metastases  and  most  of  them 
are  encountered  at  autopsy.  Malignant  transformation  into  adenocarcinoma 
or  still  more  atypical  growth  appear  to  be  of  relatively  common  occurrence. 

Carcinoma. — Malignant  tumors  presenting  epithelial  characters  are  much 
the  most  frequent  of  adrenal  growths.  Winkler  observed  10  such  cases  to 
three  sarcomas,  and  suggests  that  even  the  sarcomas  arose  from  cortical 
epithelium.  Rolleston  and  Marks,  however,  interpreted  only  9  of  26  col- 
lected cases  as  carcinoma  or  malignant  adenoma,  but  they  assume  that  sar- 
coma may  arise  from  the  cortical  epithelium.  The  average  age  of  incidence 
in  9  cases  was  44  years.  Winkler  observed  2  cases,  at  19  years  and  at  66. 
Several  of  his  cases  gave  a  history  of  trauma. 

The  tumors  are  usually  found  at  autopsy,  of  large  size,  involving  the 
whole  of  the  adrenal,  adherent  to  or  fused  with  the  kidney  and  bound  to 
neighboring  structures  by  many  extensions. 

The  earlier  tumors  are  smaller  and  embedded  in  the  enlarged  adrenal, 

of  which  the  outline  may  be  partly  retained.    At  all  stages  they  are  soft, 

yellowish,  and  prone  to  hemorrhage  and  necrosis.     Central  softening  may 

yield  cysts  of  large  size,  but  the  very  cellular  tumors  are  usually  rather  solid. 

49 


770  NEOPLASTIC  DISEASES 

Early  and  wide-spread  extensions  and  metastases  are  a  prominent  char- 
acteristic of  adrenal  carcinoma.  Although  there  are  some  reports  of  a  sta- 
tionary tumor  persisting  for  months  or  years  before  active  growth  occurred, 
most  of  the  adrenal  carcinomas  progress  rapidly  from  the  first  symptom. 

The  local  extensions  invade  the  kidney  and  perirenal  tissue  so  that  it 
may  be  difficult  to  separate  the  tumor  from  the  kidney.  The  adrenal  is  often 
obliterated.  The  suprarenal  and  renal  veins  are  early  invaded  as  in  hyper- 
nephroma.  The  renal  pelvis  may  be  distended  by  tumor  masses  (Winkler). 
The  peritoneum  is  often  the  seat  of  numerous  implantations.  The  opposite 
adrenal  is  frequently  involved,  and  there  are  extensions  to  the  spleen,  liver, 
and  abdominal  organs.  The  lymphatics  are  invaded  with  enlargements 
of  retroperitoneal,  mesenteric,  and  thoracic  nodes.  The  intravenous  growths 
may  reach  in  a  solid  column  to  the  right  heart  (Gerber),  but  usually  they 
break  up  and  give  origin  to  very  numerous  distant  metastases.  Hardly  any 
organ  of  the  body  may  escape  secondary  deposits,  but  they  are  most  frequent 
in  liver,  lungs,  and  brain.  '  The  frequency  of  bone  metastases  in  tumors  of 
supposed  adrenal  origin  has  long  been  emphasized,  but  in  most  of  the  reported 
cases  the  tumor  arose  in  the  kidney  and  its  exact  nature  was  not  fully  deter- 
mined. In  cases  of  fully  verified  adrenal  carcinoma  bone  metastases  are 
infrequent.  They  occurred  in  3  of  Winkler's  10  cases.  In  48  cases  of  various 
malignant  adrenal  tumors  collected  by  Hartmann  and  Lecene,  bone  metastases 
were  demonstrated  in  only  i,  while  the  liver  was  involved  in  23;  lungs,  9; 
preaortic  nodes  in  8;  peritoneum,  5;  stomach,  pancreas,  heart,  and  brain, 
occasionally. 

The  structure  of  atypical  adrenal  carcinoma  is  essentially  specific,  but 
there  are  atypical  forms  which  are  difficult  to  separate  from  sarcoma. 

(a)  Adenocarcinoma  or  adenoma  malignum  is  a  type  which  resembles 
adenoma,  but  shows  atypical  areas  of  malignant  character  and  yields  metas- 
tases. Yet  the  arrangement  of  cells  is  orderly  and  reproduces  the  alveoli 
of  the  zona  glomerulosa  or  the  anastomosing  sheets  of  enlarged  columns  from 
the  zona  fasciculata.  The  diffuse  growth  of  atypical  cells  as  in  true  carcinoma 
is  missing.  There  is  usually  considerable  vascular  stroma.  Lumen  forma- 
tion is  rare.  The  cells  closely  resemble  the  fatty  granular  cells  of  the  normal 
gland,  but  are  large  and  the  nuclei  are  hyperchromatic.  Various  secondary 
changes  result  from  necrosis  and  hemorrhage,  including  especially  the  forma- 
tion of  giant-cells,  cysts,  and  pigmentation. 

As  interpreted  by  Rolleston  and  Marks,  the  group  of  malignant  adrenal 
adenoma  includes  a  large  proportion  of  the  malignant  tumors,  and  transi- 
tional stages  to  carcinoma  are  so  frequently  found  in  these  growths  that  a 
sharp  separation  from  other  types  is  impossible.  Clinically  they  are  fully 
malignant,  although  Winkler  described  a  very  large  tumor  of  this  type  with- 
out extensions. 

(6)  Fully  developed  carcinoma  also  presents  several  peculiarities  of  struc- 
ture. A  prominent  type,  often  encountered,  shows  chiefly  large  granular 
and  fatty  cells  in  perivascular  arrangement.  This  structure  is  but  slightly 
removed  from  the  vascular  adenocarcinomas,  but  is  usually  more  active, 
atypical,  and  malignant.  By  softening  of  central  lines  of  cells  the  structure 
may  assume  a  pseudopapillary  type. 

Giant-cells  of  large  size  may  become  very  numerous  in  tumors  which  are 
chiefly  perivascular  carcinomas.  Almost  the  entire  tumor  and  its  metas- 
tases may  be  composed  of  giant-cells.  Such  structures  have  been  inter- 
preted as  sarcoma,  as  in  Affleck  and  Leith's  case.  They  are  fully  paralleled 
by  giant-cell  types  of  hepatoma.  Carcinosarcoma  is  a  complex  structure 
seen  in  not  a  few  adrenal  carcinomas  (Adami,  Woolley).  Certain  areas  of 


TUMORS  OF  THE  ADRENAL  771 

these  growths  may  present  any  one  of  several  carcinomatous  types,  as  alveolar 
or  perivascular,  while  in  other  large  areas  or  sheets  the  cells  are  elongated, 
spindle  shaped,  compact,  and  granular.  It  appears  possible  that  the  spindle 
form  represents  a  recrudescence  of  mesoblastic  tendencies,  but  in  many  cases 
such  cells  occur  owing  to  purely  local  factors. 

Diffuse  carcinoma  appears  in  the  most  malignant  forms  of  adrenal  car- 
cinoma. The  cells  lose  all  resemblance  to  adrenal  parenchyma,  and  appear 
as  rounded  or  polyhedral  granular  cells  notably  free  from  fats  and  glycogen. 
They  grow  diffusely  or  in  small  groups,  rapidly  penetrate  surrounding  tissues, 
and  produce  bulky  metastases.  That  some  of  the  so-called  sarcomas  of  the 
adrenal  are  highly  atypical  growths  derived  from  the  renal  parenchyma  appears 
quite  possible. 

The  course  of  malignant  adrenal  tumors  is  usually  rapid  and  fatal.  In 
several  cases  the  usual  course  has  been  interrupted  by  a  successful  extirpation 
(Hartmann,  Lecene,  Lit.).  Beginning  with  signs  pointing  to  a  growth  in 
the  region  of  the  kidney,  there  usually  follow  pain,  palpable  tumors,  asthenia, 
and  cachexia.  Pigmentation  of  the  skin  was  stated  by  Fox  to  be  very  rare, 
but  this  symptom  and  others  of  the  Addison  complex  appear  more  frequently 
in  recent  reports.  Winkler  reports  2  cases  of  well-developed  Addison's  disease 
associated  with  cortical  tumors  of  the  adrenal.  In  a  series  of  cases  various 
disturbances  of  the  sexual  characters,  hirsuties,  pseudohermaphroditism, 
precocious  development  of  the  genitals,  and  obesity  have  been  associated 
with  adrenal  tumors.  It  has  been  clearly  shown  by  Glynn  that  these  sexual 
and  nutritional  disturbances  are  observed  only  with  cortical  tumors,  hyper- 
plasia,  adenoma,  or  carcinoma. 

MEDULLARY  ADRENAL  TUMORS 

Tumors  of  the  adrenal  medulla  include  three  well-defined  types: 

(1)  Neuroma  ganglionare. 

(2)  Neurocytoma.    Neuroblastoma. 

(3)  Chromaffin  cell-tumors.    Paraganglioma. 

Virchow  refers  to  the  occurrence  of  multiple  nodules  in  the  adrenal  which 
he  assumed  to  be  gliomatous. 

While  pure  examples  of  each  of  these  tumors  are  observed  there  are  many 
transitions  between  them,  and  in  Wahl's  case  all  three  were  represented 
in  portions  of  the  same  tumor.  The  more  adult  neoplasms  occur  chiefly  in 
adult  or  elderly  subjects,  the  malignant  growths  are  practically  limited  to 
children,  while  the  chromafiin  tumors  are  often  associated  with  some  phase 
of  neurofibromatosis.  All  these  features  accord  with  the  origin  of  the  tumors, 
which  arise  from  the  sympathetic  anlage  which  goes  to  form  the  adrenal 
medulla,  and  the  varying  structure  of  the  tumors  indicates  an  origin  at  suc- 
cessive stages  of  the  differentiation  of  the  sympathetic  neuroblasts.  Similar 
tumors  have  been  reported,  and  will  doubtless  be  recognized  more  frequently, 
throughout  the  entire  distribution  of  the  sympathetic  system  and  its  chromaf- 
fin glands  (Herxheimer,  Wahl,  Lit.,  Dunn,  Lit.).  The  great  majority  occur 
in  the  adrenal  medulla  and  in  the  abdominal  sympathetic. 

(i)  Neuroma  ganglionare  is  a  rare  tumor  in  the  adrenal  and  belongs  in 
the  group  of  ganglionic  neuromas  which  arise  throughout  the  sympathetic 
system. 

A  small  glioma  composed  of  medullated  nerve-fibers  and  proliferating 
ganglion-cells  in  the  adrenal  was  described  by  Weichselbaum  in  1881,  and 
similar  cases  have  been  reported  by  Dagonet  in  a  subject  of  Addison's 
disease  by  Schmidt  and  by  Bruchanow.  Schmidt's  tumor  arose  from  the 


772 


NEOPLASTIC  DISEASES 


suprarenal  plexus  and  only  partly  involved  the  gland.  These  tumors'  may 
reach  considerable  dimensions,  but  they  are  not  locally  aggressive  and  metas- 
tases  are  absent.  They  probably  arise  from  well-differentiated  sympathetic 
nerve  tissue.  The  structure  shows  a  preponderance  of  medulla  ted  and  non- 
medullated  nerve-fibers,  among  which  lie  groups  of  more  or  less  well-formed 
proliferating  ganglion-cells.  Many  of  these  are  of  relatively  small  size  and 
approach  the  form  of  indifferent  polyhedral  cells.  Others  are  large  and  multi- 
polar  and  may  contain  lipoid  pigment.  Dagonet's  tumor  contained  much 


FIG.  371. — Drawing  of  neuroblastoma  of  right  suprarenal,  viewed  from  anterior 
aspect.  The  outline  of  the  flattened  residue  of  the  suprarenal  body  is  distinguishable  on 
the  front  of  the  upper  part  of  the  tumor.  The  hemorrhagic  character  of  the  tumor  is 
visible  through  the  thin  capsule.  The  kidney  is  seen  below  and  behind  the  lower  pole. 
(After  Dunn,  J.  P.  B.,  18.) 

fibrous  tissue  and  some  smooth  muscle-cells.  Ohse's  tumor  appears  to  have 
developed  largely  within  the  adrenal  in  a  child  of  5  years  and  was  more  cellular 
than  others  of  this  group. 

(2)  Neurocytoma. — Marchand,  1891,  described  a  cellular  tumor  of  the 
adrenal  in  an  infant  of  9  months  and  interpreted  the  structure  as  a  repro- 
duction of  the  anlage  of  the  sympathetic  nerve  tissue  of  the  organ.  A  fuller 
description  of  the  structure  and  origin  of  these  tumors  was  furnished  by  Kus- 
ter  in  1905.  In  a  child  of  14  weeks  the  right  adrenal  was  transformed  into  a 
tumor  as  large  as  a  watch,  the  medulla  of  the  other  adrenal  showed  early 


TUMORS  OF  THE  ADRENAL 


773 


stages  of  the  same  growth,  while  the  liver  was  extensively  invaded.  In  a 
second  case,  in  an  adult,  the  tumor  was  as  large  as  the  fist,  but  metastases 
were  absent.  The  tumors  were  sharply  circumscribed  from  the  cortex,  gray, 
with  dark  vascular  areas.  The  structure  presented  very  numerous  cell  nuclei 
without  definite  cytoplasm,  very  often  arranged  in  the  form  of  rosettes.  Some 
of  the  cells  were  large,  better  defined,  and  resembled  the  polyhedral  cells  of 
the  medulla.  The  matrix  was  chiefly  granular,  but  in  the  adult  case  fine  fibrils 
were  demonstrable.  The  stroma  supported  fine  blood-vessels.  Kuster  inter- 
preted the  tumors  as  of  neuro-epithelial  origin,  and  Wiesel  supported  this 
general  view,  pointing  out  that  in  the  development  of  the  adrenal  just  such 
rosettes  of  cell  nuclei  appear  in  the  sympathetic  anlage.  From  them  are 
developed  both  ganglion-cells  and  chromaffin  cells.  Lapointe  and  Lecene  in 


FIG.  372. — Neurocytoma  of  adrenal  in  an  infant.     Note  bulky  masses  of  glia  fibrils. 


describing  a  typical  case  demonstrated  glia  fibril?  in  the  matrix  and  concluded 
that  the  tumors  arise  in  misplaced  portions  of  adrenal  nerve  tissue,  but  not  in 
the  normal  anlage  that  forms  the  sympathetic  elements,  which  yield  tumors 
with  medullated  fibrils  and  ganglion-cells.  Yet  it  seems  that  there  are  transi- 
tion forms  between  the  two  groups,  indicating  a  common  origin. 

The  resemblance  between  the  cellular  "gliomas"  and  the  so-called  con- 
genital sarcomas  and  lymphosarcomas  of  the  adrenal  immediately  became 
obvious,  and  Kretz  in  1903  suggested  that  a  series  of  lymphosarcomatous 
tumors  of  the  liver  were  derived  from  the  sympathetic  formative  cells.  In 
1910  J.  H.  Wright  pointed  out  these  resemblances  in  detail,  concluded  that 
the  adrenal  and  hepatic  round-cell  sarcomas  of  infants  and  many  other  terri- 
tories, were  probably  of  neurogenic  origin,  and  he  proposed  for  them  the  term 
"neurocytoma." 


774  NEOPLASTIC  DISEASES 

This  conclusion  has  been  fully  justified.  The  grounds  for  assuming  the  existence  of 
true  mesoblastic  sarcomas  of  the  adrenal  have  never  been  adequately  established.  There 
is  no  evidence  that  the  stroma  or  blood-vessels  contribute  to  these  growths.  Of  traces  of 
fetal  blood  formation  the  adrenal  preserves  none.  The  existence  of  lymph-follicles  in  the 
normal  adrenal  is  not  proved.  Dagonet  described  groups  of  lymphocytes  in  the  cortical 
zones,  but  derives  the  parenchyma  from  these  cells.  The  lymphocytes,  lymph-follicles, 
and  plasma-cells  occasionally  seen  in  the  adrenal  are  probably  the  result  of  circulatory 
and  nutritional  disturbances  (Oberndorfer).  The  diagnosis  of  sarcoma  has  been  based 
on  the  presence  of  indifferent  round  cells,  the  origin  of  which  has  not,  as  a  rule,  been 
considered.  Yet  in  many  cases  the  supposed  sarcomas  have  presented  the  typical 
rosettes  of  neuro-epithelium,  while  the  clinical  and  anatomical  characters  are  so  uni- 
form as  to  indicate  a  single  origin.  Hence  the  work  of  many  clinical  observers  who 
have  shown  that  adrenal  "sarcoma"  appears  in  certain  characteristic  clinical  types  is 
not  reduced  in  value  by  the  demonstration  of  the  true  origin  of  these  tumors.  Not  a 
few  of  them  appear  to  be  of  bilateral  origin  (F.  Hoist,  Sabrazes,  Husnot). 

In  recent  years  the  retroperitoneal  malignant  neurocytomas  of  infants 
and  similar  tumors  in  many  other  regions  have  frequently  been  recognized 
and  the  structure  has  repeatedly  been  analyzed  in  detail  (Landau,  Anitschow, 
Symmers,  Wahl,  Dunn).  These  histological  studies  have  extended  the  scope 
of  the  tumor  so  that  it  is  necessary  to  include  in  this  group  many  if  not  most 
of  the  retroperitoneal  round-cell  sarcomas  of  infants,  and  many  embryonal 
and  peculiar  growths  of  cervical,  thoracic,  and  peripheral  nervous  system, 
while  a  few  cases  have  been  found  in  the  brain.  The  structure  varies  in  the 
degree  with  which  nerve  elements  are  developed,  but  in  the  most  immature 
types  are  imperfect  rosettes,  very  numerous  but  ill-defined  fibrils  giving  an 
abundance  of  hyaline  stroma,  or  many  hyaline  globules  staining  with  eosin. 
The  hyaline  globules  resolve  themselves  into  bundles  of  imperfect  nerve 
fibrillae  connecting  groups  of  neurocytes.  Various  other  structures  may  be 
interpreted  as  imperfect  ganglion-cells,  axis-cylinder  processes,  or  glia  fibrils. 
Falk  and  others  attribute  the  excess  of  fibrillar  material  to  the  activity  of 
sheath  cells  which  differentiate  from  the  tumor-cells  and  lay  down  nerve- 
fibers.  The  fibrils  do  not  stain  well  by  Weigert's  neuroglia  stain,  nor  by 
Mallory's  method,  yet  they  may  be  detected  in  formalin  sections  stained  by 
eosin  and  hematoxylon.  Landau  secured  excellent  results  with  iron-hema- 
toxylon  and  Van  Gieson's  stain.  Pick  and  Bielschowsky  stained  the  fibrils 
by  the  latter's  method,  which  is  not  always  successful.  Dunn,  by  means  of 
Bielschowsky 's  and  Levaditi's  stains,  was  able  to  show  that  the  "great  bulk 
of  the  fibrillar  material  is  composed  of  naked  axis-cylinders.  The  fibrillae 
forming  the  rosettes  may  resist  all  the  specific  stains.  The  metastases  are 
usually  of  round  cells  only,  with  or  without  fibrillar  material,  but  in  the  cases 
of  Miller  and  of  Jacobsthal  the  secondary  tumors  contained  ganglion-cells. 

In  a  recent  case  of  the  writer's,  in  a  child  of  2  years,  the  tumor  first  appeared  on  the 
inner  side  of  the  left  thigh  below  Poupart's  ligament  and  grew  rapidly  to  enormous 
dimensions.  It  destroyed  all  the  muscles  of  the  thigh  from  knee  upward,  invaded  and 
filled  the  pelvis,  destroying  the  muscles  and  invading  kidney  and  adrenal.  The  retro- 
peritoneal  nodes  were  extensively  involved,  and  by  way  of  the  lymphatics  the  lungs 
were  largely  replaced  by  very  numerous  masses  originating  from  the  walls  of  bronchi 
and  vessels.  The  liver  escaped.  The  tumor  appeared  to  originate  from  the  femoral 
sympathetic  plexus.  The  structure  of  the  main  tumor  was  that  of  round-cell  sarcoma 
with  indistinct  alveolar  arrangement  and  occasional  excess  of  hyaline  stroma.  In  the 
lungs  there  were  many  rosettes  surrounding  hyaline  globules  and  great  excess  of  hyaline 
stroma  in  which  many  fine  fibrils  were  discernible.  In  many  areas  there  were  occasional 
large  isolated  multipolar  cells  suggesting  abortive  ganglion-cells.  The  fibers  in  material 
fixed  in  formalin  failed  to  take  Bielschowsky's  stain,  but  were  well  defined  by  picro- 
acid-fuchsin. 

Clinical  Types  of  Adrenal  Neurocytoma. — (a)  Adrenal  Sarcoma  in  Infants 
with  Cranial  Metastases  (Hutchinson's  Type).— Hutchin  son  described  a 


TUMORS  OF  THE  ADRENAL  775 

peculiar  clinical  syndrome  in  13  cases  of  adrenal  sarcoma  occurring  in  children 
from  3  months  to  9  years  of  age.  The  disease  begins  spontaneously  or  after 
trauma,  with  ecchymosis  of  one  or  both  eyelids,  soon  followed  by  exoph- 
thalmos,  a  tumor  of  the  orbit  and  temporal  region,  with  extensions  to 
the  auricular  and  submaxillary  nodes.  The  orbital  tumor  reaches  large 
dimensions,  while  an  abdominal  growth  may  be  discovered  only  at 
autopsy.  The  adrenal  growth  may  be  as  large  as  a  walnut  or  a  child's 
head,  but  shows  little  tendency  toward  local  extension.  Secondary  growths 
appear  also  in  ribs,  spine,  and  long  bones,  as  well  as  in  liver  and  other 
organs. 

The  structure  of  the  tumors  is  usually  described  as  round-cell  sarcoma, 
but  in  2  cases  the  diagnosis  was  hypernephroma  (Aisenstein,  McCarty),  and 
in  i,  melanotic  carcinoma  (Reimann,  Chiari). 

In  the  case  of  Tileston  and  Wolbach  the  tumor  contained  many  rosettes 
very  similar  to  those  observed  in  retinal  and  other  gliomas.  These  authors 
accept  the  adrenal  origin  of  Hutchinson's  tumors  because  the  structure  was 
identical  in  all,  while  in  6  cases  only  adrenal,  lymph-nodes,  and  bones  were 
involved. 

There  is  thus  no  doubt  that  certain  adrenal  tumors  in  children  follow 
Hutchinson's  type,  but  it  appears  also  that  other  tumors,  hypernephroma, 
etc.,  may  produce  the  same  syndrome.  Moreover,  all  round-cell  tumors  of 
the  adrenal  do  not  produce  orbital  metastases. 

(6)  Congenital  Sarcoma  of  Adrenal  and  Liver  in  Infants  (Pepper's  Type). — 
The  prominence  of  the  hepatic  metastases  gives  a  somewhat  striking  clinical 
character  to  a  group  of  cases  described  by  Pepper.  The  symptoms  are  those 
of  a  rapidly  enlarging  abdominal  tumor  caused  by  diffuse  and  nodular  growths 
in  the  liver  and  adrenal.  The  other  organs  were  not  involved.  One  or  both 
adrenals  may  be  affected  and  the  tumors  may  reach  large  dimensions  with 
little  tendency  toward  local  invasion  except  to  the  liver.  The  duration  varied 
from  10  days  to  16  weeks. 

Structurally  the  tumors  were  described  as  round-cell  or  lymphosarcoma. 
Winkler  describes  a  case  in  an  infant  of  2  years  in  which  the  adrenal  and 
kidney  were  destroyed  and  there  were  bulky  metastases  in  liver,  lungs,  skull, 
musculature,  and  many  lymph-nodes.  Hence  the  presence  of  hepatic  metas- 
tases does  not  exclude  them  in  other  organs. 

Much  light  has  been  thrown  on  the  various  anatomical  and  clinical  char- 
acters of  these  tumors  by  the  study  of  P.  S.  Frew.  He  points  out  that  the 
medullary  origin  is  indicated  by  the  frequent  persistence  of  a  portion  of  ad- 
renal cortex  along  one  segment  of  the  tumor.  It  is  quite  evident,  as  empha- 
sized by  Glynn,  that  the  structure  differs  entirely  from  that  of  the  cortical 
growths.  Frew  regards  the  entire  group  as  a  type  of  medullary  carcinoma 
which  extends  along  the  lymphatics  and  yields  secondary  growths  in  different 
territories,  depending  upon  which  adrenal  is  primarily  involved.  The  lym- 
phatics of  the  left  adrenal  pass  out  with  the  vein  at  the  lower  pole  of  the  gland 
and  join  with  the  renal  vein  and  its  lymphatics,  which  have  rich  connections 
with  the  lumbar  and  preaortic  nodes.  Tumors  of  the  left  adrenal  accordingly 
invade  the  regional  nodes  extensively,  passing  (a)  downward  along  the  iliacs 
to  the  pelvis  and  groin,  (6)  across  to  the  mesenteric  nodes,  (c}  upward  to  the 
hilus  of  the  liver  and  thence  into  the  liver  by  the  portal  spaces,  (d)  through  the 
posterior  mediastinum,  (e)  along  the  intercostal  lymphatics,  and  (/)  through 
the  deep  cervical  chain  along  the  carotid  artery  to  the  base  of  the  skull.  Hence 
with  left-sided  tumors  deposits  occur  in  the  above  locations,  especially  in  the 
ribs  and  cranium  (Hutchinson's  type).  Secondary  growths  occurred  in  the 
substance  of  the  liver  in  4  of  22  cases  and  only  in  very  young  subjects 


770 


succumbing  to  very  rapid  growths  (Pepper's  type).    The  lungs  were  never  in- 
volved with  tumors  of  the  left  side. 

From  the  right  adrenal  the  vein  and  lymphatics  pass  from  the  upper  pole 
and  join  the  vena  cava  and  main  lymphatic  trunk.  This  portion  of  the  ad- 
renal is  uncovered  by  peritoneum  and  is  in  contact  with  the  bare  area  of  the 
liver.  Hence  local  lymphatics  are  less  involved,  while  the  extensions  are  to 
the  surface  of  the  liver  (20  to  29  cases) ;  the  pleura  and  lung  (9  to  16  cases  in 
which  the  disease  extended  beyond  the  diaphragm) ;  and  to  the  right  cervical 
nodes  with  right-sided  exophthalmos.  The  tumors  of  the  right  gland  were 

also  more  confined  to  the  abdomen  (12 
cases),  reached  a  larger  size,  and  tended  to 
involve  the  kidneys  by  direct  extension 
into  the  pelvis  (n  cases).  These  rules 
were  followed  by  the  neurocytomas  of 
Kuster  and  Lapointe  and  Lecene. 

(c)  Medullary  Tumors  with  Adrenalin 
Content  and  Nephritic  Symptoms. — In  a 
male  subject  of  47  years,  suffering  from 
active  nephritis  with  glycosuria,  albumi- 
nuria,  cardiac  hypertrophy  and  hyper- 
tension, and  showing  finely  granular 
dark  red  kidneys,  Orth  found  a  medullary 
tumor  of  the  right  adrenal,  7X4!  cm. 
A  watery  filtrate  of  the  tumor  gave  a 
green  color  when  treated  with  ferric 
chlorid,  and  contracted  the  living  frog's 
pupil,  showing  the  presence  of  adrenalin, 
while  an  extract  from  a  secondary  car- 
cinoma in  the  adrenal  failed  to  give  these 
reactions.  Orth  concludes  that  the  car- 
diac hypertrophy  was  referable  to  over- 
production of  adrenalin  by  the  tumor. 

The    structure    of    this    growth    was 
identical   with   many   of   the   round-cell 
sarcomas    occurring    in    children.      The 
small  round  cells   he   regarded   as   fore- 
runners of  the  chromafnn  cells,  while  others  resembled  the  larger  polyhedral 
cells  of  the  normal  medulla.    Vaquez  and  many  others  have  noted  high  arterial 
tension  with  adrenal  tumors  (Ellis,  Lit.). 

(3)  Medullary  Chromaffin  Cell  Tumors. — Nodular  hyperplasia  of  the 
pigmented  cells  is  not  infrequently  observed  in  the  adrenal,  and  appears  in  the 
form  of  small  brownish  tumors  as  large  as  a  pinhead  or  bean  (Schmorl).  Such 
nodules  are  more  common  in  the  cow  (Stilling)  and  a  pigmented  tumor  in 
the  cow's  adrenal  is  described  by  Zanfroginni. 

Definite  pigmented  tumors  of  the  adrenal  medulla  have  been  described 
by  Berdez,  Manasse,  Susuki,  Kawashima,  and  Laignel-Lavastin.  Obser- 
vations on  tumor  growth  of  chromafnn  cells  extend,  however,  over  most  of 
the  territory  known  to  contain  elements  of  the  chromafnn  system. 

Weichselbaum  found  chromafnn  cells  in  a  renal  alveolar  adenoma  which 
may  have  been  derived  from  the  adrenal.  This  observation  is  not  infre- 
quently repeated.  In  a  tumor  of  moderate  size  occupying  the  whole  of  the 
medulla  of  the  adrenal  I  found  very  large  polyhedral  non-pigmented  cells  in 
alveolar  arrangement.  The  tumor  was  evidently  derived  from  the  chro- 
maffin  cells  of  the  medulla.  A  similar  peculiar  structure  appears  in  certain 


FIG.  373. — Medullary  tumor  of 
adrenal. 


TUMORS  OF  THE  ADRENAL 


777 


renal  tumors.  Two  small  pigmented  tumors  penetrating  the  upper  pole  of  the 
renal  cortex  are  mentioned  by  Wiesel  and  Stoerk.  Stangl  found  a  hard 
brownish  tumor  at  the  bifurcation  of  the  aorta,  which  he  derived  from  the 
pigmented  cells  of  Zuckerkandl's  organ.  Monckberg  describes  a  tumor  at  the 
angle  of  the  jaw,  and  another  in  the  left  hyoid  region,  containing  scanty 
pigmented  cells  yielding  chromafrin  reaction,  which  he  derived  from  the  car- 
otid gland.  For  this  entire  group  of  tumors  Alezeis  and  Peyron  propose  the 
name  "paraganglioma." 

The  tumors  in  the  adrenal  have  been  of  relatively  small  size,  usually 
as  large  as  a  walnut,  but  Susuki's  tumor  measured  10  cm.  in  diameter.    They 


FIG.  374. — Structure  of  tumor  of  chromaffin  cells  of  medulla  of  adrenal. 


are  sharply  demarcated  from  the  cortex,  of  which  a  portion  usually  remains 
at  one  segment.  The  substance  is  soft,  cellular,  and  vascular,  with  areas  of 
hemorrhage  and  necrosis.  Manasse  found  the  large  venous  sinuses  invaded, 
but  without  metastases. 

The  structure  presents  small  groups  or  a  diffuse  growth  of  round,  oval, 
spindle-,  or  polygonal  cells  most  of  which  are  small.  Giant-cells  with  single 
or  multiple  nuclei  also  occur.  The  pigment  is  irregular  in  distribution,  but 
gives  the  morphology  and  the  many  special  staining  reactions  devised  for 
chromamn  substance.  Homogeneous  acidophile  cell  inclusions  are  usually 
present.  In  Susuki's  case  some  of  the  larger  cells  approached  the  type  of 
sympathetic  ganglion-cells.  The  stroma  is  composed  chiefly  of  capillaries. 


778  'NEOPLASTIC  DISEASES 

An  interesting  physiological  relation  of  this  tumor  appears  in  several 
cases  which  occurred  in  subjects  of  cutaneous  neurofibromatosis  and  pig- 
mentation of  the  skin  (Susuki,  Kawashima,  Herxheimer). 

Adrenal  Melanoma. — Small  brownish  benign  cortical  tumors  of  the  ad- 
renal are  described  by  Lucksch.  They  occurred  in  adults,  were  composed  of 
cortical  cells  containing  pigment  resembling  melanin,  and  they  seem  to  form 
a  probable  source  of  the  malignant  pigmented  tumors  of  the  adrenal. 

Primary  bilateral  melanotic  malignant  tumors  of  the  adrenal  are  de- 
scribed by  Davidsohn,  Goldzieher,  Tuczek,  and  Maclachlan.  The  tumors 
occurred  in  adults,  were  of  moderate  size,  and  sometimes  produced  extensive 
metastases,  but  primary  sources  in  the  skin  or  choroid  were  missing.  The 
origin  of  these  tumors  it  is  difficult  to  determine.  Not  a  few  of  the  typical 
adrenal  carcinomas  contain  areas  of  pigmented  cells  of  the  adrenal  type. 
Davidsohn  thought  he  recognized  the  structure  of  the  zona  fasciculata  in  a 
mesenteric  metastasis,  claimed  to  have  demonstrated  adrenalin  in  this  tissue, 
and  derived  the  tumor  from  pigmented  adrenal  cortical  cells.  Tuczek 
found  the  pigment  a  true  melanin  and  not  a  lipochrome  as  is  found  in  the 
adrenal  cortex.  He  derived  his  tumor  from  the  pigmented  ganglion-cells 
of  the  medulla,  which  contain  melanin.  Maclachlan  concluded  that  the 
adrenal  melanoma  arises  from  the  wandering  chromatophores  which  are 
said  to  exist  in  the  loose  tissue  about  the  adrenal.  Yet  the  tumors  seem  to 
involve  the  whole  organ,  which  long  preserves  its  form. 


CHAPTER  XXXIX 
TUMORS  OF  PROSTATE 

Hypertrophy  of  Prostate. — In  about  33  per  cent,  of  men  over  60  years  of 
age,  and  occasionally  much  earlier,  but  never  over  70  years,  the  prostate 
becomes  notably  enlarged  (Moullin).  Greene  and  Brooks  believe  that  the 
condition  may  begin  in  youth,  becoming  noticeable  only  in  later  life.  The 
process  probably  begins  in  middle  life  (Gross,  White),  but  very  early  cases, 
collected  by  Belfield,  appear  to  be  of  uncertain  nature  and  probably  neo- 
plastic. 

The  growth  affects  one  or  both  lateral  lobes,  or  the  anatomical  median 
lobe,  or  the  glandular  tissue  surrounding  the  orifice  of  the  urethra,  producing 
growths  of  variable  configuration.  Obstruction  to  the  urethra  is  caused 
especially  by  enlargement  of  the  tissue  about  the  urethra  which,  as  Home 
(1811)  showed,  produces  a  valvular,  polypoid  or  ring-shaped  tumor  at  this 
point  (Home's  lobe).  Lesions  originating  at  this  point  may  spread  to  the 
trigone,  producing  low  or  bulky  intravesical  growths.  The  dimensions  are 
often  considerable,  Gross  reporting  a  prostate  weighing  288  gm.  Tortuosity 
of  urethra,  retention  of  urine,  and  hypertrophy  and  sacculation  of  bladder 
are  frequently  observed,  and  dilatation  of  ureter  and  renal  pelvis  may  result 
from  torsion  of  the  vas  deferens  where  it  crosses  the  ureter  (Tandler,  Zucker- 
kandl).  After  reaching  a  certain  size  most  cases  remain  stationary,  and 
in  these  fibrosis  may  occur.  Or  a  tendency  toward  fibrosis  may  be  prominent 
from  the  beginning. 

The  enlarged  gland  is  hard  or  soft,  depending  on  the  prominence  of  con- 
nective tissue  and  fibrosis  or  of  gland  tissue.  On  section  there  is  diffuse 
smooth  translucent  tissue,  or  nodular  masses  some  of  which  may  shell  out 
of  their  capsule.  Many  dilated  alveoli  may  yield  a  spongy  or  cystic  appear- 
ance. 

The  structure  shows  two  main  types:  (i)  diffuse  growth  of  connective 
tissue  with  islands  or  strands  of  smooth  muscle  and  (2)  glandular  overgrowth. 
Brooks  found  fibrous  overgrowth  the  predominant  process  in  41  of  58  cases. 
The  connective  tissue  is  cellular,  edematous,  infiltrated  with  lymphocytes 
and  large  hydropic  cells,  or  firmer,  fibrous,  or  hyaline.  The  latter  is  often 
a  late  stage  of  the  former.  Atrophic  glands  may  be  included  in  the  new 
tissue.  Rarely  there  is  a  definite  increase  of  smooth  muscle-cells,  usually 
in  foci  resembling  small  myomas.  More  often  the  smooth  muscle  is  atrophic. 
The  true  prostatic  myoma  of  Virchow  should  be  separated  from  prostatic 
hypertrophy.  The  cases  of  hypertrophy  in  which  there  is  pure  overgrowth 
of  smooth  muscle  are  extremely  rare  (Halle,  Albarran,  Ciechanowski). 

The  glandular  overgrowth  yields  normal  prostatic  alveoli,  or  the  cells 
may  be  more  numerous,  appear  in  two  or  three  layers,  or  in  papillary  pro- 
jections into  enlarged  lumina.  Many  areas  are  composed  of  cystic  alveoli 
lined  by  flat  cells  or  partly  filled  by  low  papillary  projections.  Desquamation 
of  lining  cells,  retained  secretion,  concretions,  and  round-cell  infiltration  of 
stroma  are  nearly  constant,  and  while  the  structure  varies  in  different  areas, 
the  whole  picture  indicates  a  chronic  catarrhal  and  productive  inflammation 
with  unusual  epithelial  overgrowth. 

779 


780 


NEOPLASTIC  DISEASES 


Occasionally  the  multiplication  of  small  alveoli  is  extensive,  secretion  is 
missing,  the  stroma  scanty,  the  cells  hypertrophic,  and  the  condition  assumes 
an  adenomatous  character. 

Rarely  the  alveoli  are  filled  with  atypical  large  or  small  hyperchromatic 
cells,  lateral  sacculations  form,  and  the  process  passes  into  carcinoma.  The 
frequency  of  this  change  to  carcinoma  is  at  present  uncertain.  It  has  been 
observed  by  Klebs,  Socin,  Kaufmann,  and  others,  and  Greene  and  Brooks 
find  that  it  occurs  in  5  to  10  per  cent,  of  cases  of  prostatic  hypertrophy.  Halle 
and  Albarran  found  suspicious  changes  which  they  designated  as  adenocarci- 
noma  in  14  of  100  cases,  and  they  note  the  frequency  with  which  elderly 
men,  long  suffering  from  prostatic  hypertrophy,  die  with  symptoms  of  cancer. 
1  have  repeatedly  seen  miniature  carcinomas,  as  judged  by  structure,  in 
portions  of  enlarged  prostates.  The  carcinomatous  change  probably  begins 
rather  early  and  sharply,  if  it  is  to  occur  at  all. 


FIG-  375 


•  r>^V^^*^rF^bL?<SS3*C»2«!^«»!»W^ 

. — Focus  of  atypical  proliferating  alveoli  in  chronic  prostatitis.     Carcinoma  in 
other  portions  of  prostate. 


Etiology. — The  older  authors  looked  for  predisposing  and  exciting  factors, 
in  gout,  syphilis,  horse-back  riding,  alcoholism,  sedentary  habits,  constipation, 
gonorrhea,  strictures,  and  stone. 

Later  histological  studies  led  many  to  conclude  that  prostatic  enlarge- 
ment is  a  tumor  process,  and  chiefly  a  myoma,  occasionally  adenomyoma,  or 
adenoma.  Velpeau  likened  the  tumor  to  myoma  uteri.  Yet  the  prostate 
is  not  the  homologue  of  the  uterus  and  the  histology  and  history  are  not 
those  of  myoma.  Although  Casper  found  19  myomatous  cases  in  24,  later 
interpretations  have  shown  that  true  myomatous  prostates  are  very  rare. 
More  or  less  isolated  or  pedunculated  myomas  arise  in  the  prostate,  but 
the  structure  of  the  new  fibromuscular  tissue  in  ordinary  hypertrophy  is 
that  of  a  simple  overgrowth  and  quite  different  from  that  of  uterine  or  other 
myomas.  Several  features  stand  against  the  neoplastic  theory  for  the 
glandular  hypertrophy.  This  process  begins  diffusely  or  in  multiple  foci, 


TUMORS  OF  PROSTATE  781 

it  is  associated  with  periglandular  fibrosis,  and  the  process  is  self-limited. 
The  structure  is  not  that  of  a  neoplasm,  and  when  true  adenoma  of  the  prostate 
arises  in  the  course  of  hypertrophy  it  presents  a  very  different  structure.  In 
my  material  adenoma  is  rare  in  enlarged  prostates. 

An  inflammatory  origin  has  been  maintained  by  most  recent  observers, 
but  is  firmly  opposed  by  Thompson,  Frische,  and  many  experienced  clinicians. 
Ciechanowski  attributes  the  condition  to  chronic  posterior  urethritis  chiefly 
of  gonorrheal  origin;  and  he  emphasizes  the  constant  presence  of  inflammatory 
lesions.  The  inflammation  begins  in  the  ducts,  and  causes  first  partial  or 
complete  occlusion.  The  retained  secretion  leads  to  enlargement  of  alveoli, 
new  growth  of  epithelium,  perialveolar  fibrosis,  and  hypertrophy  of  muscle- 
fibers.  Exudative  changes  may  be  limited  to  portions  of  the  enlarged  gland, 
while  other  areas  show  chiefly  cellular  overgrowth.  This  distribution  is  not 
inconsistent,  as  some  assume,  with  the  inflammatory  hypothesis.  A  centrally 
located  inflammatory  process  leads  to  hypertrophy  of  glands,  while  a  periph- 
eral localization  tends  toward  glandular  atrophy  and  fibrosis  (Ciechanowski, 
Rothschild).  Greene  and  Brooks  and  Motz  also  find  the  ducts  occluded,  and 
trace  the  progress  of  overgrowth  to  infection  and  retained  excessive  secretion. 
My  own  material  all  indicates  the  presence  of  an  inflammatory  element,  but 
it  is  not  clear  that  the  inflammation  is  always  primary.  In  this  respect  the 
inflammatory  theory  is  distinctly  in  need  of  further  support.  That  all  cases 
are  not  gonorrheal  is  shown  by  Keyes,  who  in  433  cases  of  hypertrophy  found 
only  1 8  giving  a  history  of  previous  prostatitis.  Yet  he  places  the  proportion 
of  males  who  have  had  gonorrhea  as  high  as  80  per  cent.  While  the  histology 
of  the  process  may  perhaps  be  satisfactorily  explained  as  a  result  of  productive 
inflammation  in  a  peculiar  organ  yet  the  clinical  data  cannot  be  so  readily 
dismissed. 

Launois  and  Guyon  find  that  all  prostates  of  elderly  men  show  periacinar 
fibrosis,  hypertrophy  and  diminution  in  number  of  muscle-fibers,  disorder  of 
gland  tissue,  and  arteriosclerosis.  Hypertrophy  or  atrophy  may  follow.  In 
line  with  this  theory  stand  the  speculations  regarding  a  functional  disturbance 
in  the  gland.  Furbringer  suggests  that  the  marked  overgrowth  is  a  com- 
pensatory process  following  senile  insufficiency,  and  Rovsing  assumes  that 
there  may  be  increased  rather  than  senile  failure  of  functional  capacity. 
There  appears  to  be  a  relation  to  testicular  function,  but  its  details  are  not 
clear.  White.  Moullin,  and  others  find  that  prostatic  hypertrophy  recedes 
after  castration,  but  this  event  has  been  too  exceptional  to  establish  this 
method  of  surgical  treatment  (Keyes).  There  does  not  appear  to  be  any 
complete  parallel  inflammatory  condition  in  other  glands,  but  in  the  thyroid 
a  very  similar  process  results  from  functional  disturbance,  and  involution  of 
the  breast  approaches  in  some  cases  the  type  of  prostatic  hypertrophy.  Con- 
siderable importance  attaches  to  these  various  hypotheses,  since  somewhere 
in  this  field  must  be  found  the  key  to  the  unusual  glandular  overgrowth  which 
often  exceeds  the  limits  of  productive  inflammation.  It  may  become  possible 
to  divide  the  cases  into  inflammatory  and  true  hypertrophic  forms,  as  sug- 
gested by  Young  and  Geraghty,  but  at  present  it  seems  necessary  to  assume 
that  the  condition  results  from  a  combination  of  both  factors. 

Carcinoma  of  Prostate. — Until  recently  carcinoma  of  the  prostate  was  held 
to  be  a  rare  disease,  forming  0.27  per  cent,  of  the  carcinomas  in  men,  accord- 
ing to  Gurlt,  or  0.418  per  cent,  in  Heimann's  series.  Probably  through  more 
careful  examination  of  apparently  simple  hypertrophies  of  the  gland  and  more 
accurate  diagnosis,  carcinoma  of  the  prostate  now  appears  more  frequently. 
Engelbach,  1888,  collected  114  reported  cases  of  malignant  tumors.  E. 
Kaufmann  personally  observed  22,  Wolff  collected  reports  of  89  carcinomas 


782 


NEOPLASTIC  DISEASES 


and  22  sarcomas.    Since  there  is  some  uncertainty  in  the  diagnosis  of  both 
these  tumors,  present  statistical  data  are  still  open  to  revision. 

Etiology. — The  chief  condition  predisposing  to  prostatic  cancer  is  chronic 
hypertrophy.  Notable  examples  of  the  transformation  of  simple  hypertro- 
phy into  carcinoma  are  recorded  by  many  observers.  The  evidence  in  these 
cases  usually  consists  .in  a  long  history  of  hypertrophy  in  cases  presenting 
as  carcinoma,  and  about  10  per  cent,  of  prostatic  cancers  give  such  a  history 
(Wolff,  Kaufmann).  Likewise  the  careful  study  of  enlarged  prostates  reveals 
early  cancerous  changes  in  about  19  per  cent.  (Albarran,  Halle,  Greene,  Brooks). 
From  these  data  one  may  safely  conclude  that  early  or  suspicious  cancerous 
changes  in  the  prostate  are  much  more  frequent  than  is  the  established  disease. 


>•       O>     »    */.       •      >        •,   ••*"*V,        *      ,    .        •     AJLf^     I      •"      S*  ft  '*,    *%    I  *  ,'          .      . 

S^^P-;Wr  |!|1'| 

^ 


<-:-3t..  -   'r '     , .    tx»v<yw.  s:^sr. 

,rrr-  .-  -.x,^'--"  - 


FIG.  376. — Adenocarcinoma  of  prostate. 

A  satisfactory  elimination  of  previous  hypertrophy  has  not  commonly  been 
attempted,  so  that  the  relation  of  the  two  processes  still  remains  to  be  deter- 
mined. 

The  chief  age  of  incidence,  like  that  of  hypertrophy,  is  the  seventh  decade, 
when  68  per  cent,  of  the  cases  occur,  but  the  disease  has  been  observed  be- 
tween 40  and  50  years.  Wolff  collected  6  cases  under  40  years,  at  least  one  of 
which  (Billroth's)  was  probably  true  glandular  carcinoma  in  a  subject  of  30 
years.  A  rapid  carcinoma  with  regional  metastases  in  a  youth  of  17  years  is 
reported  by  Gardiner  and  Cummins. 

An  influence  of  heredity  is  not  apparent,  and  the  antecedent  personal 
history  is  usually  declared  negative.  Wolff  saw  carcinoma  develop  after 
incomplete  removal  of  an  enlarged  prostate.  The  susceptibility  of  workers 


TUMORS  OF  PROSTATE  783 

in  anilin  products  to  bladder  tumors  does  not  appear  to  extend  to  the  pros- 
tate, but  Kaufmann's  case  of  "lymphosarcoma"  occurred  in  an  anilin  worker. 

Gross  Anatomy. — In  the  early  stages  carcinoma  may  appear  in  simple  or 
multiple  foci  of  firm  opaque  texture,  in  a  hypertrophied  organ.  Usually 
the  whole  organ  is  enlarged,  hard,  and  fixed,  but  one  lobe  is  frequently  the 
chief  or  sole  seat  of  the  disease,  while  the  pars  intermedia  only  was  affected 
in  the  cases  of  Billroth  and  Tyson.  The  disease  may  also  arise  in  the  glands 
of  the  prostatic  urethra.  To  what  extent  the  seminal  vesicles  are  the  primary 
seat  of  carcinoma  involving  the  prostate  is  uncertain.  Berger,  Fenwick,  and 
Walter  describe  carcinomas  which  appeared  to  originate  in  the  vesicles,  but 
the  exact  source  of  these  tumors  is  questionable.  Guelliot's  case  of  vesicle 
cancer  in  a  man  of  50  years  failed  to  involve  the  prostate  or  bladder.  Kauf- 
mann's tumor  in  a  man  of  87  years  diffusely  invaded  the  prostate,  but  a  larger 
mass  involved  both  vesicles.  Arising  in  an  atrophic  gland  the  prostate  may 
remain  small  while  metastases  become  general  (Jolly,  v.  Recklinghausen,  Hebb). 
A  markedly  indurated  prostate  in  a  man  over  50  years  of  age  producing  urinary 
retention  is  highly  suspicious  of  carcinoma,  especially  if  it  is  very  hard  and  not 
very  large.  When  with  the  indurated  prostate  there  is  induration  along  the 
seminal  vesicles  with  pain  and  hematuria  the  presence  of  carcinoma  is  prac- 
tically certain  (Young). 

The  capsule  resists  invasion,  but  is  commonly  penetrated  first  along  the 
seminal  vesicles.  Per  rectum  the  enlarged  gland  usually  presents  a  hard 
nodular  surface,  and  extensions  to  neighboring  structures  and  lymph-nodes 
with  fixation  of  the  organ  may  be  detected.  In  advanced  cases  a  bulky  tumor 
fills  the  pelvis,  fuses  the  organ  with  neighboring  tissues,  or  invades  bladder, 
rectum,  and  lymph-nodes. 

The  bladder  is  invaded  in  57  per  cent,  of  cases  (Kaufmann).  Frequently 
the  invasion  passes  through  the  lymphatics,  producing  multiple  or  confluent 
submucous  nodules  or  diffuse  infiltration  in  the  fundus  (32  per  cent.).  Direct 
invasion  through  the  trigone,  simulating  primary  vesical  cancer,  is  also  com- 
mon. Belfield  has  described  a  bulky  tumor  filling  the  bladder.  In  late  stages 
the  secondary  vesical  tumors  may  ulcerate  with  hemorrhage,  or  perforate  the 
wall,  producing  peritonitis  (Tyson,  Engelhardt)  or  a  rectovesical  fistula. 
The  bladder  may  become  hypertrophied  and  sacculated.  The  ureters  are 
invaded  from  the  vesical  wall  as  in  bladder  carcinoma,  or  occluded  by  nodules 
at  the  orifices,  or  compressed  by  enlarged  lymph-nodes. 

The  seminal  vesicles  are  early  invaded  on  one  or  both  sides  and  may  be 
obliterated.  Rarely  the  urethra  is  involved  by  submucous  infiltration  usually 
by  way  of  the  lymphatic  connection  with  the  seminal  vesicles,  and  the  growth 
may  extend  well  along  the  urethra  and  into  the  corpora  cavernosa  (Tailhelfer, 
Kaufmann). 

Diffuse  prostatopelvic  carcinoma  (Guyon)  results  from  diffuse  invasion 
which  binds  prostate,  seminal  vesicles,  bladder,  and  rectum  in  a  firm  mass 
to  the  pelvic  bones.  Here  the  chief  symptom  may  be  obstipation.  Frisch 
observed  perforation  of  the  obturator  foramen  and  a  large  perineal  tumor. 

Lymphatic  Extensions. — According  to  Sappey,  the  prostate  is  very  richly 
supplied  with  lymphatics.  They  arise  in  the  glandular  lobules  and  pass 
chiefly  backward  and  anastomose  with  the  rectal  vessels.  Two  main  trunks 
on  each  side  drain  the  peripheral  plexus,  the  inferior  trunk  passing  outward 
to  a  lymph-node  lying  on  the  lateral  wall  of  the  true  pelvis.  The  superior 
vessels  pass  upward  along  the  wall  of  the  bladder,  communicating  with  lym- 
phatics in  the  muscle  tissue  and  leading  to  a  chain  of  nodes  on  the  external 
iliac  vessels.  There  are  rich  connections  between  the  vessels  of  prostate 
and  seminal  vesicles.  The  vesical  mucosa  is  very  poor  in  lymphatics,  but 


784  NEOPLASTIC  DISEASES 

in  the  trigone  small  vessels  may  be  infected  from  the  peri-urethral  tissues 
which,  in  turn,  communicate  with  those  of  the  seminal  vesicles.  From  these 
relations  it  appears  that  urethral  invasion  must  be  by  retrograde  transport, 
that  invasion  of  seminal  vesicles  is  early,  that  secondary  growths  readily 
form  in  the  pelvis,  while  metastases  in  the  fundus  of  the  bladder  do  not  early 
reach  the  mucosa  or  ulcerate. 

The  extent  of  lymphatic  invasion  in  prostatic  carcinoma  varies  extremely, 
but  is  less  than  with  many  carcinomas.  As  a  rule  only  the  regional  nodes 
are  involved,  especially  those  of  the  true  pelvis  in  close  relation  to  the  seminal 
vesicles.  The  frequency  of  invasion  of  the  inguinal  nodes  (16  per  cent.)  must 
be  referred  to  lymphatic  connections  with  the  seminal  vesicles,  pelvis,  and 
urethra,  and  retrograde  transport  seems  to  occur  in  these  cases  (Courvoisier). 
From  the  true  pelvis  extensions  are  along  the  great  vessels,  iliac,  lumbar, 
vena  cava,  to  mesenteric  and  retroperitoneal  nodes,  liver,  and  kidneys.  Further 
extensions  to  the  thoracic  and  cervical  nodes  are  not  infrequently  observed. 
The  supraclavicular  nodes  may  be  involved  (6  per  cent.)  with  or  without 
invasion  of  other  cervical  chains,  and  with  freedom  of  the  thoracic  duct 
(Carlier).  Very  general  lymphatic  invasion  is  described  by  Baumgarten,  and 
extensive  visceral  metastases  by  Kaufmann.  The  organs  involved  in  22  cases 
were:  liver  10,  kidneys  3,  adrenals  3,  pancreas  3,  peritoneum  4,  lungs  9,  pleura 
12,  dura  5,  brain,  heart,  thyroid,  spleen  i  in  each. 

Skeletal  metastases  of  markedly  osteoplastic  character  occur  in  a  notable 
group  of  prostatic  carcinomas  (Silcock,  Thompson,  Recklinghausen,  Cour- 
voisier). Similar  osteoplastic  processes  are  observed,  especially  with  mam- 
mary carcinoma,  and  with  tumors  of  stomach,  gall-bladder,  thyroid,  etc., 
but  the  early  and  frequent  occurrence  and  extensive  distribution  belong 
chiefly  to  the  prostatic  disease.  Kaufmann  calculated  that  about  70  per  cent, 
of  prostatic  carcinomas  cause  skeletal  metastases,  as  compared  with  37  per 
cent,  for  thyroid  carcinoma  (Limacher)  and  14  per  cent,  for  mammary  cancer. 
Of  1 6  cases  with  skeletal  metastases,  Kaufmann  found  more  or  less  osteoplastic 
tendency  in  14,  and  from  the  literature  he  collected  20  cases  with  extensive 
growth  of  bone. 

In  these  cases  the  prostate  may  be  relatively  small  and  fibrous,  the  local 
extension  moderate,  the  organs  free,  while  the  bones  are  the  seat  of  wide- 
spread osteoplastic  carcinoma.  Under  these  circumstances  the  prostatic 
tumor  may  be  overlooked.  More  often  the  pelvis  contains  a  bulky  tumor 
involving  prostate,  vesicles,  and  bladder,  and  the  viscera  are  also  invaded. 
The  spinal  column,  pelvis,  long  bones,  skull,  ribs  and  sternum,  scapula,  and 
clavicle  have  been  affected  with  extensive  thickenings,  deformities,  excava- 
tions, and  fractures.  The  new  bone  may  be  diffuse,  obliterating  the  shafts 
and  marrow  cavity,  or  perisoteal  and  stalactite,  and  the  structure  is  spongy 
or  eburnated.  The  osteoplastic  process  predominates  over  the  osteoclastic, 
but.  both  may  be  equally  prominent.  Severe  anemia  may  result  from  destruc- 
tion of  bone-marrow  (Schmorl,  Braun). 

The  histological  process  is  described  by  Recklinghausen  as  carcinomatous 
osteitis.  The  tumor-cells  lodge  in  the  small  venous  sinuses,  cause  stasis 
and  hemorrhage,  which  is  followed  by  reactive  growth  of  fibrillated,  osteoid, 
and  finally  osseous  tissue.  The  tumor-cells  become  inclosed  in  the  bone, 
assuming  the  function  of  osteoblasts,  and  bony  tissue  may  be  most  abundant 
in  very  cellular  areas  of  tumor-cells  where  connective  tissue  is  wanting  (Wolff, 
Braun,  Sasse).  Participation  of  connective- tissue  osteoblasts  is  also  observed 
(Erbsloh).  Extensive  resorption  of  the  new  bone  by  osteoclasts  may  follow 
the  plastic  process.  Schmorl  refers  to  a  similar  lesion  in  the  lungs  as  metastatic 
osteosarcoma. 


TUMORS  OF  PROSTATE  785 

Axhausen  attributes  the  osteoplastic  process  entirely  to  the  chemical 
influence  of  the  carcinoma  cells.  The  transformation  of  epithelial  tumor- 
cells  into  bone-cells,  accepted  by  Wolff  and  Kaufmann,  he  did  not  observe. 
There  is  little  actual  new  growth,  but  chiefly  an  absorption  and  redeposit 
of  the  old.  Cyanotic  hyperemia  (Recklinghausen),  inflammatory  changes 
in  the  marrow  (Lenziger,  Kaufmann),  and  primary  bone  necrosis  (Askanazy) 
he  finds  of  secondary  importance.  Lacunar  resorption  by  osteoclasts  fur- 
nished by  the  connective  tissue  is  the  chief  factor  in  the  absorption  process, 
and  the  new  bone  forms  in  the  connective  tissue  both  by  a  metaplastic  and  a 
neoplastic  process. 

The  course  of  prostatic  carcinoma  varies  from  that  of  rapid  cases  occurring 
chiefly  in  middle  life  and  terminating  within  a  few  months,  to  the  more  pro- 
longed cases,  which  extend  over  3  years  or  more.  Wolff  in  46  cases  found 


FIG.  377. — Carcinoma  of  prostate,  involving  one-half  of  the  prostate,  without  much 
enlargement,  but  giving  distant  metastases. 

39  per  cent,  lasting  less  than  i  year,  28  per  cent,  i  to  2  years,  8.7  per  cent. 
2\  years,  24  per  cent.  3  years  or  more. 

Sarcoma  is  much  more  rapid  and  has  usually  proved  fatal  within  6  months, 
but  firm  spindle-cell  sarcomas  may  continue  as  long  as  2  years.  Lympho- 
sarcoma  is  usually  of  very  short  duration. 

The  clinical  course  of  prostatic  carcinoma  is  very  notably  dependent  on 
the  structural  type  of  the  tumor,  so  that  different  forms  appear  as  radically 
different  diseases. 

(1)  Adenoma  or  adenocarcinoma  arising  on  chronic  prostatitis  may  give 
the  symptoms  of  chronic  hypertrophy  and  the  carcinoma  be  discovered  only 
in  the  extirpated  gland. 

(2)  Adenocarcinoma,  usually  arising  on  hypertrophy,  may  give  a  large, 
hard,  nodular  prostate,  which  exists  for  many  months  before  involving  lymph- 

50 


786 


NEOPLASTIC  DISEASES 


nodes.  Eventually  it  produces  local  extensions,  and  finally  it  generalizes. 
It  is  often  extirpated,  and  regularly  recurs. 

(3)  Fully  developed  carcinoma,  alveolar  or  diffuse,  may  fail  to  cause 
much  enlargement  of  the  gland,  prostatic  symptoms  are  moderate,  and  the 
disease  is  overlooked,  or  the  metastatic  tumors  are  regarded  as  primary, 
or  the  condition  is  discovered  at  autopsy. 

Structure. — Malignant  epithelial  tumors  of  the  prostate  appear  in  three 
structural  types — adenoma,  adenocarcinoma,  and  carcinoma. 

(i)  Adenoma. — A  pure  adenoma  of  the  prostate  is  rare.  Diffuse  cir- 
cumscribed areas  of  adenomatoid  overgrowth  occur  in  many  cases  of  chronic- 
ally enlarged  prostate,  and  at  times  this  process  becomes  more  pronounced 


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FIG.  378. — True  adenoma  in  an  enlarged 
prostate. 


FIG.    379.  —  Malignant    adenocar- 
cinoma of  prostate. 


and  assumes  the  characters  of  adenoma.  Yet  such  areas  usually  form  only 
a  small  portion  of  the  enlarged  prostate  and  grade  off  into  inflammatory 
overgrowth.  When  a  true  adenoma  develops  in  the  prostate  it  appears  always 
to  be  locally  aggressive,  and  in  this  respect  is  malignant.  More  often  it  passes 
freely  into  adenocarcinoma  or  carcinoma. 

I  have  examined  i  case  in  which  the  tumor  exhibited  throughout  a  rather 
uniform  structure  of  malignant  adenoma.  It  formed  a  partly  "circumscribed 
mass,  3  cm.  in  diameter,  lying  in  a  prostate  successfully  removed  for  chronic 
hypertrophy.  The  lymph-nodes  were  free.  The  structure  presented  com- 
pact groups  of  small  alveoli  lined  by  high  cuboidal  clear  epithelium  with 
hyperchromatic  nuclei.  The  stroma  was  reduced  to  a  trace.  In  some  foci 
the  outlines  of  the  alveoli  were  indistinct,  the  cells  more  atypical,  and  the 


TUMORS  OF  PROSTATE 


787 


growth  almost  diffuse.  The  tumor  capsule  was  infiltrated  with  small  groups 
of  cells  without  definite  lumen.  The  remaining  portions  of  the  prostate 
showed  the  changes  of  interstitial  and  glandular  hypertrophy.  A  somewhat 
similar  case  is  described  by  Ciechanowski  as  adenoma  malignum,  and  this 
term  seems  properly  applicable  to  the  condition. 

(2)  Adenocarcinoma  is  the  structure  assumed  by  many  malignant  tumors, 
but  it  rarely  occurs  in  pure  form,  passing  readily  into  alveolar  carcinoma. 
Kaufmann  found  no  exception  to  this  rule  and  my  own  material  is  of  the 
same  character.  Not  infrequently  one  finds  large  alveoli  of  typical  adeno- 
carcinoma  scattered  in  wide  fields  of  diffuse  or  small  alveola*  carcinoma  and 


FIG.  380. — An  area  of  adenocarcinoma  in  a  chronically  enlarged  prostate. 

it  is  evident  that  the  latter  represents  a  more  rapidly  growing  derivative 
of  the  former  structure,  of  which  transitions  may  often  be  clearly  traced. 

The  typical  adenocarcinoma  presents  large  spaces  filled  with  masses  of 
somewhat  atypical  cells  forming  numerous  secondary  alveoli.  The  size  of 
these  cells  varies  from  large,  clear  prostatic  epithelium,  to  small  granular 
acidophile  cells,  and  the  carcinomas  derived  from  them  present  corresponding 
variations.  The  simplest  form  of  adenocarcinoma  is  the  structure  usually 
observed  in  the  suspicious  or  precancerous  areas  of  chronic  hypertrophy, 
but  compact  groups  of  small  alveoli,  as  in  malignant  adenoma,  also  occur  in 
these  cases,  and  occasionally  multiple  layers  of  atypical  cells  completely 
fill  the  alveolus  and  the  structure  passes  directly  into  solid  carcinoma.  Con- 


788  NEOPLASTIC  DISEASES 

siderable  difficulty  may  be  met  in  interpreting  single  fields  presenting  these 
various  structures,  but  as  a  rule  the  usual  signs  of  malignancy,  as  atypical  cell 
form  and  excessive  multiplication  of  alveoli,  leave  no  doubt  as  to  the  nature 
and  tendencies  of  the  process. 

Pure  adenocarcinoma  is  doubtless  not  so  active  and  aggressive  as  alveolar 
carcinoma  and  its  presence  probably  signifies  that  a  preliminary  period  of 
relatively  slow  growth  has  preceded  the  more  malignant  carcinoma  with 
which  it  is  usually  associated.  The  change  to  carcinoma  is  so  nearly  con- 
stant that  the  later  course  of  the  disease  is  practically  identical  in  the  two 
conditions.  Adenocarcinomatous  structures  are  rarely  observed  in  extensions 
and  metastases. 

(3)  Carcinoma  of  the  prostate  presents  many  variations  in  structure. 
A  pseudo-alveolar  type  is  assumed  when  very  numerous  small  groups  of 
cells,  inclosing  a  definite  lumen,  are  closely  packed  together  and  infiltrate 
stroma,  gland,  capsule,  and  nodes.  This  is  really  a  more  malignant  form  of 
adenocarcinoma.  Usually  the  cells  grow  loosely,  forming  small  groups  or 
large  masses,  or  diffuse  infiltrations,  in  which  case  the  growth  is  indistinguish- 
able from  carcinomas  from  other  sources.  When  the  cells  are  small  and 
cytoplasm  scanty  the  structure  closely  resembles  round-cell  sarcoma  and  it  is 
probable  that  some  reported  cases  of  prostatic  sarcoma  are  of  epithelial  origin. 
In  McKenzie's  case,  observed  in  this  laboratory,  the  general  structure  was 
identical  with  that  of  lymphosarcoma,  and  it  was  only  after  repeated  and  very 
careful  search  in  various  sections  that  the  clear  evidence  of  its  carcinomatous 
nature  was  obtained. 

Hydropic  swelling,  formation  of  giant-cells,  collections  of  colloid  material, 
inclusion  of  fatty  crystals,  and  round-cell  infiltration  of  stroma  are  commonly 
observed,  but  it  is  noteworthy  that  extensive  necrosis  of  prostatic  carcinoma 
is  very  rare.  Schlagenhaufer  finds  much  doubly  refractive  lipoid  material 
(cholesterin  esters)  in  the  cells  of  prostatic  carcinoma,  which  he  interprets 
as  a  sign  of  exaggerated  functional  activity  of  these  cells. 

Scirrhous  carcinoma  is  observed  in  rare  cases  in  which  the  prostate  remains 
small  and  hard,  as  well  as  in  foci  of  cellular  tumors  (Thompson,  Barton, 
Matthias,  Berger,  Kaufmann).  Boyd  designated  a  case  as  colloid  scirrhus. 

Squamous  Epithelioma. — In  the  upper  anterior  portions  of  the  fetal  pros- 
tate the  ducts  are  lined  by  squamous  epithelium  up  to  the  third  month  of 
life  or  later  (Aschoff,  Schlachta).  In  chronic  supprative  prostatitis  Schmidt 
finds  extensive  squamous  epithelial  metaplasia  and  in  a  prostate  from  a  man 
°f  53  years  he  described  beginning  acanthoma.  Klebs  and  Marchand  de- 
scribe acanthoma  of  the  prostatic  urethra,  and  acanthoma  of  the  prostate 
is  reported  by  Beyer  and  Buchal. 

Sarcoma  of  the  Prostate. — Sarcoma  rarely  occurs  in  the  prostate  and 
many  of  the  reported  cases  are  of  uncertain  nature.  Kaufmann  collected 
only  24  authentic  cases,  but  discards  many  others  for  lack  of  microscopical 
report.  Three  occurred  in  infants  under  i  year,  seven  others  in  the  first  decade, 
and  only  seven  from  30  to  73  years. 

The  only  well-defined  variety  of  prostatic  sarcoma  is  the  rhabdomyo- 
sarcoma,  which  is  also  a  probable  source  for  any  genuine  mesoblastic  round- 
cell  tumor  that  may  exist.  Few  of  the  older  reports  of  sarcoma  are  of  any 
value  for  critical  analysis.  While  true  spindle-  and  round-cell  tumors  prob- 
ably arise  from  mesoblastic  elements  in  children,  it  is  highly  probable  that 
most  of  the  cases  reported  as  such,  especially  in  adults,  are  diffuse  carcinomas. 

Round-cell  sarcoma  is  the  most  frequent  and  the  least  definite  form  and 
no  uniform  description  will  apply  to  it.  Socin  describes  a  bulky  tumor  be- 
tween bladder  and  rectum  in  an  infant  of  8  months,  which  was  soft,  vas- 


TUMORS  OF  PROSTATE  789 

cular,  cystic,  and  composed  of  diffuse  small  round  and  polyhedral  cells  with- 
out uniform  stroma. 

Kaufmann's  case  was  a  large  myxomatous  round-cell  sarcoma  in  a  child 
of  15  years.  In  adults,  18,  21,  and  35  years,  round-cell  sarcomas  are  reported 
by  Oliva,  West,  and  Hughes.  These  tumors  are  difficult  to  distinguish  from 
lymphosarcoma  and  from  rapid  atypical  carcinoma.  Thus  Graetzer  and 
Dupraz  found  an  alveolar  structure  closely  resembling  carcinoma.  Dupraz's 
tumor  occurred  in  a  man  of  73  years,  and  gave  osteoplastic  metastases.  Kap- 
sammer  reports  as  lymphosarcoma  a  very  rapidly  growing  tumor  arising  from 
an  old  stricture  of  the  bulbous  urethra  and  invad'ing  the  urethra.  He  refers  to 
2  other  cases  of  round-cell  prostatic  tumors,  in  which  an  origin  from  Cowper's 
glands  was  suggested. 

Lymphosarcoma  in  adults  is  described  by  Coupland,  Kaufmann,  and 
others.  In  Kaufmann's  case  in  an  anilin  worker  the  prostate  was  much  en- 
larged, fused  with  seminal  vesicles,  tumor  folds  projected  into  bladder,  regional 
nodes  with  one  exception  free,  while  visceral  metastases  were  wide-spread,  and 
the  cervical  lymph-nodes  were  involved. 

The  existence  of  a  true  lymphosarcoma  of  the  prostate  is  not  satisfactorily 
proved.  The  structure  of  the  gland  does  not  favor  the  occurrence  of  such 
tumors.  One  of  the  cases  most  fully  described  is  Kaufmann's,  but  there  was 
nothing  in  the  gross  anatomy  of  this  case  to  distinguish  it  from  ordinary 
diffuse  carcinoma  and  the  metastases  were  exactly  as  one  would  expect  in 
carcinoma,  the  regional  nodes  being  practically  free.  The  structural  de- 
tails were  inconclusive.  In  Lefmann's  case  the  cutaneous  metastases  suggest 
sarcoma,  but  the  lymph-nodes  were  only  slightly  involved  by  very  numerous 
metastases.  Since  studying  McKenzie's  case  of  pseudolymphosarcoma  I 
have  come  to  doubt  the  existence  of  lymphosarcoma  of  the  prostate. 

Rhabdomyosarcoma  occurred  in  3  cases  described  by  Kaufmann,  2 
in  infants,  i  in  an  adult  of  26  years.  The  tumor  grew  rapidly  to  large 
dimensions.  In  the  adult  there  were  invasion  of  prostatic  veins  and  wide- 
spread metastases,  especially  in  the  bones,  with  pernicious  anemia. 

The  tissue  was  chiefly  composed  of  spindle-cells  and  resembled  ordinary 
cellular  spindle-cell  sarcoma  with  myxomatous  tendencies.  Round-cells  also 
were  abundant.  The  specific  elements  consisted  in  fusiform,  round,  and 
tubular  structures,  presenting  various  stages  of  differentiation  of  striated 
muscle-fibers  from  which  all  the  tumor  elements  were  derived.  It  is  obvious 
that  the  distinction  between  simple  spindle-cell  sarcoma  and  myosarcoma 
may  be  difficult.  Veil's  spindle-cell  tumor,  with  large  polymorphous  cells  and 
growth  into  gland  tubules,  strongly  recalls  the  myosarcomas.  Of  the  nature 
of  the  embryogenic  disturbance  which  gave  origin  to  these  tumors  there  are  no 
indications. 

Spindle-cell  sarcoma  occurs  chiefly  in  children  and  produces  a  bulky  tumor 
destroying  the  prostate  and  compressing  adjoining  organs.  Tordens  de- 
scribed a  tumor  as  large  as  the  child's  head,  arising  from  the  left  lobe,  reach- 
ing the  navel,  of  myxomatous  character  and  partly  cystic.  Other  soft  sar- 
comas were  also  myxomatous,  while  the  firm  tumors  are  free  from  this  ele- 
ment (Isambert,  Marsh,  Wind).  An  angiosarcomatous  structure  occurred 
in  Matthias'  case.  A  rapidly  growing  tumor  in  a  child  of  2  years,  composed 
of  adenoma  and  sarcoma,  is  mentioned  by  Birch-Hirschfeld.  That  the  spindle- 
cell  sarcomas  arise  from  the  prostatic  stroma  is  strongly  indicated  by  their 
structure. 

The  seminal  vesicles  were  the  primary  seat  of  a  round-  and  spindle-cell 
sarcoma,  with  metastases  in  mesentery,  kidney,  and  heart  muscle,  described 
by  Zahn. 


CHAPTER  XL 
TUMORS  OF  TESTIS 

In  the  testis  more  notably  than  in  any  other  organ  it  is  possible  to  main- 
tain a  single  embryogenic  origin  of  the  great  majo'rity  of  tumors.  It  appears 
that  all  the  common  and  nearly  all  the  rarer  tumors  of  this  organ  arise  from 
totipotent  sex-cells,  and  that  the  monodermal  forms  of  these  growths  repre- 
sent one-sided  developments  of  tridermal  teratomas.  Very  rarely  the  stroma, 
duct-cells,  interstitial  cells,  and  adult  seminiferous  tubules  give  origin  to 
characteristic  growths.  Whether  any  of  the  malignant  epithelial  tumors  may 
originate  from  fully  differentiated  cells  of  rete,  epididymis,  or  testis  it  remains 
for  future  observations  to  determine.  It  is,  therefore,  of  advantage  to  discuss 
testicular  tumors  from  the  point  of  view  of  their  teratomatous  origin  and  to 
trace  their  derivatives  as  far  as  may  be  possible.  Later  it  may  be  necessary 
to  reduce  the  scope  of  these  teratomatous  derivatives. 

TERATOMA  TESTIS  AND  ITS  DERIVATIVES 

Historical. — In  1696  Saint  Donat  identified  a  rudimentary  skull  and  pigmented  optic 
cups  in  a  testicular  tumor  and  thus  established  the  fetal  character  of  some  of  these 
growths.  In  1803  Prochaska  found  fetal  limbs,  and  in  1833  Andre  de  Perrone  observed 
hair,  teeth,  and  bones  in  testicular  tumors.  The  tridermal  composition  was  first  pointed 
out  by  Johnson,  who  distinguished  ectodermal  cysts  lined  by  squamous  cells,  entoderm 
with  columnar  ciliated  cells  and  mesodermal  tissues.  Numerous  later  observations  have 
furnished  a  nearly  complete  series  of  fetal  organ  rudiments  which  may  be  encountered 
(Ohkubo,  Lit.).  Astley  Cooper  (1845)  described  the  cystic  tumors  under  the  term  "hy- 
datid  disease,"  and  Curling  divided  the  growths  into  benign  cystic  and  malignant  solid 
types.  With  the  aid  of  the  microscope  he  detected  that  cancer  regularly  begins  in  the 
rete.  Langhans'  work  with  Kocher  marked  a  distinct  epoch,  since  with  the  aid  of  micro- 
scopical sections  he  was  able  to  classify  the  tumors  on  structure.  He  classed  many  of 
the  apparently  simple  tumors  with  teratoma,  recognized  the  carcinomatous  nature  of 
the  "alveolar  sarcomas,"  and  suspected  that  a  large  proportion  of  all  tumors  of  the 
testis  were  of  teratoid  origin.  Wilms  advanced  this  work,  showing  that  all  the  complex 
tumors  are  tridermal,  and  dividing  them  into  adult  cystic  embryomas  and  more  solid 
embryoid  teratomas.  Later  Wilms,  Ribbert,  Pick,  Ohkubo,  and  Chevassu  showed 
that  one  element  of  the  teratoma  may  overgrow  the  others,  producing  simple  growths, 
and  that  many  tumors  called  adenoma,  sarcoma,  carcinoma,  chondroma,  myxoma,  etc., 
contain  scanty  traces  of  all  three  germ  layers  and  are  teratomas.  The  writer's  study 
led  to  the  conclusion  that  all  the  common  tumors  of  the  testis  are  of  teratomatous  nature, 
while  pure  adenoma,  fibroma,  myoma,  and  sarcoma  are  rare. 

Varieties  of  Teratoma  Testis. — Three  main  varieties  of  the  tumor  occur: 

(1)  Adult  embryomas  or  teratomas. 

(2)  Embryoid.  teratoid,  or  mixed  tumors. 

(3)  Embryonal  malignant  tumors. 

Numerous  intermediate  cases  connect  these  types;  the  same  tumor  may 
present  several  structures;  and  some  peculiar  forms  call  for  special  description. 
Indeed,  the  variations  in  structure  and  course  of  these  neoplasms  are  so  numer- 
ous and  definite  as  to  require  their  description  as  distinct  clinical  and  patho- 
logical conditions,  connected  only  by  a  single  etiological  factor. 

(i)  Adult  and  complex  embryomas  constitute  a  relatively  small  group, 
characterized  by  the  presence  of  definite  rudimentary  organs  which  may  be  so 
arranged  as  to  resemble  a  parasitic  fetus. 

790 


TUMORS  OF  TESTIS 


791 


The  typical  testicular  dermoid  is  a  sharply  circumscribed  tumor  lying 
within  the  tunica,  separated  from  the  testicular  tissue  by  a  capsule  and  fused 
with  the  rete.  On  section  the  growth  presents  a  large  cyst  containing  hair 
and  sebaceous  material  and  lined  by  epidermis.  A  protuberance  containing 
the  main  body  of  the  embryo  projects  into  or  fills  the  cyst,  and  itself  exhibits 
numerous  small  cysts  and  the  various  organ  rudiments.  The  tumor  is  thus 
encysted  by  a  continuous  layer  of  epidermis  which  covers  the  embryo  as  well 
as  the  inner  surface  of  the  capsule. 

In  other  cases  the  embryo  is  fused  with  the  capsule  and  the  dermal  tissues 
appear  in  the  form  of  solid  portions,  while  multiple  cysts  occur  at  different 
points  of  the  tumor. 

Microscopical  study  reveals  an  extensive  series  of  organ  rudiments  belong- 
ing chiefly  to  the  cephalic  extremity.  The  cutaneous  covering  presents  hair, 
sebaceous  and  sweat-glands,  and  fat  tissue,  with  islands  of  smooth  muscle 


m  a.      ," 


FIG.  381. — Structure  of  an  encysted  embryoma  of  testis.  (After  A.  Mutter.)  Ho, 
Testicular  tissue  in  capsule.  H,  Skin  and  appendages.  Pep,  Squamous  epithelium. 
Ath,  Cystic  cavity  containing  sebaceous  matter.  CN,  Central  nervous  system.  Gl, 
Glia  tissue.  Nep,  Neuro-epithelial  cell  groups.  Resp,  Respiratory  tract.  Krn,  Hyaline 
cartilage.  Oe,  Esophagus.  Ch,  Choroid  plexus. 

tissue.  Beneath  lies  brain  tissue  in  which  cellular  and  fibrillar  layers  may 
be  discerned.  Choroid  plexus,  dura,  and  pia  have  been  traced  in  connection 
with  cerebral  tissue,  and  wide  canals  lined  by  flat  cells  have  been  interpreted 
as  ventricles  or  central  canal.  Amyloid  concretions,  or  brain  sand,  may  be 
present.  Bony  plates  are  often  found  about  the  brain  rudiment  and  in  Geinitz's 
case  these  plates  consisted  of  two  lamellae  inclosing  diploe  and  marrow  ar- 
ranged as  a  skull.  Cavazanni  found  nucleated  red  cells  in  the  marrow.  Adult 
ganglion-cells  in  the  course  of  nerve-trunks  represent  the  sympathetic  system. 
Isolated  groups  of  ganglion-cells,  neuro-epithelium,  and  glia  tissue  may  also 
be  found. 

Many  other  organ  rudiments  have  occasionally  been  observed.  Optic 
vessels  with  choroidal  and  retinal  pigment  cells  have  frequently  been  seen. 
Mammary  gland  tissue,  normal  or  fibro-adenomatous,  is  described  by  Chev- 
assu,  Durr,  and  many  others.  Striated  muscle  bundles  were  first  recognized 


792 


NEOPLASTIC  DISEASES 


by  Senftleben,  and  Koslowski  found  cardiac  musle  arranged  about  four  cham- 
bers as  in  the  heart. 


FIG.  382. — Teratoma  testis.     Tissue  resembling  liver  cords. 

Chevassu  and  Picque  thought  they  could  indentify  liver-cells  and  cords. 
Rudiments  of  lung  have  been  interpreted  by  Schlagenhaufer,  Pepere,  and 

Gessner.     Chevassu  pictures  character- 
^  istic  renal  tubules  and  glomeruli.     Gess- 

ner described  ovarian  tissue.  The  writer 
found  a  fibromusclar  organ  with  mu- 
cous lining,  which  resembled  stomach 
or  uterus. 

A  buccal  cavity  is  located  by  a 
superficial  area  of  mucous  membrane 
and  here  have  been  found  in  rare  cases 
bicuspid  and  molar  teeth  embedded  in 
a  bony  mass  (Wilms,  Heinen).  Che- 
vassu and  Ohkubo  identified  salivary 
glands.  The  respiratory  tract  is  repre- 
sented by  canals  lined  by  columnar  or 
cilited  cells  and  supported  by  islands 
of  cartilage. 

The  intestinal  tract  appears  hi  the 
form  of  canals  lined  by  cuboidal  mu- 
cous cells  forming  crypts.  The  cellular 
lymphoid  mucosa  may  be  thrown  up 
into  villi.  A  double  layer  of  smooth 
muscle  surrounds  these  canals. 

Ohkubo  detected,  crystalline  lens, 
spleen,  and  adrenal.  Thyroid  tissue  is  ex- 
tremely rare,  and  Szulcewski  interprets 
tissue  of  this  type  as  a  form  of  mucous 
degeneration,  but  I  have  described  four 
lobules  of  adult  thyroid  resembling  the 
normal  organ  in  the  minutest  details. 
The  stroma  supporting  these  organ  rudiments  may  be  of  adult  type  or 


FIG.  383. — Construction  of  a  tera- 
toma  testis:  C,  Carcinoma  with  lym- 
phoid stroma.  D,  Epidermoid  cysts. 
E,  Epididymis.  F,  Fat  tissue.  M, 
Fibromuscular  organ.  T,  Remains  of 
testis.  Th,  Thyroid  tissue. 


TUMORS  OF  TESTIS 


793 


show  various  forms  of  overgrowth  of  connective  tissue,  or  blood-  and  lymph- 
vessels. 


FIG.  384. — Teratoma  testis.     Embryonal  carcinoma  with  overdevelopment  of  lymphoid 

stroma. 


FIG.  385. — Teratoma  testis.     Detail  of  Fig.  383.    Embryonal  carcinoma  with  lymphoid 
stroma  in  an  organ  resembling  adult  thyroid. 

Not  all  the  definite  rudimentary  organs  are  confined  to  typical  adult  tera- 
tomas.    Many  are  definable  in  the  more  embryonal  solid  tumors,  where  they 


794 


NEOPLASTIC  DISEASES 


are  reduced  to  irregular  canals  or  cysts  lined  by  various  types  of  epithelium, 
to  neuro-epithelial  cell  groups,  and  to  different  glandular  structures. 

The  clinical  course  of  the  adult  teratoma  is  usually  slow.  Many  of  the 
tumors  are  present  at  birth  and  slowly  enlarge  until  they  are  removed  be- 
tween the  tenth  to  fortieth  years  (Tilanus,  Kalning,  Macewen,  Boeckel). 
In  these  cases  no  malignant  changes  are  present. 

Rarely  adult  teratomas  terminate  with  the  development  of  malignant 
neoplastic  processes,  which  lead  to  local  recurrence  after  operation  and  to 
general  metastases.  In  a  tumor  described  by  the  writer,  containing  adult 


FIG.  386. — Teratoma  testis.     Adenocarcinoma.     Neuro-epithelial  cell  groups. 

dermoid  cysts,  uterus,  and  thyroid,  much  of  the  tumor  was  surrounded  and 
infiltrated  with  embryonal  carcinoma  with  lymphoid  stroma.  The  patient 
died  of  internal  metastases.  The  source  of  the  carcinoma  is  undetermined. 

(2)  Teratoid,  Embryoid,  or  Mixed  Tumors.— A  large  proportion  of  testicular 
tumors  are  composed  of  more  or  less  embryonal  structures,  derived  from  all 
three  germ  layers,  but  arranged  in  such  confusion  as  to  eliminate  any  resem- 
blance to  an  embryo.  These  tumors  have  been  described  under  many  terms, 
but  Wilms  showed  that  they  belong  in  a  single  group  of  tridermal  growths 
which  he  designated  as  embryoid  or  teratoid. 

In  gross  appearance  the  tumors  are  of  moderate  or  large  size  and  solid  or 


TUMORS  OF  TESTIS 


795 


riddled  with  many  small  cysts.  They  develop  from  the  rete  and  are  well 
encapsulated,  the  testicular  tissue  being  stretched  over  them  in  a  thin  layer 
included  in  the  capsule.  Occasionally  they  arise  in  the  tunica.  The  section 
is  very  varied,  depending  on  the  proportions  of  cysts,  cartilage,  cellular  areas, 
hemorrhage,  and  necrosis. 

In  structure  the  cysts  are  lined  by  squamous  or  cylindrical  cells  and  there 
may  be  many  islands  of  squamous  cells,  while  the  solid  portions  contain 
masses  of  embryonal  cartilage,  osteoid  tissue,  cellular  connective  and  smooth 
muscle.  While  these  tissues  may  be  comparatively  adult  in  type  and  the 
tumor  quite  benign,  there  is  a  prominent  tendency  for  the  derivatives  of  one 
germ  layer  to  overgrow  the  others  and  to  exhibit  true  neoplastic  and  malig- 


FIG.  387. — Embryonal  carcinoma  of  testis.     ("Seminome"  of  Chevassu.} 

nant  qualities.  Thus  the  solid  areas  often  show  cellular  foci  composed  of 
embryonal  connective  and  myxomatous  tissue,  or  very  cellular  masses  of 
smooth  muscle-cells,  either  of  which  may  compose  the  bulk  of  the  tumor  and 
give  origin  to  metastases. 

Neuro-epithelial  cell  groups  may  be  very  abundant  and  carcinoma tous 
areas  of  this  origin  may  develop.  Entodermal  derivatives  may  be  prominent, 
in  the  form  of  small  cysts  or  alveoli  lined  by  cylindrical  cells.  In  many  of 
these  cysts  the  type  of  epithelium  may  suddenly  change,  as  from  squamous 
to  cylindrical.  Adenocarcinomatous  foci  derived  from  the  cyst  lining  are 
frequently  seen  and  these  areas  grade  into  various  structural  forms  of  car- 
cinoma. 

(3)  Embryonal  Tumors  of  the  Testis.  (i)  Sarcoma  Testis.  Seminome 
(Chevassu) . — Embryonal  carcinoma  with  lymphoid  stroma. 

The  most  frequent  tumor  of  the  testis  is  composed  of  large  round  or  poly- 


796 


N  EOF  LA  STIC  DISEASES 


hedral  cells  of  embryonal  type,  lying  diffusely  or  in  large  alveoli.  The  stroma 
is  often  richly  infiltrated  with  lymphocytes.  Through  the  demonstration  by 
Wilms,  Ohkubo,  and  others  that  many  of  these  tumors  contain  teratoid  ele- 
ments, the  suspicion  first  stated  by  Langhans,  that  the  tumors  are  teratoid, 
has  been  confirmed.  Yet  Chevassu,  Debarnardi,  and  others  derive  this  tumor 
from  the  spermatoblasts  or  their  embryonal  equivalents  and  separate  this 
group  from  the  teratomas  with  which  they  are  so  often  associated.  _ 

Several  considerations  forced  the  writer  to  conclude  that  this  common 
tumor  of  the  testis  is  always  a  one-sided  development  of  a  teratoma  and  is  not 
derived  from  the  adult  spermatoblasts. 

(i)  The  characteristic  structure  is  often  seen  in  teratomas,  adult  or  em- 
bryonal. (2)  In  a  very  early  embryonal  carcinoma  I  found  minute  traces 
of  cartilage,  entodermal  alveoli,  and  squamous  epithelial  cell  groups.  (3) 
The  rapid  growth  of  the  malignant  embryonal  element  gives  unusually  favor- 
able opportunity  for  the  overgrowth  and  suppression  of  other  elements.  (4) 
The  only  known  tumor  of  the  adult  spermatoblasts  is  very  different  from 


W*W  •T^^'V^^^WsfiS   M\   **  *<•   -  *  '       *v"  V      KJ 

HAiK 

"  M  • . ;3c.'^!w1 .'  <«.'•  •; 


FIG.  388. — Teratoma  testis.     Embryonal  carcinoma.     Spontaneous  regression. 

the  embryonal  carcinoma.  Barring  the  possibility  of  unrecognized  forms  of 
metaplasia,  the  teratomatous  relations  of  our  tumor  seem  to  be  demonstrated. 
It  remains  possible  that  the  embryonal  carcinoma  may  arise  from  spermato- 
blasts incited  to  growth  by  the  presence  of  a  teratoma.  The  occurrence  of 
extratesticular  carcinoma  speaks  against  this  possibility  (Koslowski,  the 
writer). 

The  embryonal  carcinoma  is  a  rapidly  growing,  soft,  opaque,  often  necrotic 
tumor  arising  in  the  rete  and  invading  and  destroying  the  testis.  A  portion  of 
the  organ  may  persist  as  a  thin  layer  in  the  capsule,  where  it  is  found  atrophic. 
The  tumors  reach  a  considerable  size  and  then  undergo  central  necrosis,  often 
complicated  by  hemorrhage,  ulceration,  or  suppuration. 

Excision  in  the  early  stage  may  permanently  eradicate  the  disease,  but 
usually  there  is  local  recurrence,  metastases  in  the  upper  abdominal  nodes, 
lungs,  brain,  and  other  organs.  Chevassu  reported  22  recoveries  after  one 
year  from  castration  in  59  cases  of  embryonal  carcinoma,  and  13  after  later 
periods.  No  case  died  after  3  years'  immunity.  Of  55  mixed  tumors  only 
6  remained  well  for  2  years,  4  others  showing  no  recurrence  after  6  months. 


TUMORS  OF  TESTIS 


797 


The  rapid  course  of  recurrences  is  notable.  Definite  chorioma  appears  to  be 
uniformly  fatal. 

Structure. — The  structure  is  usually  characteristic,  but  shows  several  varia- 
tions. As  a  rule  one  finds  large  round  or  polyhedral  cells  with  vesicular  hy- 
perchromatic  nuclei  lying  in  wide  sheets  or  diffusely.  The  cells  are  rich  in 
glycogen.  The  stroma  may  be  very  scanty,  or  strands  of  lymphoid  tissue 
may  be  prominent,  or  more  fibrous  bands  may  produce  alveoli.  Definite 
lymph-nodules  may  form  in  the  stroma.  Necrosis  is  common.  A  form  of  re- 
gression may  be  observed  with  atrophy  of  tumor-cells  and  formation  of  gran- 
ular or  cellular  interstitial  tissue. 

Embryonal  adenocarcinoma  is  a  somewhat  distinctive  type  of  testicular 
tumor.  It  grows  rapidly,  is  very  vascular,  and  is  often  the  seat  of  extensive 
hemorrhage.  Encapsulation  is  usually  as  marked  as  in  adult  teratoma,  and 


FIG.  389. — Embryonal  carcinoma  of  testis,  with  lymphoid  stroma. 

while  traces  of  teratomatous  elements  are  not  infrequently  found,  this  struc- 
ture may  be  nearly  pure  carcinoma.  It  is  sometimes  associated  with  chorioma. 
The  structure  presents  irregular  alveoli  lined  and  traversed  by  rows  of  large 
cuboidal  cells  with  large  hyperchromatic  nuclei.  Or  the  alveoli  may  be  in- 
distinct, the  cells  smaller  and  more  undifferentiated,  and  the  structure  may 
even  resemble  lymphosarcoma. 

Chorioma  Testis. — This  remarkable  form  of  teratoma  has  passed  through 
several  stages  of  study  and  interpretation.  In  1868  Waldeyer  observed  poly- 
poid tumor  masses,  extending  from  a  testicular  teratoma  into  the  pelvic 
veins,  which  he  compared  in  appearance  with  hydatid  mole.  A  typical  case 
was  described  by  Breus,  1878,  in  which  the  polypoid  masses  extended  into  the 
heart.  In  the  French  literature  a  series  of  these  cases  was  reported  under 
the  term  "sarcome  angioplastique"  by  Malassez  and  Monod,  Carnot  and 


798  NEOPLASTIC  DISEASES 

Marie,  and  others,  who  also  noted  the  resemblance  to  hydatid  mole.  Mac- 
Callum  likewise  interpreted  his  case  as  lymphendothelioma.  In  1902  Schlag- 
enhaufer,  Wlassow,  and  Steinert  all  pointed  out  the  exact  resemblance  of  this 
tumor  to  chorioma,  traced  the  origin  of  the  syncytial  masses  from  epithelium 
of  the  testicular  growth,  identified  glycogen-holding  Langhans'  cells,  noted 
the  hemorrhagic  character  of  the  metastases,  and  showed  that  chorioma  tes- 
tis  reproduces  exactly -the  essential  features  of  chorioma  uteri.  Warthin  and 
Gabarini  have  reported  cases  in  which  there  was  hypertrophy  of  breasts  with 
secretion  of  colostrum,  thus  adding  physiological  features  of  pseudogestation 
in  the  male.  While  Risel  denies  the  origin  from  a  true  chorionic  element  in 
the  teratoma  and  points  out  that  syncytial  masses  may  form  from  any  epithe- 
lial structure,  there  is  no  doubt  that  the  general  significance  of  chrioma  testis 
has  been  correctly  interpreted  by  Schlagenhaufer.  The  course  and  structure 
of  chorioma  testis  is  an  exact  duplicate  in  all  details  of  that  of  the  uterine 


FIG.  390. — Teratoma  testis.    Tumor  composed  of  adenocarcinoma  with  cylindrical  cells. 

tumor,  which  is  not  the  case  with  the  pseudochoriomatous  growths  of  mis- 
cellaneous epithelial  origin  to  which  Risel's  criticism  applies. 

The  testicular  tumors  giving  origin  to  chorioma  are  usually  small  and 
may  be  overlooked  during  life.  They  are  described  as  soft,  succulent,  cystic, 
or  hemorrhagic.  In  Kanthack's  case  the  tumor  was  composed  of  many  small 
cysts  of  various  types.  A  large  cystic  tumor  chiefly  of  adult  type  was  found 
by  Steinert.  In  one  case  (Blatteis)  I  found  the  small  original  tumor  largely 
destroyed  by  hemorrhage  and  presenting  the  structure  of  embryonal  adeno- 
carcinoma with  several  areas  of  syncytium.  In  another  case  the  testis  was 
very  slightly  enlarged,  but  the  rete  and  cord  presented  a  continuous  series 
of  pea-sized  dermoid  cysts.  On  section  a  small  focus  of  proliferating  syn- 
cytium was  discovered  in  the  rete.  In  the  gross  this  area  appeared  as  a  hem- 
orrhagic spot.  There  were  bulky  metastases  of  complex  structure  in  the  medi- 
astinal  and  cervical  nodes,  dermoid  cysts  and  chorioma  in  the  lungs,  and  a 


TUMORS  OF  TESTIS  799 

single  large  tumor  resembling  a  placenta  in  the  liver  from  which  fatal  hemor- 
rhage occurred.  Steinert's  case  also  gave  complex  metastases  in  mediastinum, 
lungs,  and  liver,  among  which  chorioma  was  prominent. 

The  exact  origin  of  the  syncytial  cells  is  not  clear.  Pick  has  traced  them  to 
the  neuro-epithelial  cell  groups.  In  2  cases  I  have  found  the  minute  foci 
of  chorioma  in  a  very  limited  field  and  lying  in  or  near  adenocarcinomatous 


FIG.  391. — Teratoma  testis,  composed  of  epidermoid  structures  and  a  dark  central 
nodule  of  chorioma.  In  the  body  of  the  testis  are  nodules  of  large  cell  embryonal  carci- 
noma. Same  case  as  Figs.  392  and  393. 

areas  of  which  the  cells  showed  none  of  the  features  of  neuro-epithelium. 
Nor  was  there  any  special  relation  to  blood-vessels.  No  gross  chorion-like 
structures  have  been  identified  in  the  testis.  Moreover,  similar  cells  may 
appear  in  tumors  which  have  not  yielded  choriomatous  metastases.  Hence 
it  would  appear  hazardous  to  attempt  the  diagnosis  of  chorioma  testis  in  the 
absence  of  pulmonary  or  hepatic  metastases. 


FIG.  392. — Teratoma  testis.    Same  case  as  Fig.  393.     Choriomatous  metastasis  in  liver 
resembling  a  chorion  and  giving  rise  to  fatal  hemorrhage. 

Certain  apparently  primary  tumors  of  the  liver  in  males  have  been  de- 
scribed as  chorioma  for  which  no  satisfactory  source  has  been  determined. 
It  seems  probable  that  these  are  either  primary  carcinomas  of  the  liver-cells 
simulating  chorioma,  or  metastatic  chorioma  of  the  testis,  the  primary  tumor 
having  been  overlooked. 


800  NEOPLASTIC  DISEASES 

Metastases  of  Teratoma  Testis. — Nearly  all  varieties  of  the  embryonal 
and  mixed  tumors  may  prove  malignant  and  give  rise  to  metastases  which 
are  often  of  complex  types.  The  course  and  character  of  these  metastases 
present  many  interesting  features. 

The  retroperitoneal  nodes  at  the  celiac  axis  are  often  involved  through 
the  lymph-channels  of  the  spermatic  veins,  and  an  epigastric  tumor  is  often 
the  first  sign  of  recurrence.  This  form  of  recurrence  is  especially  common  with 
the  highly  malignant  embryonal  carcinomas. 


FIG.  393. — Metastases  in  lung  and  cervical  lymph-nodes  from  a  small  teratoma  testis, 
shown  in  ¥ig.  392.  The  lung  shows  whitish  epidermoid  cysts  and  dark  nodules  of 
choriocarcinoma. 

From  this  point  there  may  be  rapid  progress  upward,  so  that  mediastinal 
and  even  cervical  tumors  may  divert  attention  and  become  the  largest  tumors 
in  the  body.  Invasion  of  the  spermatic  and  iliac  veins,  with  continuous 
tumor  growth  extending  as  far  as  the  heart,  has  been  observed  both  with 
chondrosarcoma  (Paget)  and  chorioma.  Discontinuous  metastasis  by  way 
of  the  veins  is  most  frequent,  and  gives  rise  to  tumors  of  lungs,  liver,  brain, 
kidney,  and  stomach. 


TUMORS  OF  TESTIS  801 

The  structure  of  the  metastases  may  reproduce  several  features  of  the 
original  growth,  or  only  one.  As  a  rule  the  individual  secondary  tumors 
represent  a  single  germ  layer  in  either  adult  or  embryonal  form.  Well-formed 
adult  ectodermal  cysts  may  appear  in  the  lungs  and  chondromatous  nodules 
may  exhibit  adult  characters. 

In  the  retroperitoneal  and  thoracic  nodes  one  may  find  many  adult  and 
embryonal  structures  reproducing  in  a  remarkable  degree  the  original  tumor. 
Yet  the  derivatives  of  the  germ  layers  are  usually  distinct,  showing  that  each 
embolic  cell  group  has  produced  only  its  own  kind.  In  a  case  of  chorioma  testis 
I  found  three  entirely  separate  groups  of  metastases  in  the  lungs,  one  com- 
posed of  chorioma,  another  of  epidermoid  cysts,  and  a  third  of  myxosar- 
comatous  tissue.  The  chorioma  appeared  also  in  the  liver,  while  the  two  latter 
tissues  made  up  the  bulk  of  the  mediastinal  tumors. 

In  a  case  of  embryonal  adenocarcinoma  there  was  local  recurrence,  tumors 
of  abdominal  and  thoracic  nodes,  very  extensive  diffuse  invasion  of  both 
lungs,  large  tumors  of  the  brain,  and  seven  globular  tumors  of  the  gastric 
mucosa,  from  the  central  excavations  of  which  fatal  hemorrhage  occurred. 
In  Westenhofer's  case  the  hepatic  metastases  had  the  structure  of  lympho- 
sarcoma.  Steinert  describes  combined  tridermal  metastases  in  the  liver,  which 
contained  encapsulated  nodules  composed  of  cysts  lined  by  cylindrical  cells 
backed  by  a  muscularis,  and  associated  with  epidermis,  cartilage,  and  bone. 
The  presence  of  such  structures  in  one  compact  metastatic  tumor  it  is  diffi- 
cult to  refer  to  any  other  source  than  to  emboli  of  undifferentiated  cells  capable 
of  producing  all  three  germ  layers.  Further  observations  are  needed  to  eluci- 
date the  questions  here  involved. 

4.  Miscellaneous  Tumors  of  the  Testis,  Tunica  and  Cord,  and  Their  Relation 
to  Teratoma. — The  study  of  teratoma  testis  has  greatly  narrowed  the  scope  of 
pure  simple  tumors  of  this  organ,  and  reduced  their  numbers  to  a  compara- 
tively few  cases  whose  real  nature  often  remains  uncertain.  In  no  other  organ 
has  the  principle  of  the  overgrowth  of  one  element  of  a  teratoma  been  proved 
to  be  so  predominant,  and  while  it  is  possible  to  carry  this  principle  too  far, 
the  data  seem  to  demonstrate  its  great  importance  in  the  interpretation  of 
tumors  of  this  region.  Hence  tumors  which  are  apparently  of  other  origins 
must  be  scrutinized  carefully. 

Fibroma  of  the  testis  is  very  rare,  but  apparently  pure  cases  are  described 
by  Curling  and  Kocher.  These  were  large,  firm,  cystic,  or  calcified  tumors  of 
very  slow  growth.  Fibromas  of  the  tunica  albuginea  are  reported  by  Fer- 
gusson  and  Pean. 

A  large  fibroma,  14  X  9  cm.,  replacing  the  testis,  is  described  by  Chevassu. 
It  contained  pseudocysts  and  sarcomatous  areas  and  the  author  was  unwilling 
to  eliminate  a  teratomatous  origin. 

Plexiform  fibroma  of  the  cord  is  described  by  Ehrendorfer.  Fibrolipoma 
of  the  spermatic  cord  is  a  well-recognized  tumor  which  Kolisko  regards  as  of 
teratomatous  origin. 

Chondroma. — Cartilage  is  nearly  constantly  present  in  the  testicular 
teratoid  tumors  and  often  forms  the  bulk  of  the  growth.  It  occurs  in  the 
form  of  adult  or  embryonal  hyaline  masses  of  small  size  or  large  dimensions. 
Neumann  found  bone  in  one  case.  Myxoma  may  arise  from  imperfect  forma- 
tion of  cartilage. 

The  tendency  of  cartilage  to  overgrow  other  elements  of  the  tumors  has 
long  been  recognized.  Kocher  accepted  as  pure  chondroma  only  5  of  the 
28  cases  described  by  Dauve,  adding  3  of  his  own,  but  later  writers  (Rib- 
bert,  Ohkubo)  question  the  existence  of  pure  chondroma  testis  apart  from  a 
teratomatous  origin.  Paget's  case  of  malignant  chondroma  is  now  gener- 
51 


802  NEOPLASTIC  DISEASES 

ally  regarded  as  a  teratoma  (Wilms,  Ohkubo).  Cartilaginous  metastases  in 
lungs  or  lymph-nodes  occurred  in  his  and  Kocher's  cases.  Since  the  origin  of 
these  tumors  appears  to  be  in  the  rete,  since  many  are  cystic  and  occur  in 
infants,  and  since  it  is  practically  impossible  to  eliminate  teratomatous  ele- 
ments by  microscopical  study,  it  seems  necessary  to  assume  that  all  these 
tumors  are  of  teratomatous  origin. 

Myxomatous  areas  are  frequently  present  in  mixed  tumors  of  the  testis 
and  may  form  the  bulk  of  the  tumor.  Most  reported  myxomas  have  been 
associated  with  chondroma,  sarcoma,  adenoma,  or  cystoma,  and  clearly  be- 
long in  the  teratoid  group.  Kocher  and  Wilms  could  find  no  cases  of  pure 
myxoma. 

Myoma. — Smooth  muscle-tissue  is  nearly  constant  in  the  mixed  tumors, 
but  seldom  forms  a  prominent  part  of  the  tumor,  nor  does  it  commonly  pre- 
sent blastomatous  changes.  Reports  of  leiomyoma  testis  are  likewise  rare. 
Nepveu's  case  contained  both  smooth  and  striated  muscle  and  was  probably 
of  teratoid  nature.  Leiomyoma  of  epididymis  or  vas  is  described  by  Trelat, 
following  trauma,  and  by  Hericourt.  It  is  assumed  that  these  tumors  arise 
from  the  cremaster  internus  muscle. 

Striated  muscle  is  rarely  seen  in  testicular  tumors,  but  in  a  few  cases  it  has 
been  present  in  abundance,  usually  with  cartilage  and  epithelial  canals,  thus 
demonstrating  its  teratomatous  relations.  Mixed  tumors  of  this  type  are 
described  by  Arnold,  Kocher,  Ribbert,  Chevassu,  Wood,  and  others.  Ap- 
parently pure  rhabdomyoma  attached  to  the  lower  pole  of  the  tunica  albuginea 
and  probably  derived  from  the  gubernaculum  of  Hunter  are  described  by 
Rokitansky  and  Neumann. 

The  scope  of  myoma  and  myosarcoma  of  the  testis  is  not  yet  determined. 
Neumann  and  Ribbert  found  many  spindle-  and  round-cells  which  were 
not  clearly  separable  from  the  muscle-cells,  and  Neumann  suggested  that  some 
spindle-cell  sarcomas  may  be  of  myogenous  origin.  Benenati  describes  striated 
muscle,  large  spindle-cells  lacking  striation,  and  round  cells  in  a  testicular 
tumor  with  metastases  containing  only  the  round-cell  tissue. 

Sarcoma. — Spindle-cell  sarcoma  of  the  testis  has  rarely  been  reported  and 
it  is  difficult  to  determine  the  true  nature  of  these  cases.  Chevassu,  out  of  126 
testicular  tumors,  found  only  one  which  appeared  to  be  purely  sarcomatous. 
Yet  the  cells  were  of  mixed  type,  spindle  and  round,  and  since  there  were 
also  alveoli  lined  by  epithelioid  cells,  the  opinion  is  expressed  that  the  tumor 
might  be  of  teratoid  origin.  The  probability  that  teratoid  elements  have  been 
overlooked  in  these  cases  is  shown  by  Wilms,  who,  on  re-examining  an  old  tumor 
called  plexiform  spindle-cell  sarcoma,  found  also  cysts  lined  by  cylindrical  or 
squamous  cells  and  an  island  of  cartilage  undergoing  mucoid  degeneration. 

In  view  of  these  observations  considerable  doubt  surrounds  the  interpre- 
tation of  other  so-called  spindle-cell  sarcomas.  Some  of  these  tumors  con- 
tained myxomatous  areas  and  cell  groups  of  uncertain  nature  (Ehrendorfer). 
Others  contain  many  giant-cells  suggesting  a  myomatous  element  (Kocher, 
Krompecher).  Or  both  these  structures  are  combined  with  spindle-cells 
(Debarnardi).  There  is  no  doubt  that  tumors  composed  chiefly  of  spindle- 
cells  occur  in  the  testis,  but  their  true  nature  and  the  possible  relation  to 
myoma  and  teratoma  remain  uncertain. 

Adenoma  of  the  testis  has  been  described  in  2  cases  by  Chevassu  and 
Pick.  They  were  found  in  undescended  organs,  one  of  them  in  an  hermaph- 
rodite. The  tumors  appeared  as  pinhead  or  bean-sized  yellowish  nodules 
in  the  body  of  the  atrophic  testis.  Some  small  cysts  resulted  from  dilation 
of  alveoli.  They  were  composed  of  regular  tubules  lined  by  cylindrical  cells 
about  15  micra  in  height,  with  finely  granular  cytoplasm  and  compact  nuclei 


TUMORS  OF  TESTIS 


803 


and  arranged  in  palisade  fashion.  The  transition  from  normal  tubules  was 
followed  step  by  step.  Chevassu  likens  the  tubules  to  those  of  a  sweat-gland. 

While  adenoma  of  the  testis  appears  in  many  older  reports  it  is  now  evident 
that  the  authors  were  dealing  with  teratomas. 

Interstitial  Cells. — Tumors  or  tumor-like  hyperplasias  of  the  interstitital 
cells  of  the  testis  are  rare  conditions  observed  in  undescended  and  atrophic 
testes,  in  which  the  atrophy  of  tubules  is  associated  with  moderate  hyperplasia 
of  the  large  cells  of  the  stroma.  These  tumors  are  usually  limited  to  very 
moderate  dimensions,  but  in  Kaufmann's  case  it  measured  9X6  cm.  They 
are  well  encapsulated  and  of  rusty  brown  color  due  to  the  lipoid  pigment 
in  the  cells.  The  structure  exhibits  alveolar  groups  of  large  polygonal  cells 


rfe* .  *• 


-     •    -..-  .p--- 


FIG.  394. — Adenoma  of  testicular  tubules.      (After  Chevassu.) 

closely  resembling  the  interstitial  cells.  Neoplastic  characters  may  be  dis- 
tinct (Durck).  Cases  of  this  characteristic  type  are  described  by  Chevassu, 
Pick,  and  Kaufmann. 

Waldeyer  (1872)  derived  certain  plexiform  angiosar comas  from  the  inter- 
stitial cells,  and  Hansemann  (1895)  attributed  certain  alveolar  sarcomas  to  the 
same  origin. 

Adrenal  Tumors  of  the  Testis. — Rarely  a  solid  carcinoma  of  the  testis 
presents  a  structure  recalling  that  of  adrenal  carcinoma  or  perithelioma. 
Debarnardi  has  described  such  a  tumor  and  attributed  its  origin  to  an  adrenal 
rest.  It  occurred  in  a  child  of  10  months  and  involved  the  upper  pole  of  the 
testis  and  extended  up  the  cord.  As  the  testis  and  rete  were  intact  it  was  not 
strictly  a  tumor  of  the  testis,  but  rather  of  the  epididymis  and  cord.  The 
structure  was  complex,  presenting  sarcomatous  and  adenocarcinomatous  areas. 

The  occurrence  of  adrenal  islands  in  and  about  the  testis  has  been  fully 
demonstrated  by  Marchand,  Wiesel,  and  Kirkbride,  and  such  cell  groups  may 
well  give  origin  to  tumors. 

In  Debarnardi's  case,  and  in  others  of  my  collection,  in  which  the  question 
of  adrenal  origin  arose,  the  structure  presented  alveoli  of  large  polyhedral 


804 


NEOPLASTIC  DISEASES 


cells  which  lacked  the  embryonal  character  of  the  ordinary  carcinoma  and 
resembled  adrenal  carcinoma.  A  perithelial  structure  was  not  prominent, 
nor  were  the  gross  features  strongly  indicative  of  adrenal  nature.  In  one  case 
the  tumor  proved  to  be  secondary  to  a  tumor  in  the  adrenal.  The  structure 
of  perithelioma  appeared  also  in  a  recurrence  of  embryonal  carcinoma.  Further 
observations  would  appear  necessary  to  establish  the  existence  of  a  testicular 
carcinoma  of  adrenal  origin. 

Lymphosarcoma  Testis. — An  apparently  distinct  group  of  lymphosar- 
coma  of  the  testis  was  described  by  Malassez  in  1877  and  later  by  Tala- 
vera  and  other  French  observers.  More  recently  Chevassu  has  shown  that 
the  majority  of  these  tumors  are  embryonal  carcinomas,  but  his  further  claim 
that  true  lymphosarcoma  in  the  testis  is  always  secondary  must  be  ques- 
tioned. Curling  observed  the  disease  in  1866  and  Ehrendorfer  described  a 
typical  case  with  cutaneous  metastases,  and  recent  cases  are  reported  by 
Debarnardi  and  by  the  writer.  The  disease  is  distinguished  by  its  develop- 
ment in  most  cases,  in  both  testicles,  by  its  occurrence  chiefly  in  children,  by 


FIG.  395. — Island  of  adrenal  tis- 
sue in  testis  of  newborn  infant. 
(After  Kirkbride.) 


FIG.  396. — Epidermoid  in  rete  testis  of  newborn 
infant.     (After  Kirkbride.) 


its  rapid  course,  and  by  multiple  metastases  in  the  skin.  The  structure  is 
that  of  a  diffuse  tumor  composed  of  embryonal  large  round  cells  resembling 
large  lymphocytes,  lying  in  a  reticular  stroma. 

The  origin  of  lymphosarcoma  of  the  testis  would  naturally  be  referred  to 
lymphoid  tissue  of  the  normal  organ,  but  no  such  structures  are  commonly 
present  in  this  organ.  It  seems  possible  that  the  tumor  may  be  derived  from 
some  elements  of  a  teratoma  of  which  the  rapidly  growing  cells  lose  all  differ- 
entiation. Areas  of  such  embryonal  round  cells  may  occasionally  be  seen  in 
teratomas.  Yet  there  are  no  definite  observations  which  may  be  used  in  sup- 
port of  the  hypothesis  that  lymphosarcoma  of  the  testis  is  of  teratoid  nature 
and  its  origin  remains  quite  undetermined. 

Etiology. — The  study  of  the  formal  genesis  of  teratoma  testis,  quite  as 
much  as  any  other  teratoma,  has  contributed  important  data  in  the  field  of 
teratology.  The  questions  involved  almost  exactly  duplicate  those  of  tera- 
toma ovarii,  but  the  testicular  group  is  distinguished  by  the  wide  variety  of 
simple  tumors  derived  from  the  parent  teratoma. 


TUMORS  OF  TESTIS  805 

Virchow  held  that  the  testicular  mixed  tumors  arise  from  the  normal  ele- 
ments of  the  organ,  in  which  theory  he  attributed  to  metaplasia  a  very  wide 
scope.  While  modern  views  greatly  restrict  the  field  of  metaplasia,  it  may 
still  be  well  not  to  ignore  entirely  the  possible  influence  of  this  factor  in  the 
structure  of  mixed  tumors.  The  idea  that  metaplasia  alone  can  account  for 
the  organic  structures  of  these  growths  cannot,  however,  be  entertained,  and 
since  the  entire  series  is  connected  by  abundant  intermediate  types  which 
demonstrate  their  single  origin,  the  theory  of  metaplasia  has  been  abandoned. 
The  testicular  embryomas,  for  the  same  and  other  reasons,  must  be  excluded 
from  the  group  of  fetal  inclusions.  The  results  of  the  various  forms  of  double 
embryos  are  seen  in  the  sacral  and  cephalic  teratomas,  where  the  conditions 


FIG.  397. — Embryonal  carcinoma  of  testis.     So-called  alveolar  sarcoma. 

are  favorable  for  the  separation  or  attachment  of  multiple  embryos,  but  these 
conditions  are  not  provided  in  the  testis. 

The  Marchand-Bonnet  theory  of  origin,  from  polar  bodies  or  isolated  blas- 
tomeres,  is  less  satisfactory  for  the  testicular  growths  and  their  peculiar 
derivatives  than  for  any  of  the  fields  to  which  it  may  conceivably  apply. 

An  origin  from  some  member  or  members  of  the  sex-cell  series  is  now  gener- 
ally accepted  as  applicable  to  the  testicular  tumors.  This  theory  fully  accounts 
for  the  predilection  of  teratomas  for  the  sex  glands  and  for  the  peculiarities 
of  these  growths  as  compared  with  extragenital  teratomas.  The  exact  form  of 
this  originating  sexual  cell  cannot  well  be  determined,  but  the  conceptions  held 
have  included  every  stage  from  an  original  sex  blastomere  down  to  the  adult 
spermatoblast.  Unless  one  chooses  to  distinguish  essentially  between  adult 
embryomas  and  embryonal  mixed  tumors,  for  which  there  are  no  adequate 
reasons,  the  entire  group  must  be  derived  from  a  cell  commonly  present  in 


806  N  EOF  LA  STIC  DISEASES 

the  testis.  Hence  a  nearly  mature  spermatoblast  or  its  near  antecedents  are 
most  probably  the  source  of  the  tumors. 

Cavazanni  distinguishes  between  the  benign  congenital  embryomas  of 
early  life  and  the  malignant  tumors  of  young  adults  following  trauma.  Both 
arise,  he  thinks,  in  cell  groups  of  much  more  limited  potencies  than  an  ovum, 
probably  from  remnants  of  the  Wolffian  body.  Yet  his  bilobed  teratoma  ex- 
hibited, in  one  lobe,  tumor  structures  which  he  interprets  as  essentially  dif- 
ferent in  origin  from  those  of  the  other  lobe.  A  misplacement  of  spermato- 
blasts  with  incomplete  development  would  strengthen  the  sex-cell  theory,  and 
these  conditions  are  provided  at  the  junction  of  tubules  and  rete  where  the 
tumors  regularly  arise  and  where  Kirkbride  finds  much  disorder  in  the  struc- 
ture of  the  embryonal  and  fetal  testis.  Teratoma  testis  is  also  particularly 
prone  to  develop  in  atrophic  undescended  organs. 

Why  one  teratoma  grows  slowly  and  produces  adult  tissues,  while  another 
develops  rapidly  and  remains  embryonal  in  type,  cannot  readily  be  explained 
and  this  variation  may  possibly  call  for  a  wide  difference  in  the  stage  of  develop- 
ment of  the  originating  cell.  A  more  obvious  factor  is  probably  found  in  the 
influence  of  the  blastomatous  process  which  is  usually  added  to  the  embryonic 
growth.  Such  a  process  at  once  interferes  with  the  orderly  progress  of  simple 
embryonal  growth  and  converts  the  embryo  into  a  true  tumor.  Beginning 
early,  the  blastema  may  completely  suppress  the  embryo,  or  if  late  the  em- 
bryo may  reach  the  limit  of  its  growth  before  the  blastema  assumes  serious 
proportions.  The  reported  cases  illustrate  both  of  these  relations. 

The  incitement  to  growth  seems  to  have  been  furnished  in  many  instances 
by  trauma,  and  while  it  is  difficult  to  establish  an  essential  connection,  the 
traumatic  theory  is  in  accord  with  experimental  data  showing  that  trauma 
may  readily  excite  spontaneous  growth  of  ova. 

Undescended  testes  are  unusually  prone  to  develop  malignant  tumors,  of 
which  Bulkeley  has  collected  59  cases.  In  three  the  tumors  were  bilateral 
(O.  C.  Smith)/ 


CHAPTER  XLI 
TUMORS  OF  LUNG 

CARCINOMA  OF  LUNG 

Primary  tumors  of  the  lungs  have  long  attracted  much  clinical  and  patho- 
logical interest.  Bayle  in  1810  vaguely  described  pulmonary  cancer,  and 
Stokes,  1842,  recognized  several  varieties  of  the  disease.  Ebermann  as  early 
as  1857  collected  72  cases,  one  occurring  before  the  age  of  9  years.  Jaccoud 
appears  first  to  have  sharply  distinguished  the  disease  from  phthisis.  Behier 
pointed  out  the  prominence  of  pressure  symptoms  and  the  frequent  invasion  of 
supraclavicular  nodes.  Bennett's  Lumleian  Lectures  in  1872  dealt  fully  with 


FIG.  398. — Carcinoma  of  lung. 

the  clinical  aspects,  from  an  analysis  of  39  cases.  Rokitansky  recognized 
several  gross  varieties  of  the  pulmonary  lesions,  but  the  earliest  microscopical 
studies  were  those  of  Langhans,  Marchiafava,  and  Malassez,  1871  to  1876. 

The  more  detailed  interest  and  knowledge  date  chiefly  from  the  later 
studies  of  Wolf,  1895,  and  Passler,  1896.  Since  that  time  the  literature  has 
grown  to  very  considerable  proportions,  so  that  Adler  in  1911  was  able  to 
tabulate  374  cases  of  carcinoma  and  90  of  sarcoma.  Since  1922  Scott  and 
Forman  find  reports  of  1 20  new  cases. 

807 


808  NEOPLASTIC  DISEASES 

Etiology. — Primary  malignant  tumors  of  the  lung  form  about  i  per  cent, 
of  all  cancers.  Among  16,578  cancer  autopsies  from  various  Continental 
sources  168  pulmonary  cancers  were  recorded  (compiled  from  Karrenstein 
and  Adler).  Kaufman  places  the  proportion  much  higher,  at  1.83  per  cent. 
It  is  evident  that  increased  attention  has  greatly  augmented  the  list  of  ob- 
served cases.  Knierim  (1909)  reported  that  at  Leipsic,  during  9  years,  66  cases 
of  bronchial  carcinoma',  7  acanthomas,  and  2  alveolar  tumors  had  been  ob- 
served. 

Males  are  much  more  frequently  affected  than  females,  71.9  per  cent, 
to  24.8  per  cent.  Alder  gives  the  following  analysis  of  age  incidence: 

10-20  years 6 

20-30  years 10 

30-40  years 30 

40-50  years 78 

50-60  years 113 

60-70  years 94 

70-80  years 23 

80-90  years 2 

356 

Horn '  observed  an  adenocarcinoma  in;^a  girl  of  18  years.  A  congenital 
multiple  tumor  appears  to  have  been  encountered  by  McAldowie  in  an  infant 
of  sljmonths,  while  Nuscheler  reported  a  ca,se  in  a  girl  of  7  years,  and  Werner 
described  a  small  cell  carcinoma  in  a  female  of  19  years.  Sarcoma  occurs  at 
somewhat  earlier  ages,  chiefly  between  30  and  40  years,  and  6  cases  have  been 
reported  in  the  first  decade.  The  right  lung  is  more  frequently  affected  than 
the  left.  Of  1 06  cases  Perrutz  located  35  per  cent,  on  the  left  side,  54  per  cent, 
on  the  right,  while  10  per  cent,  were  bilateral. 

The  chief  etiological  factor  is  tuberculosis.  Of  Wolf's  31  cases,  13  were 
associated  with  tuberculosis.  Squamous-cell  carcinoma  developing  in  the 
wall  of  a  tuberculous  cavity  is  described  by  Schwalbe,  Friedlander,  and  Perrone. 
Wolf  found  tuberculous  lesions 'throughout1  diffuse  carcinoma,  or  surrounding 
tumor  masses.  In  the  old  scleroses,  atelectases,  ancl  Yeparative  lesions  of 
tuberculosis  may  be  found  many  alterations  of  bronchial  and  pulmonary  epi- 
thelium, marked  by  cSnsiderable  cellular  overgrowth-  Oe'irtel  points  out  that 
the  association  may  be  accidental,  at  other  times  tHe  two  processes  exist  in 
symbiosis,  while  rarely  tuberculosis  appears  to  inhibit  the  carcinoma.  Several 
cases  in  which  there  was  active  mih*ary  tuberculosis  with  carcinoma  suggest 
that  the  malignant  process  may  light  up  latent  tuberculous  foci  (Wolf). 

Rupture  of  anthracotic  nodes  into  the  bronchi  is  held  by  Wolf  as  re- 
sponsible for  some  cases  of  bronchial  carcinoma.  *  A  .history  of  chronic  bron- 
chitis has  often  preceded  bronchial  carcinoma,  and  the  lesions  of  chronic 
bronchitis  often  present  very  marked  overgrowth  of  bronchial  epithelium. 

In  chronic  interstitial  pneumonia  also  the  overgrowth  and  metaplasia 
of  alveolar  epithelium  is  sometimes  excessive.  Menetrier  offers  evidence 
to  show  that  primary  sclerotic  lesions  in  the  lung  may  lead  to  cancer,  and  this 
view  is  supported  by  Ribbert.  Yet  many  alveolar  carcinomas  appear  to  have 
developed  in  previously  normal  parenchyma. 

Trauma  has  figured  prominently  in  the  history  in  many  series  of  cases  and 
sometimes  the  relation  between  the  two  has  been  rather  striking  (Aufrecht). 

In  many  carcinomatous  lungs  anthracosis  is  extremely  marked  and  in  the 
much  quoted  cancer  of  the  Schneeberg  miners  this  condition  has  been  held 
chiefly  responsible  for  the  disease.  While  some  of  these  cases  have  proved 
to  be  tuberculosis  or  other  infectious  granuloma,  a  few  must  be  accepted 


TUMORS  OF  LUNG 


809 


as  primary  carcinoma.  In  a  recent  case  Arnstein  found  chiefly  squamous- 
cell  carcinoma  of  bronchial  origin,  while  portions  of  the  tumor  contained 
spindle-cells  which  also  appeared  in  the  hepatic  metastases. 

Classification. — Tumors  of  the  upper  third  of  the  trachea  are  relatively 
common,  but  they  closely  resemble  laryngeal  growths  with  which  they  are 
usually  grouped.  The  lower  portion  of  the  trachea  is  very  rarely  the  seat 
of  tumors. 

Among  pulmonary  tumors  are  considered  the  growths  arising  from  the 
bronchi  and  pulmonary  parenchyma. 

According  to  histogenesis  three  groups  of  pulmonary  carcinoma  must 
be  recognized,  as  rising  from  (a)  bronchial  epithelium,  (b)  bronchial  mucous 
glands,  (c)  alveolar  epithelium. 


FIG.  399. — Beginning  carcinoma  of  bronchial  mucosa.     (After  Langhans,  V.  A.,  53.) 

To  a  considerable  extent  these  tumors  are  distinguished  by  gross  anatomical 
features  and  probably  also  by  certain  clinical  characters.  It  is,  however,  not 
possible  to  separate  all  advanced  cases,  especially  of  the  more  malignant 
types,  and  the  specific  features  belong  chiefly  to  the  earlier  stages  of  the 
tumors. 

(a)  Bronchial  Carcinoma  of  Lining  Epithelium. — Carcinoma  of  the  bron- 
chial lining  epithelium  produces  extensive  changes  in  the  bronchial  mucosa, 
advancing  along  the  walls  of  the  bronchi,  septa,  and  pleura,  but  seldom  pro- 
ducing a  diffuse  tumor  of  the  lung.  The  process  usually  begins  at  or  below 
the  bifurcation  and  extends  toward  the  trachea  above  and  the  smaller  bronchi 
below.  The  bronchi  may  be  filled  with  papillary  projections  over  a  wide  area, 
while  the  walls  are  thickened  and  the  parenchyma  invaded.  Wolf  describes 
a  case  in  which  the  lower  half  of  the  trachea  and  both  main  bronchi  were 
filled  with  papillary  masses  and  encased  in  dense  connective  tissue  infiltrated 
with  tumor-cells. 


810  NEOPLASTIC  DISEASES 

Domeny  found  the  main  bronchus  of  the  left  lower  lobe  occluded  by  a 
protruding  tumor  mass,  while  the  mucosa  was  the  seat  of  large  carcinomat- 
ous  ulcers.  Packward  describes  a  large  tumor  involving  the  two  lower  tracheal 
rings  and  both  bronchi  and  extending  through  the  lung  to  the  pleura.  There 
were  numerous  bronchiectases.  A  distinctly  polypoid  tumor  of  the  right 
bronchus  with  pulmonary  metastases  is  recorded  by  Merklen  and  Girard. 

Excavations  of  the  superficial  tumor  tissue  and  bronchiectasis  are  fre- 
quently established  and  lead  to  the  formation  of  one  or  several  cavities  filled 
with  mucopus  and  walled  by  disintegrating  tumor  tissue.  In  tuberculous 
bronchiectatic  cavities  one  or  many  polypoid  tumors  may  project  into  or  fill 
the  cavity,  while  the  walls  are  infiltrated  by  tumor  tissue.  Localized  stenos- 
ing  and  ulcerating  tumors  may  surround  bronchi  of  the  first  or  second  order 
and  on  account  of  their  limitation  to  the  hilus  may  readily  be  overlooked 
(Kaufmann,  Harbitz). 


FIG.  400. — Relations  of  a  squamous-cell  carcinoma  of  bronchus.     (After  Ernst.) 

In  advanced  stages  a  main  tumor  mass  surrounds  the  hilus  and  large 
bronchi,  while  ulcerating  and  usually  dilated  bronchi  form  cavities  in  the 
centers  of  tumor  masses  in  the  affected  lobes.  Extension  to  the  pleura  is 
frequently  observed  in  the  form  of  wide-spread  lymphatic  injection  or  of 
very  marked  thickening.  The  ribs  and  chest  wall  may  be  eroded. 

Secondary  complications  greatly  alter  the  picture.  The  remaining  lung 
tissue  becomes  emphysematous,  atelectatic,  and  sclerosed,  or  pneumonic 
areas  appear  in  the  terminal  stages.  Putrefaction  of  retained  mucus,  pus, 
and  tumor  detritus  often  excites  fatal  gangrene.  Large  vessels  are  eroded  with 
fatal  hemorrhage.  The  tumor  process  extends  into  mediastinum,  pericar- 
dium, auricles,  and  great  veins.  Serous  or  bloody  pleural  effusion  is  very 
frequent. 

The  structure  of  this  type  of  bronchial  carcinoma  is  that  of  squamous-cell  or 
cylindrical  cell  alveolar  carcinoma.  While  the  squamous-cell  tumors  usually 


TUMORS  OF  LUNG  811 

maintain  a  uniform  structure  throughout,  the  cylindrical  cell  growths  often 
vary  extensively  both  in  the  type  and  in  the  arrangement  of  the  cells.  Thus 
many  histological  varieties  of  carcinoma  are  represented  in  these  bronchial 
tumors.  Watsuji  calculates  that  32  per  cent,  of  all  pulmonary  carcinomas 
are  squamous. 

Wolf  found  8  acanthomas  and  7  cylindrical  cell  tumors  among  15  of  bron- 
chial origin.  The  cylindrical  cells  are  arranged  in  small  or  large  groups  or  they 
grow  diffusely.  Adler  describes  a  very  cellular  growth,  medullary  carcinoma, 
which  it  was  difficult  to  separate  from  round-cell  sarcoma.  Harbitz  describes 
a  bilateral  gelatinous  tumor  with  bronchiectatic  cavities,  of  which  the  struc- 
ture was  adenocarcinomatous.  He  also  found  high  cylindrical  cells,  with  mu- 
coid  changes,  proliferating  in  small  bronchi  which  formed  the  centers  of  mul- 
tiple tumor  nodules. 

Horn's  tumor  in  a  young  subject  was  also  adenocarcinomatous  and  grew 
from  a  broad  pedicle  into  a  bronchiectatic  cavity  penetrating  large  and  small 
bronchi.  Chiari  described  a  cylindrical  cell  tumor  of  distinctly  papillary 
structure.  Ernst's  papillary  tumor  contained  hornifying  squamous  epithelium. 

Fibrocarcinomatous  areas  are  often  observed  in  old  lesions  and  in  the 
pleura,  while  in  some  contracted  organs  the  lesion  is  chiefly  of  this  type. 
Spindle-cell  areas  are  occasionally  observed,  and  in  Hodenpyl's  and  Arn- 
stein's  cases  this  form  persisted  in  metastases.  It  is  highly  probable  that  cer- 
tain so-called  spindle-cell  sarcomas  of  the  lung  are  atypical  carcinomas. 

(ft)  Bronchial  Carcinoma  Arising  from  Mucous  Glands. — In  a  consider- 
able series  of  cases  tumors  of  this  origin  have  yielded  somewhat  characteristic 
gross  and  microscopical  features,  which  are:  limitation  chiefly  to  the  walls 
and  especially  to  the  submucosa  of  the  bronchi;  relatively  intact  condition 
of  the  bronchial  lining;  stenosis  rather  than  dilatation  of  the  bronchi;  often 
considerable  infiltration  of  the  parenchyma;  and  a  structure  of  glandular 
carcinoma  recalling  that  of  the  bronchial  mucous  glands.  Typical  cases  of 
this  group  are  described  by  Langhans,  Beck,  Fuchs,  Ebstein,  Ehrlich,  Ron- 
deau, Decreton,  Kretschmar,  Wolf,  and  others.  Hansemann  considers  that 
most  bronchial  cancers  arise  from  the  mucous  "glands. 

A  very  early  stage  is  described  by  Langhans.  The  lower  4  cm.  of  the 
trachea  and  2\  cm.  of  the  bronchi  presented  very  numerous  nodular  eleva- 
tions of  the  mucosa  chiefly  on  the  posterior  aspect,  while  submucosa  and 
adventitia  were  diffusely  thickened.  The  mucous  lining  itself  was  intact. 
The  changes  were  most  advanced  at  the  bifurcation  of  the  trachea,  where  the 
nodules  projected  7  mm.  into  the  lumen  and  caused  a  ring-like  constriction. 
There  were  no  metastases.  The  nodules  proved  to  be  markedly  hyperplastic 
and  carcinomatous  mucous  glands.  The  solid  alveoli  were  composed  of 
small  polyhedral  or  cylindrical  cells  and  extended  through  the  layers  of  mucosa 
and  submucosa  down  to  the  cartilage. 

A  tumor  of  the  size  of  a  cherry  of  glandular  carcinomatous  structure  and 
with  numerous  metastases  is  described  by  Lehmkuhl.  An  advanced  but 
characteristic  condition  is  reported  by  Domeny.  The  tumor  surrounded  and 
compressed  the  larger  bronchi  with  sclerosis,  atelectasis,  atrophy,  and  contrac- 
tion of  the  lung.  The  pleura  was  much  thickened  and  the  hilus  nodes  were 
invaded.  There  was  marked  thickening  of  the  bronchial  mucosa  with  stenosis, 
but,  while  the  mucosa  was  thrown  into  folds,  its  ciliated  lining  was  everywhere 
intact.  In  another  case  the  chief  lesion  was  bronchial  stenosis.  Rondeau 
describes  a  markedly  contracted  and  sclerosed  right  lung  in  which  the  bronchi 
were  almost  completely  occluded,  while  the  pleura  was  4  to  6  cm.  in  thickness. 
The  indurated  tissues  and  pulmonary  lymphatics  were  infiltrated  with  ade- 
nocardnoma  in  which  the  alveoli  contained  colloid  masses.  A  sharp  limita- 


812  NEOPLASTIC  DISEASES 

tion  of  the  peribronchial  tumor  from  the  parenchyma  is  mentioned  by  Beck, 
Meunier,  and  Ducreton.  Gelatinous  changes  were  prominent  in  several  cases, 
and  the  presence  of  much  mucoid  material  led  Willert  to  designate  his  tumor 
as  carcinoma  myxomatodes.  Others  have  referred  mucoid  carcinomas  to  the 
bronchial  lining  epithelium  and  to  the  alveolar  epithelium  (Harbitz,  Le  Sourd). 

The  structure  presents  an  adenocarcinoma  or  alveolar  carcinoma  recalling 
the  mucous  glands  of  the  trachea  and  bronchi.  The  alveoli  may  be  regular, 
lined  by  two  or  more  layers  of  cubical  cells,  and  dilated  or  compactly  filled. 
The  cells  are  usually  of  small  size  and  cubical  or  polymorphous,  while  high 
cylindrical  and  squamous  cells  are  missing.  Highly  malignant  tumors  may 
yield  alveolar  or  diffuse  and  atypical  carcinoma.  The  secretion  of  mucus  is  a 
prominent  feature  and,  while  not  wholly  limited  to  mucous  gland  cancers,  is 
strongly  indicative  of  this  origin.  In  many  cases  the  mucous  secretion  is 
limited  to  single  cells,  but  it  may  fill  or  distend  alveoli  and  lead  to  pronounced 
gelatinous  or  even  cystic  changes  (Coats).  From  this  typical  structure  there 
are  many  variations,  corresponding  to  the  duration  and  malignancy  of  the 
process  and  its  secondary  changes. 

(c)  Carcinoma  arising  from  the  pulmonary  alveoli  is  either  (i)  diffuse  or 
(2)  multiple  and  nodular.  In  the  diffuse  form  one  whole  lobe  or  the  whole 
lung  is  uniformly  consolidated,  while  cavities  may  form  from  necrosis.  The 
lesion  may  resemble  organizing  pneumonia  or  croupous  pneumonia  in  gray 
hepatization  (Levene,  Pepere),  and  there  are  indications  that  the  condition 
may  really  follow  an  atypical  acute  pneumonic  process  (Loser,  Cahen).  The 
pleura  is  usually  involved,  and  local  and  general  metastases  are  frequent. 

In  the  nodular  form  one  or  both  lungs  are  the  seat  of  many  poorly  defined 
tumor  foci  from  miliary  to  marble  size  or  larger.  Even  the  small  nodules  may 
show  necrotic  areas,  and  the  lesions  are  not  always  readily  distinguished 
from  tubercles  (Marchiafava).  The  larger  tumors  may  be  solid  or  cystic. 

The  structure  of  the  diffuse  tumors  presents  partial  or  complete  filling  of 
the  air  vesicles  with  cuboidal,  cylindrical,  or  flat  cells.  The  walls  of  the  vesicles 
may  be  preserved  or  obliterated  by  diffuse  growth  or  by  inflammatory  proc- 
esses. Domeny  and  others  describe  diffuse  carcinomas  of  the  parenchyma 
largely  composed  of  squamous  cells.  Extensive  inflammatory  changes  may 
reduce  the  proportion  of  cells  and  give  excess  of  new  connective  tissue. 
Kretschmar  in  a  diffuse  tumor  described  a  papillary  structure  with  cylindrical 
cells.  Extension  through  the  lung  occurs  by  way  of  the  air  passages,  septa, 
lymphatics,  and  blood-vessels,  which  may  be  found  infiltrated  by  tumor-cells 
(Edlavitch). 

The  structure  of  the  nodular  tumors  was  clearly  pictured  by  Malassez, 
and  presents  groups  of  slightly  dilated  air  vesicles  filled  with  papillary  projec- 
tions of  cylindrical  cells.  The  central  spaces  may  be  occupied  by  desqua- 
mated cells,  mucus,  or  necrotic  material  (La  Sourd).  Multiple  tumors  com- 
posed of  high,  cylindrical  or  goblet-cells  of  adenomatous  type  and  without 
metastases  are  reported  by  Kelly.  A  combination  of  high  cylindrical  cells  in 
papillary  arrangement  and  solid  masses  of  polygonal  cells  was  observed  by 
Knierim  and  attributed  to  a  dual  origin  from  alveolar  and  bronchiolar  epi- 
thelium. Bjornsten  found  many  cystic  tumors  of  both  lungs  in  a  child  of  9 
years,  of  which  the  structure  was  that  of  papillary  cystadenoma  proliferum. 

The  metastases  of  pulmonary  carcinoma  are  usually  very  numerous  and 
wide-spread,  but  vary  greatly  with  the  grade  of  malignancy.  The  vascularity 
of  the  organ  and  the  frequent  invasion  of  blood-vessels  facilitate  dissemina- 
tion, while  the  abundant  lymphatic  channels  lead  to  infection  of  the  bron- 
chial nodes  in  a  high  proportion  of  cases  and  to  early  extension  throughout 
lung  and  pleura.  The  tumors  extend  also  along  the  lumen  of  the  bronchi 


TUMORS  OF  LUNG  813 

replacing  the  mucosa,  but  Stilling's  conclusion  that  aspirated  tumor  par- 
ticles produce  secondary  growths  may  be  doubted.  In  374  cases  Adler  re- 
ports invasion  of  bronchial  nodes  in  117,  mediastinal  45,  tracheal  26,  cervical 
23,  retroperitoneal  23,  and  in  many  other  regions  less  frequently.  The  liver 
was  invaded  in  103  cases,  pleura  52,  pericardium  39,  heart  30,  kidney  58, 
adrenal  38,  spleen  18,  brain  53.  The  bones  were  involved  57  times  and  often 
extensively,  the  ribs,  spine,  skull,  and  sternum  suffering  in  the  order  named. 
In  a  case  reported  by  Turnbull  and  Worthington  the  bones  were  the  sole  seat 
of  metastases.  Metastases  were  absent  in  33  cases. 

Few  organs  fail  to  appear  as  possible  sites  of  secondary  growths,  which 
have  been  noted  in  skin,  finger-tip,  nasal  septum,  eye,  bladder,  tubes,  ovary, 
uterus,  pancreas,  thyroid,  spinal  cord,  and  hypophysis.  Deposits  in  the  vol- 
untary muscles  were  observed  in  9  cases  and  in  i  case  they  were  found  only 
in  this  tissue. 

Histogenesis. — The  exact  sources  of  pulmonary  carcinoma  have  been 
traced  in  detail  by  many  observers  who  have  shown  that  these  tumors  arise 
from  the  bronchial  mucosa,  the  bronchial  mucous  glands,  and  the  alveolar 
epithelium.  The  impression  of  Schottelius  that  the  pulmonary  endothelium 
gives  rise  to  carcinomatoid  tumors  has  not  been  verified. 

Comparatively  few  cases  have  furnished  any  opportunity  to  trace  the 
beginnings  of  pulmonary  carcinoma.  On  the  other  hand,  when  the  evidence 
of  histological  structure,  gross  anatomy,  and  clinical  history  is  combined,  the 
conclusions  regarding  histogenesis  may  be  regarded  as  reasonably  certain  and 
acceptable. 

An  origin  from  bronchial  lining  epithelium  is  indicated  by  extensive  in- 
volvement of  the  bronchial  mucosa  and  by  invasion  chiefly  along  the  bron- 
chial tree.  Papillary  projections  from  atypical  prolifeation  .of  lining  epi- 
thelium were  observed  by  Reinhard  and  Chiari  and  speak  strongly  in  favor 
of  an  origin  from  this  epithelium.  A  high  papillary  structure,  as  in  Chiari's 
case,  has  a  similar  significance.  While  cylindrical  cells  may  be  present  in  all 
forms  of  pulmonary  carcinoma,  the  presence  of  very  high  cylindrical  cells 
and  their  persistence  in  metastases  accords  best  with  an  origin  from  the  bron- 
chial mucosa  (Chiari,  Tillmann,  Peck).  In  a  case  of  alveolar  carcinoma  with 
high  cylindrical  cells  Ravenna  traced  the  rather  sharp  transition  of  the  bron- 
chial lining  into  the  tumor  tissue. 

Bronchial  papillomas  are  probably  a  source  of  malignant  tumors.  Such 
growths  are  much  less  frequent  in  the  bronchi  than  in  the  trachea.  Siegert 
described  such  a  tumor  at  the  bifurcation  and  assumed  that  it  arose  from  a 
misplaced  fetal  remnant,  Werner  described  a  bronchial  papilloma  with 
ciliated  cells.  The  great  majority  of  squamous-cell  tumors  arise  from  bron- 
chial epithelium.  Squamous  metaplasia  of  the  bronchial  mucosa  has  been 
shown  to  be  of  frequent  occurrence  in  tuberculosis  and  other  pulmonary 
lesions,  and  this  change  probably  precedes  the  development  of  carcinoma  in 
many  instances  (Griffini,  Kitamura,  Hay  thorn). 

E.  Froelich  found  extensive  bronchial  pachydermia  with  squamous-cell 
cancer.  It  is  especially  in  and  about  tuberculous  cavities  that  squamous 
alterations  are  observed,  and  in  these  situations  squamous-cell  cancer  is  most 
frequent. 

In  many  cases  squamous  epithelium  is  mingled  with  cuboidal  and  cylin- 
drical cells,  as  in  Kretschmar's  case,  indicating  that  the  metaplasia  may  take 
place  in  the  established  tumor.  In  a  bulky  tumor  of  bronchial  origin  Henrici 
found  non-keratinizing  squamous  mingled  with  cylindrical  cells,  while  in  the 
main  branches  there  were  papillary  projections  and  foci  of  squamous  meta- 
plasia. 


814  N  EOF  LA  STIC  DISEASES 

Bronchial  malformations  appear  to  be  connected  with  the  origin  of  certain 
tumors  which  are  characterized  by  a  cystic  or  papillary  structure  and  by 
abundant  secretion  of  mucus.  Stoerk  describes  cases  of  cystic  malformation 
of  the  lung  in  infants  which  he  refers  to  two  types  of  embryogenic  disturb- 
ance: (i)  overgrowth  of  misplaced  and  fetal  portions  of  the  bronchial  tree; 
(2)  overgrowth  of  areas  of  fetal  bronchiectasis  resulting  from  inflammation 
and  leading  to  occlusion  of  bronchus  and  retention  of  mucus.  He  reports  a 
spongy  fetal  cystic  adenoma  replacing  the  middle  lobe  of  the  right  lung, 
and  presenting  many  cavities  lined  by  bronchial  epithelium.  The  septa  were 
deficient  in  elastic  fibers  and  contained  many  glandlike  alveoli.  Some  tumors 
of  children  and  adults  seem  to  belong  in  this  series.  Aschenborn  found  the 
right  lung  in  a  boy  of  12  years  replaced  by  a  cystocarcinoma  containing  sev- 
eral large  cysts  and  eroding  the  ribs.  Linser  found  a  large  cystadenoma  with 
cellular  stroma  reproducing  fetal  bronchi  in  a  boy  of  13  years.  Couvelaire 
described  a  large  cystadenoma  in  a  newborn  infant  with  many  adenomatous 
alveoli  branching  off  from  abortive  bronchi.  Dionisi's  tumor  recalled  the 
structure  of  thyroid  gland.  Lohlein  describes  a  sharply  circumscribed  tumor 
of  the  right  upper  lobe  exuding  much  mucus  from  cystic  cavities  which  were 
dilated  interlobular  bronchioles.  The  structure  was  of  papillary  projections 
of  cylindrical  epithelium  into  spaces  filled  with  mucus.  This  tumor  was  inter- 
preted as  originating  from  an  area  of  fetal  atelectasis.  Weichselbaum's  small 
coarsely  papillary  adenosarcoma  in  the  lung  of  a  woman  of  67  years  may  rep- 
resent a  late  development  in  a  malformed  bronchiole. 

The  bronchial  mucous  glands  have  been  shown  to  give  origin  to  a  well- 
defined  group  of  pulmonary  growths.  In  a  multiple  nodular  submucous  car- 
cinoma of  trachea  and  bronchi  Langhans  traced  an  unbroken  series  of  hy- 
perplastic  glands,  showing  extensive  overgrowth  of  saccules,  their  dislocation 
between  the  layers  of  connective  tissue,  the  loss  of  membrana  propria,  and 
finally  breaking  up  into  infiltrating  cords  of  tumor-cells.  Beck  and  Rondeau 
also  were  able  to  trace  the  transition  from  hypertrophic  to  neoplastic  glands 
in  more  advanced  tumors.  In  most  cases  the  diagnosis  of  bronchial  gland 
origin  has  been  based  on  gross  anatomy  and  microscopical  structure.  The 
tumors  are  often  distinctly  glandular,  but  many  other  histological  varieties 
probably  arise  from  this  source  (Ehrich,  Fuchs,  Passler).  A  large  scirrhous 
tumor  with  small  round  or  cubical  cells  is  referred  by  Wolf  to  the  bronchial 
glands. 

In  the  pulmonary  parenchyma  it  is  difficult  to  distinguish  the  parts  played 
by  vesicular  and  by  bronchiolar  epithelium,  and  in  many  instances  tumors 
appear  to  arise  from  both  sources.  In  a  multiple  nodular  tumor  Malassez 
described  groups  of  slightly  widened  alveoli  lined  by  papillae  of  low  cylindrical 
epithelium,  but  he  was  unable  to  determine  whether  the  cells  were  alveolar  or 
bronchiolar.  Since  alveolar  epithelium  readily  changes  to  cuboidal  in  atelec- 
tatic  foci,  it  is  clear  that  tumors  with  such  cells  may  originate  in  the  alveoli. 
By  exaggeration  of  the  papillary  structure  and  fusion  of  adjoining  foci  some 
more  diffuse  tumors  may  perhaps  be  safely  traced.  Thus  Knierim  describes 
a  diffuse  tumor  of  the  midlobe  exuding  much  mucus  and  resembling  a  con- 
fluent lobular  pneumonia.  There  was  mucus  in  outlying  alveoli.  The  tumor 
presented  alveoli  and  spaces  lined  by  cylindrical  cells  in  papillary  outgrowths 
and  solid  masses  of  polygonal  cells.  The  papillary  structure  persisted  in  lymph- 
nodes.  The  author  suggested  an  origin  from  both  bronchioles  and  alveoli. 

The  exact  mode  of  origin  of  the  solid  diffuse  carcinomas  is  somewhat 
obscure.  In  many  cases  the  air  vesicles  are  filled  with  solid  masses  of  cubical 
or  cylindrical  cells  suggesting  an  origin  from  altered  alveolar  epithelium  or 
from  the  bronchioles.  Ramon  and  Boidin,  among  others,  found  all  transitions 


TUMORS  OF  LUNG  815 

from  flat  to  cubical  to  neoplastic  epithelium.  The  secondary  changes  of 
atelectasis  seem  to  precede  the  advance  of  the  tumor. 

In  other  cases  the  history  and  the  minute  structure  indicate  that  the 
neoplasm  has  arisen  as  a  sequel  or  incident  of  croupous,  productive,  or  tuber- 
culous pneumonia.  In  a  case  of  supposed  croupous  pneumonia  Loser  was 
unable  to  decide  whether  he  had  an  inflammatory  proliferation  of  endothelial 
or  epithelial  cells,  or  a  true  carcinoma.  Yet  there  were  subpleural  nodules 
of  alveolar  carcinoma. 

Pepere's  small  contracted  lung  resembled  interstitial  pneumonia,  but 
was  the  seat  of  alveolar  carcinoma.  Cahen  found  a  structure  which  he  likened 
to  desquamative  pneumonia.  Diffuse  or  miliary  tuberculous  lesions  in  or 
about  the  tumor  have  suggested  that  the  neoplasm  may  arise  from  exaggerated 
proliferation  connected  with  this  infection  (Wolf,  Domeny).  Many  of  the 
diffuse  carcinomas  arising  from  the  alveolar  epithelium  contain  pavement  or 
distinctly  squamous  cells  (Fuchs,  Grunewald,  Edlavitch,  Domeny).  Menetrier 
could  not  demonstrate  eleidin  granules  in  these  flat  cells,  while  pearls  and 
spine-cells  appear  to  be  limited  to  the  bronchial  tumors.  A  bulky  colloid 
acanthoma  in  the  lung  of  a  dog  was  referred  by  Rievel  to  the  alveolar  epi- 
thelium. 

Symptomatology. — The  symptoms  and  course  of  pulmonary  carcinoma 
vary  extremely  according  to  the  type  of  the  tumor  and  the  conditions  which 
have  led  to  its  development. 

A  large  number  of  cases  have  been  regarded  clinically  as  acute  or  chronic 
phthisis,  and  since  tuberculosis  is  often  present  with  bacilli  in  the  sputum  a 
differential  diagnosis  may  be  impossible.  Other  cases  appear  as  sequels  of 
prolonged  pneumonia.  An  apparently  sudden  onset  is  often  due  to  acute 
changes  in  a  long  existant  tumor.  A  long  history  of  bronchitis  with  or  with- 
out hemoptysis  has  preceded  the  discovery  of  bronchial  tumors.  The  un- 
complicated bronchial  tumor  usually  gives  physical  signs  of  a  progressive 
intrathoracic  growth,  with  cough,  hemoptysis,  pain,  recurring  pleural  effusion, 
serous  or  bloody,  dyspnea,  and  cyanosis.  According  to  Herrmann  about  half 
the  cases  are  of  the  pleuritic  type.  Extensive  infiltration  of  the  pleura  with 
adhesions  may  prevent  effusion.  Fever  must  be  referred  to  complications. 
The  diagnosis  of  a  neoplasm  has  repeatedly  been  made  from  tumor  fragments 
in  sputum  or  pleural  effusion  (Betschart,  Rondeau),  by  #-ray  photography 
(Muser),  and  by  the  bronchoscope  (Karrenstein) .  The  duration  has  varied 
from  4  years  (Adler)  to  10  days  (Jaccoud).  A  fatal  hemoptysis  may  be  the 
only  symptom  (Beveridge,  Degen). 

Cachexia  is  slight  in  uncomplicated  cases,  but  terminal  stages  are  often 
marked  by  suppuration,  pneumonia,  and  gangrene.  Immediate  causes  of 
death  also  include  rupture  of  large  veins,  thrombosis,  pulmonary  edema,  and 
asphyxia. 

In  not  a  few  cases  the  effects  of  metastatic  growths  have  attracted  chief 
attention,  and  have  centered  chiefly  in  the  central  nervous  system  (Coats, 
Domeny,  Wolf).  Finally,  pulmonary  tumors  have  occasionally  appeared  as 
wholly  unsuspected  conditions  at  autopsy. 

Operative  interference  with  pulmonary  tumors  has  been  attempted  by 
Lenhartz,  and  in  i  case  the  excision  of  the  affected  lobe  was  survived  for  18 
months. 

SARCOMA  OF  LUNG 

From  both  clinical  and  pathological  standpoints  sarcoma  of  the  lung  is 
a  very  ill-defined  group  of  processes  of  varied  origin  and  course.  While 
Adler  was  able  to  select  90  cases  from  the  literature,  only  a  minority  of  the 


816  NEOPLASTIC  DISEASES 

reports  present  sufficient  evidence  to  justify  their  separation  from  diffuse 
carcinoma. 

In  not  a  few  cases  the  sarcoma  has  been  associated  with  extensive  chronic 
exudative  necrotic  or  productive  inflammation,  with  abscesses,  gangrene, 
empyema,  or  fistulous  tracts,  which  in  a  reactive  tissue  like  the  lung  may 
readily  lead  to  overgrowth  of  reparative  tissue  simulating  round-  and  spindle- 
cell  sarcoma.  In  another  group  active  tuberculous  lesions  have  been  present 
and  so  intimately  associated  with  the  whole  process  as  to  render  a  distinction 
between  tumor  and  inflammatory  product  somewhat  hazardous.  Thus  Pater 
and  Rivet  found  tubercle  bacilli  in  multiple  nodules  of  large  round-cell  sar- 
coma at  both  bases  and  in  the  liver,  while  Schnick  describes  as  spindle-cell 
sarcoma  a  large  excavated  tumor  mass,  partly  calcined,  in  an  actively  tuber- 
culous lung.  Sangalli's  round-cell  fibrosarcoma,  irregularly  distributed 
throughout  an  old  tuberculous  lung,  does  not  accord  with  the  usual  behavior 
of  sarcoma. 

Old  syphilis  is  strongly  suggested  in  a  curious  cystic  tumor  filled  with 
mucus  and  pus  described  by  Milian  and  Mante.  The  precocious  develop- 
ment of  pulmonary  tumors  secondary  to  growths  in  other  organs,  especially 
in  the  bones,  stands  in  the  way  of  accepting  certain  bulky  spindle-  and  giant- 
cell  tumors  as  primary  in  the  lung.  Before  sarcoma  or  carcinoma  can  be 
regarded  as  primary  in  the  lung  a  very  thorough  search  for  primary  tumors 
in  other  organs  must  be  made.  There  are  possibly  on  record  less  thoroughly 
studied  cases  than  that  of  Lesieur  and  Rome,  who  found  a  massive  apparently 
primary  carcinoma  of  the  lung,  but  in  the  rectum  a  carcinomatous  ulcer. 
Of  the  lymphosarcomas  very  few,  if  any,  can  be  regarded  as  primary  in  the 
lung,  while  in  many  instances  it  is  clear  from  the  anatomical  descriptions 
that  the  tumor  arose  in  the  bronchial  or  mediastinal  nodes  or  the  thymus. 
It  also  appears  that  many  authors  describe  as  lymphosarcoma  any  tumor  in 
which  the  cells  are  small  and  round.  Nearly  all  the  primary  large  and  small 
round-cell  sarcomas  of  the  lung,  as  of  many  other  organs,  are  under  suspicion 
because  of  the  fact  that  atypical  carcinoma  may  yield  exactly  similar  pictures 
in  rapidly  growing  areas.  Adler  among  others  has  pointed  out  the  necessity 
of  extensive  study  of  all  portions  of  such  tumors  and  their  metastases  before 
the  mesoblastic  origin  can  be  assumed.  I  can  support  Fuchs'  statement 
that  areas  of  spindle-cells  may  be  found  in  pulmonary  carcinoma.  Hodenpyl 
found  spindle-cells  in  the  hepatic  and  lymphatic  metastases  of  a  carcinoma. 
The  carcinosarcomas  of  the  lung  are  probably  thus  explained. 

Finally,  no  one  has  succeeded  in  tracing  the  origin  of  any  of  the  malig- 
nant sarcomas  of  the  lung,  and  the  general  field  of  pathological  changes  in 
this  organ  does  not  point  clearly  to  specific  conditions  under  which  meso- 
blastic tumors  may  arise.  The  very  marked  overgrowth  of  endothelium  in 
some  organizing  pneumonias  may  perhaps  have  some  significance. 

Nevertheless  these  uncertainties  hardly  warrant  the  conclusion,  once 
drawn  by  Hertz,  that  primary  sarcoma  of  the  lung  does  not  exist,  for  the  litera- 
ture offers  not  a  few  reports  indicating  that  mesoblastic  tumors  occasionally 
arise  in  this  organ. 

A  provisional  classification  of  pulmonary  sarcoma  based  on  anatomical 
features  may  be  employed  as  follows: 

(1)  Diffuse  spindle-cell  sarcoma. 

(2)  Peribronchial  sarcoma. 

(3)  Large  round-cell  sarcoma. 

(4)  Lymphosarcoma. 

(i)  Diffuse  spindle-cell  sarcoma  produces  a  characteristic  gross  and 
microscopical  picture  and  is  the  best  defined  type  of  pulmonary  sarcoma. 


TUMORS  OF  LUNG  817 

The  tumors  are  usually  bulky,  exceeding  in  size  the  largest  carcinomas. 
Bock's  tumor  in  a  child  filled  the  entire  left  thorax,  obliterating  all  pulmonary 
structures.  The  ribs  may  be  eroded  (Elkan)  and  chest  wall  perforated 
(Koblynski).  Cavities  may  form  from  central  necrosis  and  hemorrhage 
(Ranglaret),  or  the  whole  tumor  may  be  very  soft  and  hemorrhagic  (Rolles- 
ton,  Trevor).  In  several  cases  the  tumor,  while  large,  has  been  well  encap- 
sulated (Fuchs). 

Smaller  firm  tumors  are  usually  fibrous.  In  Chiari's  case  there  was  ex- 
tensive calcification.  Blumental  describes  a  large  myxosarcoma.  Metastases 
are  usually  absent,  but  there  are  extensions  through  lung  and  pleura  and  to 
the  neighboring  nodes. 

The  structure  presents  large  and  small  spindle-cells,  or  occasionally  giant- 
cells,  with  varying  proportions  of  stroma.  This  structure  suggests  an  origin 
from  the  pulmonary  connective  tissue,  as  mentioned  by  Mironescu.  The 
bronchi  may  be  normal  (Rutimeyer). 

(2)  Peribronchial  sarcoma  presents  a  specific  anatomical  distribution 
which  indicates  an  origin  from  the  bronchial  wall,  with  extension  along  the 
bronchus.    The  infiltration  follows  the  bronchi  from  the  root  of  the  lung  or 
trachea  throughout  the  parenchyma  and  into  the  septa  (Peritz,  Pollak). 
The  bronchial  walls  may  be  ulcerated  and  weakened  with  ectasise  (Anderson, 
Levitt)  or  compressed. 

Nearly  all  the  peribronchial  tumors  are  composed  of  small  round-cells 
and  some  are  often  designated  as  lymphosarcoma.  Their  origin  is  obscure. 
Since  the  bronchial  nodes  are  constantly  involved,  the  condition  may  repre- 
sent a  pulmonary  invasion  from  these  nodes.  In  Hildebrand's  case  the  tumor 
arose  in  a  phthisical  lung  and  tubercle  bacilli  were  numerous.  Small  cell 
carcinoma  of  the  bronchi  may  be  difficult  to  distinguish  from  the  round-cell 
tumors  of  this  class. 

(3)  Large  Round-cell  Sarcoma. — This  highly  indefinite  term  may  be  ap- 
plied to  a  group  of  tumors  which  do  not  appear  to  belong  to  lymphosarcomas 
and  which  cannot  be  positively  identified  with  small  cell  diffuse  carcinomas. 
They  differ  from  lymphosarcoma  by  their  limitation  chiefly  to  the  lung. 
Several  cases  have  been  reported  in  children  or  young  subjects,  Bjornsten 
observing  the  disease  at  2  years,  Lehndorff  at  3  years,  Box  at  5  years,  Davies  at 
1 8  years,  and  Poore  and  Pitot  at  20  years.    They  are  usually  bulky,  involving 
the  whole  of  one  lung  with  pleura,  in  a  solid  opaque  tumor  which  obliterates 
most  pulmonary  structures.    In  some  cases  the  tumor  is  smaller  and  encapsu- 
lated (Lehndorf,  Roth).    Areas  of  necrosis  and  large  cavities  may  form.    Met- 
astases are  local  or  absent,  but  there  may  be  extensions  to  hilus,  nodes,  ribs, 
and  vertebrae.    In  the  case  of  Millian  and  Bernard,  of  4  months'  duration, 
the  left  lung  was  represented  by  a  large  cavity  with  sarcomatous  walls. 

The  structure  presents  small  or  large  round  cells  in  diffuse,  perivascular, 
or  alveolar  arrangement.  The  alveolar  structure  described  by  Roth,  Meyer, 
Adami,  and  McDonnell  strongly  suggests  a  carcinomatous  nature. 

(4)  Lymphosarcoma. — Although  a  large  proportion   of  the  round-cell 
tumors  of  the  lung  have  been  described  as  lymphosarcoma,  there  is  no  satis- 
factory evidence  that  true  lymphosarcoma  arises  in  the  pulmonary  paren- 
chyma.    It  seems  much  more  probable  that  the  lymphosarcomas  arise  in 
the  bronchial  or  mediastinal  nodes  or  elsewhere  and  invade  the  lung  along 
the  bronchi.     Such  tumors  present  bulky  masses  about  the  hilus  and  more 
or  less  extensive  invasion  of  the  parenchyma.     Cases  of  this  type  are  de- 
scribed by  Powell,  Cohen  and  Kirkbride,  Coats,  and  others. 

52 


EPIDERMOID  CARCINOMA 
EPIDERMOID  CARCINOMA  OF  SKIN 

Carcinoma  of  the  skin  is  remarkable  for  diversity  of  origin  and  course 
and  variety  of  histological  structure. 

Two  main  histological  types  of  the  tumor  occur:  (i)  Hornifying  cancroid, 
acanthoma,  (2)  basal-cell  carcinoma. 

Of  each  of  these  there  are  several  siibvarieties  which  are  distinguished 
by  structural,  etiological,  or  clinical  features. 

(i)  Acanthoma.— This  tumor  is  distinguished  by  the  presence  of  adult 
squamous  cells,  hornification,  and  pearl  formation.  The  tumors  are  single 
or  multiple.  The  multiple  tumors  may  be  very  numerous  and  widely  dis- 
tributed over  face,  trunk  and  limbs,  and  their  early  stages  may  be  marked 
by  erythema,  seborrhea,  eczema,  or  pruritus. 

The  early  lesion  of  acanthoma  of  the  skin  appears  in  two  main  types  which 
it  is  highly  important  to  distinguish. 

(a)  Many  acanthorrias  pass  through  a  preliminary  papillomatous  stage, 
in  which  they  appear  as  definite  elevated  warty  outgrowths  movable  on  the 
superficial  fascia.  Histologically  these  lesions  are  malignant,  but  they  long 
remain  localized  and  tend  to  spread  laterally.  In  this  phase  they  offer  a  good 
prognosis,  which  is  lost  when  the  lesion  becomes  fixed,  ulcerated,  and  de- 
pressed. 

(b)'  Other  acanthomas  are  flat,  depressed,  indurated,  and  infiltrating 
from  a  very  early  period.  They  are  less  impressive  externally,  but  early 
ulcerate  and  invade  the  deeper  tissues  and  lymph-nodes,  usually  with  a 
tendency  to  assume  the  structure  of  tubular  carcinoma,  in  which  squamous 
characters  are  lost. 

In  the  more  advanced  stages  of  both  types  there  is  erosion  and  ulceration, 
and  the  lesion  gradually  extends  in  the  form  of  a  broad  ulcer  with  raised 
nodular  indurated  edges  and  granulating  base.  Acanthoma  of  the  skin  dif- 
fers from  rodent  ulcer  chiefly  in  its  early  papillary  appearance,  more  rapid 
lateral  extension,  and  more  destructive  course.  Yet  both  types  of  carcinoma 
may  occur  in  the  same  lesion.  Occurring  in  tissues  previously  altered  by 
syphilis,  tuberculosis,  etc.,  its  progress  is  facilitated  by  this  association.  The 
local  aggressive  tendencies  of  acanthoma  tend  to  produce  deep  ulceration 
with  extensions  along  blood-vessels  and  nerves  with  pain  and  hemorrhage, 
and  invasion  of  lymphatics  with  metastases  in  lymph-nodes  and  occasionally 
in  internal  organs.  Bulky  internal  metastases,  however,  are  rare.  The  largest 
I  have  observed  were  in  the  inguinal  nodes  and  liver,  from  epithelioma  of 
prepuce.  Secondary  infection  by  streptococcus  is  nearly  constant  with  deep 
ulcers,  may  accompany  the  metastases,  greatly  influences  the  course  and 
termination,  or  may  even  dominate  the  clinical  picture. 

The  seats  of  single  acanthoma  of  the  skin  are  chiefly  the  mucocutaneous 
junctions,  the  face,  scalp,  chest,  breast,  back  of  hands,  shins,  and  toes.  The 
location  varies  with  the  numerous  peculiar  etiological  factors.  Thus  chim- 

818 


EPIDERMOID  CARCINOMA 


819 


ney- sweep's  and  paraffin  cancers  occur  on  scrotum  and  thighs;  Kangri  cancer 
on  the  abdominal  wall,  while  the  scars  of  burns,  chronic  ulcers,  #-ray  derma- 
titis, and  various  forms  of  trauma  are  followed  by  tumors  in  many  regions. 
Acanthoma  occurs  chiefly  in  advanced  life,  but  has  been  observed  as  early  as 
the  1 4th  year  (Borrmann).  Selberg  has  collected  a  series  of  cases  occurring 
in  infants  and  children. 

Structure. — Acanthoma  of  the  skin  presents  the  most  typical  form  of 
adult  epithelioma  and  tends  to  maintain  this  structure  rather  rigidly.  Hence 
flat  squamous  epithelial  cells,  intercellular  fibrils,  and  pearl  formation  are 
often  observed  both  in  the  primary  tumor  and  in  local  or  distant  metastases. 
Thus  one  finds  in  metastatic  nodules  in  liver  or  bone-marrow  extensive  horni- 
fication,  spine-cells,  and  small  cysts  filled  with  exfoliated  scales,  and  these 


FIG.  401. — A  hornified  pearl  in  acanthoma.     (Photo,  by  B.  H.  Buxton.) 


adult  features  may  be  more  pronounced  than  in  the  primary  tumor.  On  the 
other  hand,  many  acanthomas  lose  their  adult  characters  in  the  growing  edges 
of  the  primary  tumor,  where  the  cells  appear  in  narrow  cords  of  opaque  granular 
cells  with  hyperchromatic  nuclei.  This  structure  may  be  called  "tubular 
acanthoma."  It  is  usually  associated  with  a  high  grade  of  malignancy.  In 
certain  acanthomas  the  coherent  masses  of  epithelial  cells  are  replaced  by  a 
diffuse  growth  of  rounded  cells  each  of  pavement  character.  Giant-cells  may 
be  very  numerous  in  such  tumors  and  may  even  predominate  over  other 
forms.  The  cause  of  such  marked  variations  in  structure  is  not  clear,  but 
edema  seems  to  play  a  part.  Many  peculiarities  of  cell  structure  appear  in 
acanthoma,  which  Unna  has  made  an  effort  to  classify.  These  include  many 
of  the  bodies  once  regarded  as  parasites  and  elaborately  pictured  by  Pianese. 
Unna  has  called  attention  to  a  peculiar  X-cell  seen  in  condyloma  and  acan- 


820  NEOPLASTIC  DISEASES 

thoma.  Its  cytoplasm  is  homogeneous  and  basophilic,  and  its  microchemical 
reactions  have  been  studied  by  Pansini. 

In  the  metastases  there  may  be  great  anaplasia,  and  after  repeated  recur- 
rences there  may  be  entire  loss  of  adult  epithelial  characters  and  the  tumor 
may  appear  as  an  indifferent  round-  or  spindle-cell  growth.  Unless  the  history 
of  such  changes  has  been  followed  an  erroneous  diagnosis  may  be  made. 

Secondary  changes  in  acanthoma  are  numerous  and  frequent.  Polynu- 
clear  leukocytic  infiltration  follows  from  infection.  Round  cells,  lymphocytes, 
and  plasma-cells  may  gather  in  large  numbers  about  early  lesions,  but  dimin- 
ish as  the  tissue  resistance  fails  and  the  rate  of  growth  increases.  Extensive 
calcification  appears  in  some  tumors  without  greatly  influencing  the  course. 
Giant-cells  form  from  fusion  of  tumor-cells  or  from  phagocytic  tissue  cells 
which  gather  about  the  tumor  masses.  Fibrosis  is  prominent  in  most  cases, 


FIG.  402. — Prickle-cell  in  acanthoma.     (Photo,  by  B.  H.  Buxton.} 

•but  seems  to  have  little  effect  in  limiting  growth.  Extensive  hornification 
and  calcification  of  tumor-cells  with  overgrowth  of  hyaline  connective  tissue 
Orth  regards  as  evidence  of  spontaneous  healing. 

-  In  an  interesting  group  of  cases  fatty  degeneration,  necrosis,  and  calcifica- 
tion may  become  very  extensive,  so  as  to  destroy  many  or  all  of  the  epithelial 
cells.  Growth  may  then  be  very  slow,  but  in  time  the  tumor  may  reach  a 
large  size.  In  Landau's  case  it  weighed  250  gm.  Walkohff  reports  a  case  of 
50  years'  duration.  Strassberg  observed  extensive  bone  formation.  The 
exact  nature  of  these  "petrified  epitheliomas"  has  remained  in  doubt.  Barlow 
regards  them  as  forms  of  adenoma  sebaceum,  but  Ribbert  and  most  authors 
consider  that  all  of  them  are  acanthomas. 

•  Etiology. — Acanthoma  of  the  skin  is  almost  exclusively  the  result  of  chronic 
traumatism,  but  the  forms  of  the  irritation  are  extremely  varied,  and  the 


EPIDERMOID  CARCINOMA  821 

relation  to  the  tumor  is  indirect.  Yet  from  the  practical  standpoint  irritation 
is  the  important  factor,  and  all  other  influences,  such  as  heredity,  or  local 
predisposition,  are  secondary.  This  tumor  arises  from  previously  normal 
epithelium  after  a  period  of  overnutrition  and  overgrowth,  during  which 
the  subepithelial  tissues  become  altered  and  less  resistant.  Lymphocytic 
infiltration,  swelling  with  mucoid  or  other  forms  of  degeneration,  followed  by 
atrophy  of  elastic  tissue,  and  chronic  edema  or  fibrosis,  usually  but  not  al- 
ways precede  the  downward  growth  of  epithelium.  Yet  the  controlling  influ- 
ence must,  I  believe,  be  regarded  as  inherent  in  the  epithelial  cell.  All  cuta- 
neous epithelium  must  be  considered  capable  of  developing  acanthoma,  for 
which  it  is  only  necessary  to  supply  the  proper  conditions.  These  conclusions 
seem  to  be  justified  especially  by  study  of  the  conditions  under  which  acan- 


FIG.  403. — Giant-cell  forming  about  an  epithelial  pearl  in  acanthoma.    (Photo,  by  B.  H. 

Buxton.} 


thoma  occurs.  Thus  the  peculiar  irritation  to  which  chimney  sweepers  and 
paraffin  workers  are  sometimes  exposed  determines  a  peculiar  localization 
of  the  disease.  The  observations  on  Kangri  cancer  of  Indian  natives,  which 
develops  on  the  abdominal  wall  at  the  point  of  irritation  of  a  hot  earthen 
oven,  is  a  very  direct  demonstration  of  the  rule.  #-Ray  dermatitis  appears 
to  occur  indifferently  in  any  region  where  the  rays  may  have  been  applied. 
Yet  there  is  some  evidence  of  a  personal  predisposition  to  #-ray  dermatitis 
and  its  sequelae.  Chronic  ulceration,  eczema,  lupus,  and  the  scars  of  burns 
present  somewhat  more  complex  but  essentially  the  same  conditions  in  which 
acanthoma  develops.  In  the  localization  about  mucocutaneous  junctions  there 
is  an  added  factor  in  the  anatomy  of  these  regions,  as  well  as  increased  ex- 
posure to  trauma.  Cheatle  believes  that  cutaneous  cancer  develops  mainly 
at  the  points  where  nerve-trunks  reach  the  skin,  and  tend  to  spread  chiefly 


822 


NEOPLASTIC  DISEASES 


in-such  areas  of  nerve  distribution.    Warts,  both  simple  and  venereal,  may  be 
the :  starting-points  of  acanthoma . 

Some  very  malignant  acanthomas  have  developed  after  the  bites  of  ani- 
mals, especially  the  horse,  and  of  insects. 

In  a  series  of  cases  of  acanthoma,  chiefly  of  the  face,  Borrel  has  found  a 
parasitic  insect,  Demodex  folliculorum,  which  he  regards  as  the  direct  exciting 
cause  of  the  tumor.  He  finds  that  about  50  per  cent,  of  all  subjects  show  an 
invasion  of  the  skin  by  this  insect.  I  have  observed  the  structures  he  depicts 
in  acanthoma,  but  find  it  difficult  to  draw  any  conclusions  concerning  their 
significance. 

;:B.  Fischer,  by  injections  of  sudan  III  in  olive  oil,  produced  hyperplasia 
of  epithelium  and  downward  growth  resembling  epithelioma,  but  the  proc- 
ess ceases  when  the  oil  is  extruded.  Specific  "attraxines"  of  this  and  other 
types  may  well  exist,  including  derivatives  of  insect  bodies,  but  the  scope  of 
their  activity  in  human  acanthoma  remains  to  be  determined. 

Certain  deep  acanthomas  arising  from  particular  conditions  require 
mention.  The  sebaceous  cyst  sometimes  develops  a  somewhat  malignant 

deep  epithelioma,  in  which  the  char- 
acters of  the  duct-cells  are  promi- 
nent. The  true  congenital  epider- 
moid  cyst  of  the  skin  is  another 
source  of  deep  epithelioma.  The 
branchiogenic  cyst  is  a  frequent 
source  of  deep  and  often  very  malig- 
nant acanthoma  of  the  neck.  This 
tumor  may  appear  anywhere  from 
the  mastoid  to  the  clavicle  and  often 
reaches  considerable  development  be- 
fore its  true  nature  is  recognized. 

Many  other  congenital  dermoid 
cysts  have  given  rise  to  deep  epithe- 
lioma. These  occur  chiefly  in  the 
neck,  head,  buttock,  navel,  and  wher- 
ever embryonal  fissures  form  (Krische, 
Mertens,  Linser).  In  the  breast 
Kaufma'nn  found  a  deep  dermoid 
with  epitheliomatous  changes,  asso- 
ciated with  carcinoma  of  the  breast. 
The  frontal  dermoid  appears  beneath 
the  skin  of  the  forehead,  or  within  the 
tables  of  the  skull,  or  within  the  cra- 
nial cavity,  where  it  may  present  the 
changes  of  acanthoma,  usually  with 
bulky  lamellated  concretions  of  horny 
scales  (Hartley).  Occasionally  it  shows  an  opening  through  the  scalp.  Em- 
bryomas  of  ovary  or  testis  may  be  the  seat  of  epitheliomatous  change  of  the 
skin.  I  have  studied  an  ovarian  dermoid  which  ruptured  into  the  colon,  and 
presented  a  papillary  acanthoma  at  one  point  invading  the  rest  of  the  com- 
plex tumor. 

Xeroderma  pigmentosum  is  a  condition  regarded  by  many  as  an  aggra- 
vated form  and  sequel  of  the  common  lentigines  (freckles).  It  is  marked  by 
overgrowth  of  pigmented  epithelium,  scaling,  even  ulceration,  and  eventually 
by  atrophy  of  the  affected  skin  (Crocker).  Several  tumor-like  processes  in 
the  derma  have  been  described  as  secondary  to  the  disease,  as  angioma,  my- 


FIG.  404. — Xeroderma  pigmentosum  with 
multiple  epidermoid  carcinomas. 


EPIDERMOID  CARCINOMA  823 

oma,  pigmented  sarcoma,  and  especially  epithelioma.  The  epitheliomas  may 
be  of  the  type  of  acanthoma  or  of  rodent  ulcer  (Kreibich,  Fernet,  Halle). 
They  are  often  pigmented,  as  in  sailor's  carcinoma  (Unna).  Hutchinson 
described  as  lentigo  maligna  juvenilis,  v.  senilis,  cases  of  progressive  freckles 
of  cheek  and  eyelid  which  become  the  seat  of  epithelioma.  It  occurs  chiefly 
between  the  seventh  and  ninth  years  (juvenile)  or  in  old  age.  It  appeared 
in  7  of  8  boys  in  one  family  in  which  5  girls  were  unaffected  (Ruder).  The 
exciting  cause  is  exposure  to  sunlight,  acting  on  the  skin  of  constitution- 
ally and  congenitally  predisposed  subjects  (Councilman,  Magrath).  Accord- 
ing to  Dalous  and  Constantin  the  most  marked  feature  of  xeroderma  is  atrophy 
and  scarring  of  the  derma,  with  secondary  carcinoma,  while  Unna's  pigmentecj 
epithelioma  is  a  primary  miniature  carcinoma. 

That  the  prolonged  use  of  arsenic  has  an  influence  upon  the  development 
of  epithelioma  of  the  skin  has  been  urged  especially  by  Hutchinson,  who 
reported  2  cases.  The  first  effects  are  a  hardening  and  pigmentation,  the 
appearance  of  palmar  or  plantar  psoriasis,  followed  later  by  epithelioma. 
Darier  observed  multiple  carcinoma  following  xeroderma  pigmentosum  which 
resulted  from  excessive  use  of  arsenic.  Fordyce  described  characteristic  cell 
changes  in  the  epidermis. 

Lupus  Carcinoma. — Epithelioma  develops  in  a  considerable  proportion 
of  cases  of  lupus  vulgaris  and  much  less  frequently  with  1.  erythematodes 
(Ashihara,  Lit.).  It  arises  both  in  the  active  regions  of  the  tuberculous  proc- 
ess in  skin  or  mucous  membranes  and  in  about  30  per  cent,  of  cases  in  the 
lupus  scar  tissue  (Steinhauser),  and  as  early  as  the  fourth  or  as  late  as  the 
fifty-fifth  year  of  the  original  disease,  the  average  period  being  about  the 
thirtieth  year.  In  many  cases  but  not  in  all  the  course  is  relatively  rapid  for 
cutaneous  carcinoma,  with  invasion  of  lymph-nodes  and  internal  growths. 
The  prognosis  is  very  grave,  only  9  cases  of  Ashihara's  list  of  122  re- 
covering. 

The  initial  stages  of  lupus  carcinoma  may  be  somewhat  difficult  to  sepa- 
rate from  the  usual  hyperplasia  and  displacement  of  epithelium  in  the  lupus 
process.  As  a  rule  the  tumor  appears  in  multiple  foci  with  the  usual  local 
signs  and  increased  destruction  of  tissue.  The  structure  is  that  of  acanthoma, 
becoming  tubular  and  atypical  in  advanced  stages  and  metastatic  areas. 
Lupus  erythematodes  has  been  followed  by  carcinoma  in  7  reported  cases 
collected  by  Ashihara.  Hartzell  reports  i  case  after  tuberculosis  cutis  ver- 
rucosa,  and  Blaschko  observed  a  case  with  leprosy.  'Several  cases  developing 
in  leutic  scars  are  mentioned  by  Ashihara,  and  Rabaioye  reported  a  case  fol- 
lowing blastomycosis.  Senger  reports  a  case  of  malignant  recurring  sarcoma 
following  lupus. 

JC-Ray  Dermatitis  and  Carcinoma. — A  single  severe  exposure  to  x-ray, 
or  repeated  slight  exposures,  lead  to  a  peculiar  form  of  dermatitis  which  in 
many  instances  has  been  followed  by  multiple  acanthoma  of  the  skin,  and  in 
not  a  few  cases  by  fatal  extension  of  the  tumor  process  to  internal  organs. 
The  growth  of  knowledge  in  this  field  has  been  coincident  with  the  develop- 
ment of  the  lesions  in  the  unfortunate  early  workers  with  x-ray,  who  watched 
the  appearance  first  of  the  acute  dermatitis,  then  of  the  thickened  skin, 
alopecia,  telangiectases,  ribbed  nails,  and  keratosis,  and  later  of  the  warty 
outgrowths,  ulceration,  and  finally  malignant  carcinoma.  Since  the,  first 
formal  report  of  these  lesions  (Marcuse,  1896)  observations  have  multiplied 
rapidly.  In  1900  Kienbock  gave  a  very  full  description  of  the  dermatitis 
and  its  immediate  sequelae  and  pointed  out  methods  of  avoiding  the  "soft" 
or  burning  rays.  The  development  of  fatal  carcinoma  began  to  be  reported 
in  1904  (Porter),  and  at  the  time  the  urgent  interest  in  the  subject  brought 


824 


NEOPLASTIC  DISEASES 


out  the  careful  histological  study  of  Unna  and  the  experimental  work  of 
Gassmann  and  of  Linser. 

Clinical  Course. — re-Ray  dermatitis  appears  in  the  form  of  an  erythema 
which  follows  a  few  hours  after  the  application  and  varies  in  intensity  and 
character  with  that  of  the  energy  employed.  The  immediate  effects  have 
been  compared  with  heat  burns  of  various  degrees.  Many  of  these  lesions  soon 
run  into  ulceration  which  long  remains  painful  and  indolent. 

After  repeated  slight  exposures  a  period  of  incubation  is  commonly  ob- 
served, lasting  from  3  to  n  years  and  marked  by  thickening  of  the  skin,  dry- 
ness,  scaling,  fissures,  keratosis,  alopecia,  and  cyanosis.  At  any  time  in  this 
period  local  warty  areas  of  keratosis  may  form  or  painful  ulceration  develops. 
The  deeper  tissues  being  involved,  whole  phalanges  or  limbs  may  be  destroyed 
by  a  dry  gangrenous  process.  Carcinoma  develops  either  on  a  severe  acute 
burn  after  prolonged  ulceration  (Porter)  or  after  the  more  chronic  changes 
which  have  not  been  preceded  by  any  severe  acute  dermatitis,  and  it  has  fre- 
quently arisen  as  a  combined  result  of  a  lupus  or  other  lesion  treated  by  #-ray. 
Da  Costa  found  that  18  per  cent,  of  lupus  cases  develop  carcinoma  after 


FIG.  405. — Epidermoid  carcinoma  following  x-ray  dermatitis. 

x-ray  treatment,  but  carcinoma  is  by  no  means  uncommon  in  untreated 
lupus.  The  carcinoma  occurs  in  the  bases  and  edges  of  ulcers,  or  beneath 
multiple  foci  of  keratosis,  and  both  because  of  its  initial  malignancy  and  from 
the  progressive  development  of  new  foci  it  is  extremely  difficult  to  combat. 
Involvement  of  lymph-nodes  and  internal  metastases  follow,  with  death,  as 
recorded  in  at  least  9  cases  (Porter). 

Structure. — The  early  lesions  are  those  of  a  subacute  exudative  inflamma- 
tion hi  which  vascular  lesions  are  prominent.  Linser,  who  excised  pieces  of 
skin  at  intervals  during  treatment  for  lupus,  found  thrombi  hi  the  vessels 
in  4  days,  which  with  swelling  and  desquamation  of  endothelium  reached  an 
acme  in  8  eight  days,  and  was  followed  by  obliterating  endarteritis.  Unna 
emphasizes  the  telangiectasis,  which  he  refers  to  deep  obliterating  endo- 
phlebitis.  In  a  severe  burn  of  30  days'  standing  I  find  hyaline  necrosis  of 
endothelium  and  entire  wall  of  venules,  wide  subepithelial  telangiectases, 
extensive  edema,  general  infiltration  with  lymphocytes,  swelling  of  collagen 
fibrils,  hydrops  of  the  epithelium,  and  beginning  keratosis. 


EPIDERMOID  CARCINOMA 


825 


In  more  chronic  lesions  fibrosis  and  atrophy  are  predominant,  so  that  the 
condition  resembles  premature  senescence  (Lindhorn).  Wolbach,  who  finds 
foci  of  necrosis  in  the  corium  after  many  months,  interprets  the  lesions  as 
the  result  of  progressive  degeneration  from  vascular  changes  and  imperfect 
efforts  at  repair.  The  lymphatics  are  obliterated  by  endothelial  proliferation 
(Gassmann).  The  muscle-tissue,  at  first  swollen  and  vacuolated,  atrophies 
and  disappears.  The  connective-tissue  cells  are  swollen  and  multiplied  and 
their  nuclei  may  be  hyperchromatic.  Exaggeration  of  this  feature  has  led 


1  FIG.  406. — Chronic  x-ray  dermatitis.  Precancerous  stage.  Showing  keratosis,  telan- 
giectasis,  destruction  of  collagen  fibrils,  lymphocytic  infiltration,  hypertrophy  and  hyper- 
chromatism  of  epithelial  cells,  and  beginning  heterotopia  of  epithelium. 

to  conditions  interpreted  by  some  as  sarcoma  (Schumann,  Lit.).  I  have 
seen  one  case  of  this  type,  but  the  conditions  were  too  obscure  for  positive 
diagnosis.  The  structure  resembled  that  of  Clunet's  experimental  #-ray 
sarcoma  in  a  rat.  The  epithelium  is  altered  from  the  first,  showing  hydropic 
degeneration,  keratosis  or  scaling,  and  erosion  and  overnutrition  of  the  deeper 
layers  of  cells.  Proliferation  of  these  cells,  usually  under  a  thick  covering 
of  keratin,  gradually  leads  to  downward  growth  into  the  edematous  corium, 
or  into  dilated  thrombosed  vessels  (Wolbach).  In  this  stage  the  structure  is 
usually  that  of  acanthoma  or  tubular  epithelioma. 


826 


NEOPLASTIC  DISEASES 


Much  use  has  been  made  of  this  experimental  cancer,  especially  by  Wyss, 
for  its  bearing  on  the  genesis  of  epithelioma,  but  it  does  not  appear  that  the 
factors  concerned  in  x-ray  cancer  are  simpler  than  in  other  conditions.  A 
specific  change  in  the  blood  rendering  it  injurious  to  vessels  and  cells  (Unna), 
repeated  efforts  at  regeneration  (Wolbach),  disturbed  relations  of  tissue 
tension  from  dermal  fibrosis  (Wyss),  and  acceleration  of  autolytic  processes, 
all  deserve  consideration.  Those  who  assume  that  the  dense  fibrosis  of  the 
deeper  corium  is  the  essential  factor  have  perhaps  underestimated  the  im- 
portance of  the  changes  in  the  epithelium  which  are  constantly  present. 

Paget's  disease  is  a  specific  chronic  progressive  disease  of  the  epithelium 
of  the  mammary  nipple  and  adjoining  skin  which  is  closely  related  to  and 
almost  invariably  followed  by  carcinoma.  It  is  probably  to  be  interpreted  as 


FIG.  407. — Diffuse  carcinoma  of  breast  (Paget's  disease). 


a  precancerous  affection  at  first  limited  to  the  epidermis  and  the  gland  ducts, 
but  later  becomes  true  carcinoma.  Commonly  included  under  this  term  are 
also  cases  of  diffuse  carcinoma  of  the  breast  which  invade  the  skin  at  the 
nipple  and  extend  widely  over  one  or  both  breasts,  often  with  marked  hyper- 
emia. 

It  first  appears  as  a  keratosis  of  the  nipple,  soon  followed  by  an  itching 
eczematoid  condition  of  the  nipple  and  surrounding  skin  which  extends  in 
continuous  concentric  areas  over  most  of  the  breast,  producing  a  moist, 
slightly  indurated,  glazed,  partly  eroded  or  scaling  surface  that  shows  no 
tendency  to  heal.  Extensions  over  the  axilla  and  much  of  the  thorax  have 
been  observed  (Kaufmann,  Vignoli-Lutati),  and  the  disease  may  occur  in  the 
skin  of  penis,  scrotum,  vulya,  navel,  abdominal  wall,  or  axilla  (Zieler,  Lit.). 


EPIDERMOID  CARCINOMA 


827 


It  begins  usually  between  the  ages  of  40  and  60  years  and  commonly  runs  a 
very  chronic  course  of  10  or  even  20  years  before  death  from  the  associated 
carcinoma  or  from  intercurrent  diseases.  The  nipple  is  usually  retracted  and 
a  definite  carcinoma  of  this  portion  of  the  breast  may  be  present  from  the  first, 
or  develop  later.  These  tumors  may  run  a  rapidly  fatal  course  (Krogius),  but 
more  often  their  progress  is  relatively  slow. 

Structure. — The  earliest  changes  have  been  located  in  the  squamous  epi- 
thelium of  the  nipple,  or  in  the  milk-ducts  below  the  nipple  (De  Page),  or  in 
the  parenchyma  of  the  gland  (Kryle,  Elbogen),  but  it  is  doubtful  if  the  very 
earliest  stages  of  the  process  have  been  observed.  Usually  both  epidermis  and 
milk-ducts  are  found  to  be  affected,  and  the  fact  that  the  lesion  is  not  always 
continuous  from  one  to  the  other  is  referred  by  Jacobeus  to  a  sphincter  action 


FIG.  408. — Mammary  cancer, 


Carcinoma  simplex. 
Paget's  disease. 


Duct  carcinoma  associated  with 


of  the  tissues  at  the  mouths  of  ducts.  In  the  epidermis  characteristic  "Paget's 
cells"  appear  as  swollen,  rounded,  clear  staining  hydropic  cells,  single  or  in 
small  groups,  with  hyperchromatic  nuclei  often  in  mitosis.  Many  observers 
have  traced  their  derivation  from  the  normal  prickle  cells,  by  a  process  of 
hydropic  degeneration  with  loss  of  fibrils  (cellules  dyskeratosiques,  Darier). 
Sekiguchi  regards  them  as  wandering  carcinoma  cells.  The  marked  isolation 
of  some  of  these  cells,  especially  when  small,  rounded,  and  pigmented,  led 
Darier  to  regard  them  as  psorosperms.  The  Malpighian  layer  containing  these 
cells  is  usually  thickened  and  the  papillae  elongated.  The  corium  is  usually 
rich  in  plasma-cells.  In  advanced  stages  much  of  the  epidermis  is  replaced  by 
Paget's  cells,  which  appear  in  alveolar  groups  or  sheets  or  extend  along  the 
basal  portions  and  into  sweat-glands.  The  basal  layer  alone  may  exhibit  the 


828 


NEOPLASTIC  DISEASES 


characteristic  changes  (Zieler).  In  the  milk-ducts  a  similar  process  is  usually 
present,  but  Unna  and  Karg  both  found  lesions  limited  to  the  epidermis,  with 
milk-ducts  intact.  A  notable  feature  is  the  long  integrity  of  the  corium,  but 
eventually  there  may  be  invasion  of  the  connective  tissue  from  the  enlarged 
rete  pegs.  Many  have  noted  the  long  delay  in  the  appearance  of  the  usual 
structure  of  carcinoma,  which  takes  the  form  of  an  adenoid  growth.  Pearl 
formation  was  observed  by  Darier.  In  Krogius'  case  the  secondary  carcinoma 
was  thought  to  be  derived  from  the  sweat-glands. 

The  exact  nature  and  origin  of  Paget's  disease  remain  a  subject  of  active 
discussion  and  it  seems  probable  that  the  disease  in  its  various  stages  is  not 
always  one  and  the  same.  The  long  duration  of  the  disease,  the  very  wide 


FIG.  409.  —  Paget's  disease  of  the  buttock,  showing  edema  and  vacuolization  of  cells. 
(From  collection  of  Dr.  J.  A.  Fordyce.) 


and  superficial  extent  of  the  lesion,  the  occurrence  in  several  regions  besides 
the  breast,  and  the  long  absence  of  any  definite  tumor  render  it  unlikely 
that  the  condition  can  be  dismissed  as  a  peculiar  form  of  skin  invasion  by 
duct  carcinoma.  There  are  many  cases  of  epidermal  invasion  by  mammary 
and  other  cancers,  but  they  rarely  take  the  form  of  Paget's  disease.  Hence 
Darier,  Unna,  and  many  others  regard  the  condition  as  a  disease  sui  generis, 
and  a  type  of  precancerous  condition.  Zieler  draws  an  apt  parallel  between 
Paget's  disease  and  xeroderma  pigmentosum,  both  of  which  represent  pri- 
mary disturbances  of  the  epidermis  which  tend  to  result  in  cancer.  For  many 
very  extensive  lesions  without  definite  localized  carcinoma  this  interpretation 
is  probably  correct.  Such  a  case  is  that  of  Fox  and  McLeod,  who  were  unable 
to  find  any  definite  primary  tumor  associated  with  Paget's  disease  of  the 


EPIDERMOID  CARCINOMA 


829 


navel  of  n  years'  duration.  Others,  rinding  a  definite  tumor  of  the  breast  or 
nipple  regard  the  disease  as  nothing  more  than  an  early  and  extensive  intra- 
epidermal  growth  of  a  primary  cancer  of  the  mamma  (Jacobaeus,  Ribbert, 
Schambacher,  Hirschel,  Sekiguchi).  My  own  observations  indicate  that 
Paget's  disease  occurs  in  two  quite  different  forms:  (i)  The  characteristic 
changes  in  the  epithelium  affect  the  epidermis  about  the  nipple,  but  do  not 
extend  deeply  into  the  milk-ducts.  There  is  no  tumor  of  the  breast.  The 
progress  is  slow,  and  the  prognosis  favorable.  (2)  A  rapidly  progressive 
carcinoma  of  the  breast,  probably  arising  from  the  ducts,  extends  through 
the  nipple  to  the  skin  and  spreads  widely  over  the  breast.  There  is  often 
no  definable  tumor  of  the  breast,  but  rather  a  diffuse  invasion  of  much  of 


FIG.  410. — Paget's  disease.  Lesion  of  the  buttock  showing  epidermal  hyperplasia, 
edema,  vacuolation,  loss  of  prickles,  and  multinuclear  cells.  (Photo,  from  collection  of 
Dr.  J.  A.  Fordyce.) 

the  organ,  with  general  swelling  and  early  metastases.  The  course  of  the  dis- 
ease is  rapid  and  the  prognosis  highly  unfavorable. 

Hannemuller  and  Landois,  while  accepting  the  origin  from  a  primary 
carcinoma  of  the  breast,  interpret  the  Paget  cells  as  swollen  overactive  ede- 
matous  epidermal  cells.  Others  again,  and  among  them  some  of  the  earlier 
observers,  regard  the  process  as  a  peculiar  form  of  primary  cancer  of  the 
skin  (Thin,  Duhring  and  Wile,  Ehrhardt).  Thus  the  three  main  theories  cover 
a  precancerous  condition,  a  definite  carcinoma  of  the  skin,  and  a  growth,  some- 
times early,  more  often  terminal,  of  the  breast,  so  that  the  composite  picture 
of  Paget's  disease  presents  prolonged  stages  of  the  evolution  of  carcinoma. 

Whatever  the  histogenesis  may  be,  remarkable  clinical  and  anatomical 
characters  are  quite  sufficient  ground  for  recognizing  the  condition  as  a  specific 


830 


NEOPLASTIC  DISEASES 


malady.  According  to  Fabry  and  Trautmann  there  is  also  a  specific  etiological 
factor  in  the  presence  of  an  yeast  which  they  were  able  to  cultivate,  but  which 
is  probably  a  secondary  invader. 

(2)  Basal-cell  Epithelioma. — Two  somewhat  distinct  but  related  histo- 
logical  types  of  tumors  develop  chiefly  or  exclusively  from  the  basal  cells  of  the 
Malpighian  layer  of  the  skin,  viz.,  (a)  Reticulated  epithelioma,  and  (b)  ade- 
noid epithelioma. 

(a)  Reticulated  Epithelioma.  Rodent  Ulcer. — The  characteristic  clinical 
history  of  this  disease  is  associated  with  a  specific  histological  structure. 
It  occurs  chiefly  on  the  face,  neck,  and  scalp,  at  mucocutaneous  junctions, 
especially  about  eye,  nares,  or  ear,  and  is  notably  limited  to  adult  or  advanced 
ages.  Williams  finds  the  average  age  42  to  44  years,  but  records  a  case  in  a 
girl  at  14  years  fatal  at  36  years. 


FIG.  411. — Basal-cell  carcinoma  of  scalp. 


It  first  appears  as  a  flat  papule  or  smooth  wart  which  long  remains  without 
marked  change,  or  what  is  mistaken  for  a  pimple  maintains  a  persistent 
ulceration  which  resists  efforts  at  cure.  The  early  lesions  may  appear  as 
broader  flat  elevations  or  as  multiple  small  thickenings  which  coalesce.  Occa- 
sionally in  cases  of  multiple  tumors  there  is  a  history  of  local  erythema,  ec- 
zema, or  seborrhea  (Janeway).  After  a  period  which  may  cover  several  years 
and  often  marked  by  inadequate  therapeutic  procedures  and  other  forms  of 
trauma  the  lesion  ulcerates.  The  characteristic  rodent  ulcer  shows  a  remark- 
able tendency  to  remain  superficial.  It  destroys  the  skin  down  to  superficial 
fascia,  where  its  progress  is  long  restrained.  Later  it  strips  the  tissues  down 
to  bone  or  muscle,  where  again  it  makes  slow  progress.  Thus  the  base  varies 
in  depth,  but  is  usually  covered  by  granulation  tissue  and  warty  islands  of 
tumor.  Extensive  fibrosis  of  the  base  may  limit  the  downward  growth  and  at 


EPIDERMOID  CARCINOMA  831 

the  same  time  obstruct  any  natural  or  artificial  efforts  at  cure.  The  secretion 
is  first  thin  and  serous,  later  purulent,  and  with  frequent  small  bleedings.  The 
edges  are  raised,  nodular,  indurated,  pearly,  and  constantly  hyperemic.  The 
vicinity  may  be  glazed  and  hyperemic  over  a  wide  margin  or  the  indurated 
border  may  be  sharply  marked.  Extension  being  through  the  superficial 
lymphatics,  new  areas  when  involved  first  show  subepithelial  nodules  which 
later  break  through  the  epidermis.  As  the  ulcer  widens  there  may  be  a  distinct 
tendency  toward  healing  in  the  older  areas. 

In  advanced  stages  the  dimensions  of  the  rodent  ulcer  become  very  wide, 
involving  much  of  the  face,  neck,  or  scalp.    The  destruction  of  tissue  becomes 


FIG.   412. — Structure   of  a   basal-cell   carcinoma  of  skin.      Widely   infiltrating   under 

normal  epidermis. 

deeper,  especially  with  the  aid  of  incomplete  excision.  The  eye,  ear,  and 
nose  are  often  completely  destroyed.  The  periosteum  is  invaded  with  de- 
struction of  bone,  with  penetration  of  bony  sinuses,  cranium  and  middle  ear, 
or  bone-marrow.  Erosion  of  large  vessels  may  lead  to  fatal  hemorrhage. 
Cachexia  results  chiefly  from  chronic  suppuration,  hemorrhages,  and  mental 
depression. 

Rodent  ulcer  seldom  involves  the  lymph-nodes  even  after  many  years 
of  growth,  but  in  a  few  cases  the  regional  nodes  become  invaded  and  the 
progress  is  more  rapid  with  certain  changes  in  structure  (Dubreuilh,  Auche, 
Fordyce). 

Crateriform  tdcer  is  a  special  variety  of.  rodent  ulcer  which  appears  on 


832 


NEOPLASTIC  DISEASES 


the  face  in  the  form  of  a  conical  induration  which  resembles  a  furuncle.  In 
a  few  months  it  ulcerates  deeply,  involves  lymph-nodes,  and  proves  fatal  in 
i  to  2  years,  but  early  excision  is  usually  successful  (Hutchinson). 

Many  of  the  clinical  features  of  rodent  ulcer  may  be  simulated  by  a  less 
malignant  low  papillary  acanthoma  of  wide  extent. 

The  structure  of  rodent  ulcer  is  usually  characteristic  and  uniform.  Sec- 
tion shows  relatively  bulky  compact  masses  of  darkly  staining  cells  connected 
by  narrow  strands  of  similar  cells,  all  lying  in  dilated  lymph-channels  or 
artificial  spaces  from  which  they  readily  shrink  on  hardening  (reticulated 
epithelioma).  Or  the  cells  appear  in  narrower  columns  separated  by  hyaline 
connective  tissue  after  the  manner  of  cylindroma.  Or  large  cell  masses  may 
exhibit  numerous  small  clear  areas  resulting  from  mucous  degeneration,  and 
these  spaces  may  reach  the  size  of  small  cysts.  In  cases  with  a  certain  adenoid 
character  the  cystic  structure  may  approach  that  of  adenoid  cystic  epithelioma. 


*->wf<e  ,••   j^a«r''a(W^«»rv«?««TT'TH-'»t«E'i.  _••  wr**i .  >T»v»>»7r"*»  /a. .•-^aEvr.iwms  »:.-»., 'fx^af 

FIG.  413. — A  basal-cell  carcinoma  of  skin,  showing  origin  from  rete  pegs. 


The  whole  tumor  mass  usually  appears  well  circumscribed  and  sepa- 
rated from  the  overlying  epithelium,  and  in  all  ordinary  forms  of  the  disease 
a  derivation  from  the  overlying  epithelium  cannot  be  demonstrated.  This 
rule  is,  however,  not  invariable  and  is  quite  inapplicable  to  the  earliest  stages. 
In  advancing  lesions  long  slender  strands  of  tumor-cells  may  be  traced  for 
some  distance  through  the  lymphatics  and  eventually  connecting  with  what 
may  appear  to  be  multiple  foci  of  origin.  This  histological  feature  explains 
the  persistent  recurrence  of  these  tumors  after  apparently  thorough  extirpation. 

The  tumor-cells  resemble  the  basal  cells  of  the  epidermis  and  are  small, 
polyhedral  or  spindle,  with  relatively  large  vesicular  nuclei,  minute  nucleoli, 
and  scanty  cytoplasm.  Flat  pavement  characters,  spines,  hornification, 
and  pearl  formation  are  regularly  absent,  but  in  rare  cases  may  appear  in 
traces.  Definite  combinations  of  acanthoma  and  reticulated  epithelioma 
have  been  observed.  In  certain  cases  which  clinically  and  anatomically 


EPIDERMOID  CARCINOMA 


833 


resemble  rodent  ulcer  the  structure  presents  convoluted  or  lenticular  rows 
of  columnar  cells  which  suggest  an  approach  to  the  type  of  adenoid  epithe- 
lioma.  In  a  few  cases  all  the  cells  are  of  spindle  form  and  closely  resemble 
spindle-cell  sarcoma.  Thus  the  cells  of  rodent  ulcer  tend  to  maintain 
their  original  and  partly  embryonal  character  throughout,  but  the  varying 
origin  of  these  tumors  gives  opportunity  for  the  exhibition  of  many  cell 
forms. 

The  histogenesis  of  reticulated  epithelioma  and  rodent  ulcer  has  been 
the  subject  of  much  careful  study.  Krompecher,  1900,  first  adequately 
emphasized  the  specific  structure  of  the  group  of  epidermal  tumors  which 
maintain  the  characters  of  basal  cells  and  introduced  the  term  "basal-cell 


fmm^mmm 


{ 


FIG.  414. — Epidermoid  carcinoma  of  skin  arising  from  hair-follicles  and .  reproducing 

small  hair  shafts. 


carcinoma."  He  traced  the  origin  to  the  basal  cells  of  the  Malpighian  layer 
and  of  the  ducts  of  sweat,  hair,  and  sebaceous  follicles.  He  described  in  de- 
tail the  clinical  and  histological  characters  of  many  tumors  of  this  class  oc- 
curring in  various  situations.  Many  such  tumors  had  previously  been  regarded 
as  endothelioma  of  skin,  mucous  membranes,  and  salivary  glands  (Coenen, 
Lit.).  Hansemann  argues  against  the  use  of  the  term  "basal  cell,"  urging 
that  all  epidermal  tumors  arise  from  basal  cells.  Yet  this  view  is  probably  not 
entirely  correct  even  for  rodent  ulcer,  and  Krompecher's  choice  of  terms  may 
be  justified  on  the  ground  that  the  tumors  maintain  the  characters  of  the 
basal  cells  from  which,  also,  they  probably  arise. 

Bormann,  in  an  elaborate  study  of  epidermal  carcinoma,  also  derives 
S3 


834  NEOPLASTIC  DISEASES 

the  reticulated  epithelioma  from  basal  epithelium.  He  concludes  that  the 
origin  is  not  from  the  normal  epidermis,  but  from  misplaced  superfluous  and 
embryonal  cell  groups  derived  from  the  skin  and  appendages  (corium  carci- 
noma). The  apparently  complete  isolation  from  the  epidermis  of  many 
early  tumors,  their  occurrence  chiefly  along  embryonal  fissures,  on  the  face, 
and  in  salivary  glands,  as  well  as  their  partly  embryonal  character,  are  con- 
siderations which  favor  this  view.  Some  basal-cell  tumors  with  compact 
groups  of  small  elongated  cells,  or  occasionally  with  adenoid  characters,  arise 
from  the  hair  follicles.  Mallory  finds  that  these  tumors  differ  from  the  others 
in  producing  long  fibrils  recalling  the  formation  of  the  hair  shaft.  Jane  way 
has  clearly  shown  that  epithelioma  of  basal-cell  type  may  arise  either  from 
isolated  epithelial  structures  in  the  corium  or  from  areas  of  basal  cells  which 
are  normally  incorporated  in  the  epidermis.  The  two  origins  impress  some- 
what different  characters  on  the  resulting  tumors.  Preceding  the  neoplastic 
change  in  the  basal  cells  he  observed  transient  erythema  and  a  dilatation  of 
subepithelial  lymphatics,  about  which  the  epithelial  cells  first  showed  hyper- 
trophy and  hyperchromatism  and  into  which  the  first  downward  growth  occurs. 
Ribbert  accepts  the  origin  from  multiple  foci  of  normal  basal  cells  and  em- 
phasizes the  changes  in  the  connective  tissue  which  frequently  precede  the 
downward  growth  of  epithelium.  Whether  these  changes  are  constant  it  is 
difficult  to  determine.  Bonney,  who  analyzed  the  connective-tissue  changes 
in  detail,  found  them  of  very  constant  occurrence.  Wyss,  in  a  series  of  early 
carcinomas  of  skin  and  other  regions,  found  extensive  infiltration  of  the  con- 
nective tissue  in  77  per  cent,  of  36  cases,  and  some  form  of  alteration  in  91  per 
cent.  In  some  cases  the  changes  are  so  slight  as  to  escape  demonstration  by 
the  usual  methods  of  detection.  They  appear  to  be  more  constant  with  acan- 
thoma  than  with  reticulated  epithelioma. 

(6)  Adenoid  Epithelioma  of  Skin. — Many  epithelial  tumors  of  the  skin 
show  a  tendency  more  or  less  pronounced  to  reproduce  the  dermal  glands  and 
are,  therefore,  designated  as  adenoid.  They  differ  from  the  rarer  true  adenomas 
of  the  dermal  glands  in  the  predominance  of  squamous  or  basal  epithelial  cell 
characters.  Several  varieties  of  these  tumors  are  observed. 

(i)  Adenoid  Cystic  Epithelioma  (Brooke). — This  tumor  was  long  grouped 
with  the  adenomas  of  sebaceous  glands  and  confused  with  many  other  con- 
ditions, from  which  it  was  separated  by  the  careful  clinical  and  histological 
studies  of  Brooke,  Fordyce,  Unna,  Walters,  and  others.  It  differs  from  ade- 
noma sebaceum  in  its  occurrence  in  much  smaller  numbers  and  in  the  absence 
of  the  definite  histological  characters  of  sebaceous  gland  tumors  and  prominence 
of  squamous  cells. 

It  occurs  in  the  form  of  a  limited  number  of  small,  firm,  nodular,  painless, 
circumscribed  tumors  in  the  skin  of  forehead,  eyelids,  nose,  cheek  or  scalp, 
notably  about  the  age  of  puberty.  They  are  also  seen  on  back,  chest,  and 
limbs,  but  not  below  the  pelvis  (Brooke).  Fordyce  observed  them  in  mother 
and  daughter,  and  Brooke,  in  three  members  of  a  family.  The  early  lesions 
may  resemble  milium  and  they  slowly  reach  but  do  not  exceed  the  size  of  a 
pea  or  bean,  continuing  to  enlarge  slightly  for  some  years.  While  no  serious 
grade  of  malignancy  has  been  reported,  there  is  no  tendency  toward  regression. 
The  color  differs  little  from  that  of  the  skin,  with  a  tendency  to  become  darker, 
yellowish,  shiny,  and  occasionally  translucent. 

The  structure  varies,  but  is  dominated  by  the  presence  of  embryonal 
epithelial  cells  arranged  in  cords,  masses,  and  alveoli,  and  of  groups  of  con- 
centric hornifying  epithelium  inclosing  homogeneous  material.  Brooke  found 
more  of  the  adenomatous  structure  than  is  usual.  Unna  emphasizes  the 
squamous-cell  elements  in  his  designation,  "acanthoma  adenoides  cysticum," 


EPIDERMOID  CARCINOMA 


835 


and  he  regards  the  tumor  as  a  pure  embryonal  acanthoma  with  marked  tend- 
ency to  cyst  formation. 

The  adenoid  structures  appear  as  finger-like  projections  from  the  basal 
epithelium  or  ducts  of  glands,  and  they  commonly  contain  minute  or  large 
cystic  areas  of  hyaline,  colloid,  or  mucoid  material.  The  cells  inclosing  these 
foci  are  often  cylindrical.  The  squamous  cells  in  concentric  form  undergo 
extensive  hornification  or  calcification,  and  these  structures  may  compose  the 
bulk  of  the  tumor  (Schapper).  Or  the  structure  of  reticulated  epithelioma, 
resembling  rodent  ulcer  with  many  thin  cell  strands,  may  be  prominent 
(Czillag,  Walters). 

The  origin  of  the  tumor  is  referred  by  Brooke  to  the  normal  cells  or  to  em- 
bryonal cell  groups  derived  from  the  hair  follicles  (lanugo)  and  from  the  basal 
cells  of  the  epidermis.  While  this  view  is  supported  by  most  recent  observers, 
Torok  and  Darier  derived  their  tumors  from  the  sweat-glands  and  W.  Pick 
from  the  sebaceous  glands.  The  identity  of  these  cases  with  Brooke's  tumor 
is  doubtful,  but  it  seems  probable  that  in  different  cases  the  origin  may  in- 


FlG.  415. — -Low  magnification  of  epithelioma  adenoides  cysticum. 


volve  different  elements  with  corresponding  variations  in  structure.  Thus 
Dorst  and  Delbanco  observed  multiple  tumors  of  the  scalp  in  the  same  pa- 
tient, some  of  which  had  the  structure  of  adenoma  sebaceum,  others  that  of 
adenoid  cystic  epithelioma. 

In  addition  to  the  relatively  small  and  multiple  tumors  of  the  above  type, 
the  structure  of  adenoid  and  cystic  epithelioma  occurs  in  larger  and  even 
bulky  single  tumors  of  the  skin  and  subcutaneous  tissue  about  the  face  and 
neck.  Such  a  tumor  has  been  described  by  Buxton  as  arising  at  the  orifice  of 
Steno's  duct.  It  ran  a  slow  course  for  20  years,  producing  a  growth  as  large  as 
a  hen's  egg,  and  finally  involved  the  submaxillary  lymph-nodes.  The  struc- 
ture presented  many  cystic  cavities  lined  by  convoluted  layers  of  basal  cells, 
among  which,  in  turn,  were  many  small  spaces  filled  with  mucoid  material. 

(2)  Simple  Adenoid  Epithelioma. — At  the  usual  seats  of  rodent  ulcer  larger 
and  usually  more  active  tumors  often  arise  in  which  there  are  large  alveoli 
lined  and  filled  with  cylindrical  or  cuboidal  epithelial  cells  of  a  type  inter- 
mediate between  squamous  epithelium  and  the  duct  cells  of  dermal  glands. 


836  NEOPLASTIC  DISEASES 

These  tumors  are  not  cystic,  they  are  usually  sharply  circumscribed  and 
relatively  large,  and  their  course  is  progressive,  with  occasional  involvement 
of  lymph-nodes  or  ulceration. 

The  structure  often  suggests  a  large  alveolar  carcinoma,  but  certain  areas 
may  usually  be  found  containing  flat  squamous  epithelium  without  spines 
of  hornification,  and  in- many  cases  the  derivation  from  the  rete  pegs  and 
especially  from  the  basal  cells  is  revealed  with  striking  clearness.  In  one 
group  of  cases  clinically  resembling  rodent  ulcer  I  found  alveoli  composed 
of  low  cylindrical  epithelium  which  was  probably  derived  from  hair  follicles. 
In  another,  large  alveoli  are  lined  by  low  columnar  cells  and  filled  with  cu- 
boidal  granular  epithelium  and  occasional  squamous  cells.  In  a  third  type 
all  the  rete  pegs  over  a  large  area,  i  to  if  cm.,  are  hypertrophied  and  con- 
tinuous, with  broad  cellular  columns  of  cuboidal  cells  which  compose  a  rather 
bulky  tumor  of  the  derma. 


FlG.  416. — Topography  of  sweat-gland  tumor  of  skin.      (Photo,  by  B.  H.  Buxton.) 


Tumors  of  Sweat-glands. — The  sweat-glands  have  been  assigned  as  the 
source  of  a  variety  of  tumors  which  have  figured  extensively  in  dermatological 
literature  under  many  different  terms  (Petersen,  Lit.).  The  tumors  vary  in 
structure  and  form  according  to  their  exact  point  of  origin  and  the  conditions 
under  which  they  arise.  From  the  alveoli  arise  the  somewhat  specific  spir- 
adenomas,  with  many  well-formed  alveoli  surrounded  by  membrana  propria 
and  filled  with  small  cuboidal  cells.  They  appear  as  pearly  white  tumors 
beneath  the  epidermis,  and  they  may  be  small  and  multiple.  Carcinomas  of 
this  type  are  occasionally  encountered.  Dilated  alveoli  of  spiradenoma 
probably  constituted  the  tumor  described  by  Jarisch  as  lymphangioma  tuber- 
psum  multiplex.  The  ducts  of  the  glands  may  be  dilated,  forming  cysts,  and 
into  these  papillary  outgrowths  occur,  which  have  been  described  as  papillary 
adenomas  (Elliott).  Neither  rodent  ulcer  nor  epithelioma  adenoides  cysticum 


EPIDERMOID  CARCINOMA 


837 


have  been  positively  traced  to  the  ducts  of  sweat-glands,  but  it  appears  prob- 
able that  the  ducts  give  origin  to  a  certain  proportion  of  the  adenoid  epithe- 


FJG.  417. — Adenocarcinoma  of  sweat-glands. 

liomas  of  the  skin.     The  adenomas  are  regularly  benign,  while  the  adeno- 
carcinomas  are  relatively  slow  in  invading  lymph-nodes. 

EPITHELIOMA  OF  THE  LIP 

Epithelioma  of  the  lip  is  chiefly  a  disease  of  elderly  men,  50  to  70  years 
but  occurs  in  women  and  in  young  adults.  Among  73  cases  collected  by  Warren, 
4  were  in  women,  3  of  whom  were  smokers.  Of  1338  cases  Fricke  found 
91  per  cent,  in  men,  4  of  which  were  multiple.  A  definite  group  of  cases 
follows  seborrheic  keratosis  (Montgomery,  Sutton).  Many  cases  are  clearly 
traceable  to  the  irritation  of  pipe  or  cigar.  Hence  it  appears  usually  on  the 
side  of  the  lower  lip,  rarely  on  the  upper.  Dugue  believes  that  tobacco  causes 
a  leukoplakia  of  the  lip,  as  on  the  tongue,  which  is  followed  by  epithelioma. 
Many  forms  of  trauma  have  preceded  the  disease,  as  simple  scratches,  bee 
stings,  erosion  by  teeth.  One  patient,  syphilitic  in  youth,  a  smoker  until  45 
years,  developed  a  minute  chronic  fissure  of  the  lip  at  50,  which  remained 
indolent  and  indurated  for  three  years,  when  ulceration  supervened  and 
gradually  extended  over  li  cm.  for  i  year  longer  before  it  was  recognized  as 
epithelioma.  Contact  infection  has  been  held  responsible  for  the  appearance 
of  epithelioma  on  the  upper,  opposite  a  lesion  on  the  lower  lip,  but  lymphatic 
connections  offer  an  alternative  explanation,  since  both  blood-  and  lymph- 
vessels  encircle  the  lips. 

Two  main  forms  of  the  lesion  occur,  (i)  papillary  and  (2)  ulcerative  in- 
filtrating types.  The  papillary  form  appears  as  a  wart-like  thickening  which 
long  remains  elevated,  at  times  with  much  elongated  papillae.  It  extends 
slowly  in  all  diameters,  as  a  flat  thickening  in  the  epidermis,  is  slow  to  invade 


838 


NEOPLASTIC  DISEASES 


the  deeper  tissues  or  lymph-nodes,  and  the  underlying  tissues  remain  soft. 

Later  it  may  ulcerate  and  follow  the  usual  course  of  infiltrating  epithelioma. 

This  type  of  epithelioma  is  of  long 
duration  and  of  somewhat  character- 
istic gross  appearance,  and  since  it 
yields  to  conservative  operation  it 
should  be  carefully  distinguished  from 
the  more  malignant  variety. 

The  early  infiltrating  process  may 
appear  as  a  flat  thickening  of  the  epi- 
thelium, or  as  a  nodular  growth  invad- 
ing from  the  first  the  submucosa,  and 
lying  beneath  rather  than  in  the  epi- 
thelial layer.  Early  ulceration  pro- 

~"^^P"'B^B  duces  a  broad  deep  ulcer  with  pearl}' 

P^***^  J^SMffSfif^  indurated  edges,  or  a  more  bulky  ex- 

':&Mn^V>  cavated  tumor  which  may  become 

fungating.  With  these  lesions  there 
is  often  much  inflammatory  reaction, 
extension  along  the  floor  of  the  mouth, 
involvement  of  periosteum,  and  early 
invasion  of  submental,  lingual,  and 
maxillary  nodes. 

The  structure  is  usually  that  of 
typical  acanthoma  with  many  varia- 
tions in  details.  A  preliminary  soften- 
ing and  cellular  infiltration  of  the  sub- 

FIG.  418.— Epidermoid  carcinoma  of  lip.       mucosa   usually   precedes   the   over- 
growth of  epithelium.    Ribbert  insists 

that  downward  growth  of  epithelium  never  occurs  into  normal  connective 

tissue,  but  only  after  infiltration  by  round  cells.    In  the  papillary  form  the 


FIG.  419. — Early  carcinoma  of  lip. 


EPIDERMOID  CARCINOMA 


839 


outgrowth  produces  long  papillae  with  or  without  hyperkeratosis.  Some  down- 
ward growth  of  altered  papillae  is  nearly  constant,  but  may  long  be  held  in 
check  by  round-cell  exudate  and  fibrosis  of  deeper  tissues.  In  the  ulcerating 
tumors  the  invasion  of  tissues  is  preceded  by  edema  and  perivascular  infiltra- 
tion by  leukocytes.  After  the  tumor  has  become  established  there  is  no  evi- 
dence of  lateral  extension  over  normal  epithelium,  but  the  papillae  over  a 
wider  area  may  be  much  hypertrophied. 

The  tumor-cells  may  retain  the  type  of  adult  squamous  epithelium  (acan- 
thoma)  or  they  may  lose  these  characters  and  appear  in  anastomosing  columns 
of  opaque  granular  polyhedral  cells.  Infiltration  of  perivascular  sheaths, 
nerve-trunks,  and  areolar  tissue  is  attended  by  much  growth  of  firm  con- 


Sl^ffe^f^ 

^*«.    «  -     *        >* .  - 1***       v*"     -A     ..        '^"'  f.f  *  *  •  •  "^*  ^Sjfl?      .**,"*"*."' 


FIG.  420. — Infiltrating  epidermoid  carcinoma  of  lip. 

nective  tissue.  This  infiltration  tends  to  follow  preexisting  lymph  paths,  but 
is  by  no  means  limited  thereto. 

While  the  lymph-nodes  may  be  involved  early,  they  seldom  reach  a  large 
size,  and  visceral  metastases  are  occasionally  observed.  Yet  I  have  seen  the 
right  submental  nodes  as  large  as  an  orange,  while  the  left  were  uninvaded 
from  a  left-sided  tubular  epithelioma  of  lip.  Secondary  infection  usually  by 
Streptococcus  pyogenes  plays  a  prominent  part  in  the  progress  of  the  disease, 
and  leads  to  extensive  local  suppuration,  erysipelas,  septicemia,  thrombosis 
of  vessels,  edema  of  glottis,  and  pneumonia. 

The  operative  treatment  of  carcinoma  of  the  lip  is  comparatively  favorable. 
Fricke  placed  the  cures  at  60  per  cent,  and  Steiner  (1908)  reported  35  definite 
cures  after  a  5-year  limit  out  of  43  cases  (70  per  cent.).  The  decisive  influ- 
ence of  the  character  and  extent  of  the  disease  appears  in  the  fact  that  three- 


840 


NEOPLASTIC  DISEASES 


fourths  of  the  fatal  results  occurred  within  a  year  after  operation.  Surgical 
experience  emphasizes  the  necessity  of  removing  the  lymph-nodes  of  both 
sides,  even  with  comparatively  early  lesions.  Of  32  cases  in  which  only  the 
tumor  but  not  the  lymph-nodes  were  removed  Bloodgood  found  only  2  cured. 
After  invasion  of  the  maxillary  bone  he  could  find  no  record  of  recovery. 
The  more  favorable  statistics  probably  include  many  comparatively  benign 


.-./jy  "•£.**!  -/=.,  fy.~  i-v 
'  »/??•>,  •  -Vv  -^.^  O5*«%  ?J-  r; 


FIG.  421. — Invasion  of  labial  artery  by  recurrent  epidermoid  carcinoma  of  lip. 
evidences  of  growth  restraint. 


Note  the 


lesions.  Fully  developed  carcinoma  of  the  lip  is  a  very  fatal  disease,  and  only 
when  the  lesion  is  early  and  limited  can  a  favorable  result  be  assured  by 
operation.  Such  lesions  also  respond  well  to  radium. 

EPIDERMOID  CARCINOMA  OF  TONGUE  AND  MOUTH 

Several  general  peculiarities  distinguish  this  form  of  cancer.  In  fre- 
quency it  is  placed  by  Jessett  second  only  to  uterine  cancer,  by  Jacobsen  third, 
and  by  Winiwarter  fourth.  While  among  the  most  accessible  of  cancers  and 
readily  recognizable  in  its  early  stages,  it  is  yet  one  of  the  most  fatal  of  malig- 
nant diseases,  with  a  mortality  of  75  to  90  per  cent.  (Warren,  Butlin,  Meller). 
Although  its  microscopical  anatomy  is  rather  uniform,  the  gross  features  and 
clinical  course  vary  extensively,  so  that  a  very  detailed  acquaintance  with 
the  disease  is  demanded  of  one  who  hopes  to  deal  with  it  successfully.  The 
failure  to  recognize  the  significance  of  early  or  precancerous  conditions,  tem- 
porizing with  small  but  fully  developed  lesions,  and  extravagant  sacrifice  of 
tissue  in  mild  cases,  are  common  errors  committed  in  the  case  of  these  pa- 
tients, and  are  largely  responsible  for  the  ultimate  mortality  and  for  that 
dread  of  the  disease  which  leads  many  to  conceal  its  existence  as  long  as 
possible. 


EPIDERMOID  CARCINOMA 


841 


Etiology. — The  disease  occurs  chiefly  in  the  fourth  to  sixth  decades.  Sigel 
observed  a  case  in  a  boy  of  6  years.  Piquantin  estimated  that  17  per  cent, 
of  the  cases  occur  in  women. 

The  important  factors  in  the  causation  of  buccal  cancer  are  syphilis, 
tobacco,  and  defects  of  the  teeth.  In  a  large  group  of  cases  all  three  factors 
are  combined,  while  one  or  more  are  nearly  constantly  present. 

The  frequency  of  syphilis  is  variously  estimated,  Meller  finding  signs 
of  lues  in  only  7  of  207  cases  of  buccal  cancer,  while  Fournier  found  the  dis- 
ease in  155  of  184  case's.  The  action  of  syphilis  is  indirect  and  the  epithelioma 
is  always  preceded  by  a  definite  and  usually  prolonged  luetic  lesion.  The 
pearly  white  thickening  of  the  epithelium  in  leukoplakia  is  a  characteristic 
picture  which  must  always  be  regarded  with  suspicion  as  furnishing  the  be- 
ginning of  cancer.  According  to  Fournier  leukoplakia  is  followed  by  cancer 
hi  30  per  cent,  of  the  cases,  but  many  authors  hold  all  such  lesions  under 
suspicion,  and  there  is  no  doubt  that  the  disease  has  a  definite  tendency  to 
become  malignant  and  should  be  treated  in  every  case  as  a  specific  precan- 
cerous  condition.  Of  159  cases  of  cancer  of  tongue,  v.  Bergmann  found  leuko- 


FIG.  422. — Leukoplakia  of  tongue. 

plakia  in  34.6  per  cent.  Other  syphilitic  lesions  which  lead  to  cancer  are 
localized  wart-like  epithelial  hypertrophies,  fissures,  gummas  with  or  without 
ulceration,  and  chronic  glossitis  with  atrophy  of  papillae  (Jacobson).  The 
epithelial  overgrowth,  submucous  edema,  lymphocytic  infiltration,  and  even- 
tual scarring  with  loss  of  elastic  tissue  are  microscopical  features  explaining 
the  remarkable  relation  between  lues  and  cancer  of  this  organ.  It  is  a  notable 
fact  that  the  syphilitic  process  may  subside  or  even  completely  heal  under 
treatment,  while  a  coexistent  cancer  may  continue  or  develop  later  in  the 
scar,  or  appear  in  the  lymph-nodes  under  a  smooth  epidermis  (Landau,  Sachs, 
Warren,  Lang,  Lydston). 

Tobacco  has  a  predominant  influence  in  the  development  of  cancer  of 
the  buccal  mucosa.  Its  action  is  not  fully  understood,  but  the  irritant  effects 
stimulate  the  epithelium,  produce  chronic  hyperemia,  local  erosions,  lympho- 
cytic infiltration,  edema,  and  ulceration.  The  effects  of  heat  must  also  be 
considered,  while  mechanical  irritation  appears  in  the  cancers  of  the  tip  of 
tongue  in  pipe  smokers.  Tobacco  chewers  often  develop  cancer  at  the  point 
where  the  quid  is  held.  Many  of  the  tobacco  cancers  arise  at  the  base  of  the 


842 


NEOPLASTIC  DISEASES 


tongue,  on  palate,  tonsil  or  pharynx,  while  the  relation  to  laryngeal  cancer  is 
well  known. 

An  imperfect  condition  of  the  teeth  is  directly  responsible  for  many  buccal 
cancers.  The  most  obvious  cases  are  those  in  which  a  projecting  or  ragged 
tooth  continually  abrades  the  edge  of  the  organ,  along  the  sides,  or  at  the 
frenum.  It  is  often  difficult  to  detect  the  exact  source  of  the  effective  dental 
irritation  and  it  is  often  overlooked.  An  imperfect  alignment  of  the  teeth,  a 
sharp  although  smooth  edge,  or  chronic  caries  especially  of  the  roots,  pyor- 
rhea,  chronic  alveolar  abscesses,  or  the  traumatism  of  extraction,  may  be 
sufficient  to  incite  a  cancerous  growth,  especially  in  luetic  smokers. 

Many  other  forms  of  irritation  resulting  in  chronic  inflammatory  changes 
have  been  observed  to  precede  buccal  cancer,  and  they  were  early  designated 

by  Hutchinson  as  precancerous 
states.  They  are  thus  enumerated 
by  Jacobson:  (i)  Chronic  glossitis 
with  hypertrophy  and  fissuring,  (2) 
leukoplakia,  especially  when  warts 
appear,  (3)  ichthyosis,  or  late  stage 
of  leukoplakia,  (4)  chronic  atrophic 
glossitis,  "bald  tongue,"  (5)  papil- 
lomas  of  various  types,  (6)  fissures, 
(7)  ulcers  of  any  type. 

Structural  abnormalities  or 
other  forms  of  tissue  predisposition 
are  not  commonly  considered  in  the 
genesis  of  buccal  cancer,  and  prob- 
ably have  little  relation  to  the  su- 
perficial acanthomatous  forms,  but 
for  many  tumors  located  in  the 
floor  of  mouth,  tonsil,  or  pharynx, 
which  exhibit  the  structure  of  ade- 
noid or  embryonal  epithelioma, 
such  factors  cannot  be  ignored  and, 
indeed,  demandmore attention  than 
they  have  received.  This  entire 
region  is  beset  with  mucous  glands 
and  their  ducts,  and  with  tortuous 
ducts  of  large  salivary  glands,  while 
the  remnants  of  branchial  clefts 
and  other  embryonal  fissures  must 
also  be  considered  as  contributing 
to  certain  forms  of  epithelioma,  es- 
pecially the  deeper  lying  tumors. 
The  thyroglossal  duct  is  a  source  of 
cysts  at  the  base  of  the  tongue,  and 
it  seems  probable  that  remnants  of 
the  endodermal  portions  of  the 
upper  branchial  clefts  may  also  be 
included  in  the  sources  of  buccal 
cancer.  A  characteristic  lingual  cancer  develops  in  the  middle  line  of  the 
organ,  often  appearing  first  as  a  slowly  growing  papilloma. 

Gross  Anatomy.- — The  usual  form  of  buccal  epithelioma  is  an  indurated 
ulcer,  which  extends  with  considerable  activity  and  much  pain  and  discharge, 
over  a  widening  area.  The  indurated  base  and  edges  are  characteristic.  The 


FIG.  423. — Invasion  of  capsular  vessel  of 
lymph  node  by  epidermoid  carcinoma. 


EPIDERMOID  CARCINOMA  843 

lesion  arises  from  fissures,  abrasions  and  erosions,  and  is  ulcerated  and  super- 
ficial from  the  first. 

Beginning  as  a  deeper  submucous  nodule  another  type  of  the  lesion  re- 
mains for  a  time  as  a  solid  tumor  of  moderate  dimensions,  but  eventually 
breaks  down,  producing  a  deep  ragged  excavation. 

After  leukoplakia  epithelioma  appears  as  a  broad,  flat,  pearly  white  in- 
duration which  may  long  escape  necrosis,  but  infiltrates  the  tissues  over  a 
wide  area  and  finally  ulcerates.  Multiple  points  of  origin  may  exist  in  this 
type,  and  after  excision  the  disease  may  recur  in  new  areas. 


FIG.  424. — Diffuse  permeation  of  pulmonary  lymphatics  from  squamous  carcinoma  of 

tongue. 

A  diffuse  infiltration  of  one  or  both  sides  of  the  tongue  occurs  in  rare  cases 
and  leads  to  extensive  increase  in  the  size  of  the  entire  organ,  interfering 
with  deglutition  and  preventing  extrusion.  Simple  papilloma  of  the  tongue 
may  become  malignant,  the  enlarged  papillae  invading  the  submucosa.  Steiner 
observed  malignant  changes  in  a  lingual  wart  of  6  years'  duration.  The 
change  is  indicated  by  an  increase  in  the  dimensions  of  the  lesion,  but  ulcera- 
tion  may  long  be  delayed.  Sachs  describes  an  extensive  papillary  epithelioma 
of  the  tongue,  with  very  slight  structural  indications  of  malignancy,  but  with 
invasion  of  lymph-nodes. 

Diffuse  papillomatosis  of  any  part  of  the  lingual  or  buccal  mucosa  presents 
a  most  noteworthy  lesion,  from  one  or  many  points  of  which  carcinoma,  us- 
ually of  moderate  malignancy,  may  develop. 


844 


NEOPLASTIC  DISEASES 


\ 


I  have  seen  cases  of  very  extensive  lingual  cancer  without  invasion  of 
lymph-nodes,  in  which  the  lesion  consisted  of  plexiform  infolding  of  the  entire 
epithelial  layer  without  invasion  by  loose  cell  groups. 

The  location  of  the  lesion  may  be  in  any  part  of  the  lingual  or  buccal 
mucosa.  The  edges  of  the  tongue,  the  under  surface  near  frenum,  the  tip 
or  base,  are  most  frequently  affected.  The  dorsum  is  relatively  immune. 
Equally  frequent  is  a  primary  location  in  the  floor  of  the  mouth.  Tonsillar 
lesions  constitute  about  10  per  cent,  of  the  cases,  while  a  still  smaller  propor- 
tion occur  in  pharyngeal  wall,  gums,  and  palate  (Meller,  Warren). 

Local  extensions  of  buccal  cancer  are  usually  early  and  wide.  In  the  tongue 
the  arrangement  of  blood-vessels  and  lymphatics  may  somewhat  restrict  the 
growth  to  one  lateral  half  or  to  the  base,  but  advanced  lesions  invade  both 
sides,  extend  from  the  base  in  all  directions,  and  from  the  tip  and  edges  to  the 
floor  of  the  mouth.  Lesions  of  the  cheek  remain  relatively  localized;  those  of 

the  tonsil  invade  pharyngeal  wall,  larynx, 
nares  and  soft  and  hard  palate,  and  base 
of  tongue;  those  of  the  buccal  floor  ex- 
tend actively  to  tongue,  gums,  lips,  and 
deeper  tissues. 

Lymph-node  involvement  occurs 
early  in  the  course  of  buccal  cancer  and 
may  be  the  first  symptom  to  attract 
notice,  but  there  is  great  variation  in  the 
period  of  its  occurrence,  depending  on 
the  very  variable  structure.  Meller  de- 
scribes extensive  carcinoma  of  tongue, 
tonsil,  and  buccal  floor  without  invasion 
of  nodes,  while  Sachs'  superficial  papil- 
loma  of  indistinct  cancerous  structure 
had  already  invaded  the  nodes.  Most 
observers  urge  that  it  is  impossible  to 
establish  any  rule  regarding  the  occur- 
rence of  metastases.  Yet  I  venture  to 
think  that  this  impression  is  due  largely 
to  lack  of  acquaintance  with  the  ana- 
tomical varieties  of  the  disease.  Papil- 
lary, plexiform,  superficially  diffuse,  and 
leukoplakic  lesions  are  of  relatively  slow 
course. 

Metastases  are  unquestionably  fa- 
vored by  a  malignant  atypical  structure, 
by  an  origin  from  deep  rather  than  super- 
ficial structures,  by  deep  ulceration,  by 
long  duration  of  the  disease,  and  by  the 
presence  of  inflammatory  complications.  Reclus  mentions  the  later  occurrence 
of  metastases  in  cases  following  leukoplakia.  Tumors  of  tonsil,  and  especially 
of  antrum,  are  often  slow  in  involving  lymph-nodes. 

The  affected  nodes  are  usually  those  directly  draining  the  diseased  focus, 
but  in  many  cases  the  extension  seems  to  violate  anatomical  rules.  Thus 
both  sides  of  the  neck  may  early  be  involved,  and  in  a  notable  group  of  cases 
there  is  extensive  involvement  of  one  or  both  sides  from  a  primary  lesion 
which  it  is  difficult  to  locate  even  at  autopsy. 

The  mode  of  extension  of  buccal  and  lingual  cancer  to  the  lymph-nodes, 
I  have  been  led  to  conclude,  is  chiefly  by  embolism.  This  conclusion  is  based 


FIG.  425. — Vertical  view  of  lym- 
phatics of  tongue  in  relation  to  tonsil. 
(After  Kuttner.) 


EPIDERMOID  CARCINOMA 


845 


on  the  very  early  invasion  of  nodes  in  some  cases,  the  appearance  of  infected 
nodes  at  anomalous  points  while  intervening  nodes  escape,  and  the  failure  to 
find  permeated  lymphatics  in  sections  of  tissue  leading  from  the  original  lesion. 
The  great  vascularity  of  the  tissues  and  the  active  muscular  movements  of  the 
parts  seem  to  be  a  sufficient  explanation  of  the  events  observed. 

Metastases  in  the  organs  are  rare,  but  have  been  observed  in  liver,  heart, 
adrenal,  and  mesentery.  Extensions  to  lungs  and  pleura  are  even  rarer.  The 
total  number  of  cases  with  internal  metastases  is  small  (i  per  cent.,  Crile) 
and  bulky  internal  growths  are  rare.  In  148  autopsies  at  the  Middlesex  Hos- 
pital there  were  metastases  in  the  liver  (8),  lungs  (7),  pleura  (4),  adrenal 
(3),  heart  (2). 


FIG.  426. — Diagram  of  lymphatics  of  tongue.     (After  Kuttner.)     Note  chain  leading 
directly  from  tip  of  tongue  to  supraclavicular  node. 

The  distribution  of  metastases  is  determined  by  the  course  of  the  cervical 
lymphatics,  which  has  formed  the  subject  of  careful  study  by  many  observers 
(Poirier,  Kuttner,  Crile).  The  main  groups  are  defined  by  Warren.  The 
submaxillary  group  drains  the  border  of  the  tongue  as  far  back  as  the  fauces, 
the  middle  section  of  the  anterior  half  of  tongue,  and  under  surface  of  tip  and 
floor  of  mouth.  The  superior  deep  cervical  group,  lying  on  internal  jugular 
vein  and  carotid,  drains  all  parts  of  mouth,  tongue,  fauces,  and  upper  part  of 
pharynx.  Nodes  at  the  lower  end  of  the  parotid  drain  the  anterior  surface 
of  palate.  The  inferior  deep  cervical  nodes,  lying  on  the  jugular  vein  and 
extending  down  behind  the  clavicle,  receive  branches  directly  from  apex  and 
base  of  tongue,  and  anterior  portion  of  floor  of  mouth.  The  submental  nodes 
drain  the  lips  and  anterior  portions  of  the  buccal  floor.  The  submaxillary 
gland,  often  extirpated,  is  rarely  invaded. 


846 


NEOPLASTIC  DISEASES 


Structure.— The  great  majority  of  buccal  epitheliomas  are  of  the  simple 
acanthomatous  type.  Their  early  stages  illustrate  many  phases  of  the  de- 
velopment of  epidermoid  carcinoma  from  chronically  inflamed,  hypertrophied 
papillae.  Lymphocytic  infiltration  and  edema  of  submucosa  and  hyperkera- 
tosis  nearly  always  precede  the  downward  growth  of  epithelium.  The  adult 
characters  of  the  epithelial  cells  may  long  be  preserved,  or  they  may  assume 
the  type  of  indifferent  polyhedral  cells  as  in  tubular  epithelioma.  An  original 
papillary  structure  may  persist,  even  after  metastases  have  occurred.  Rarely 
the  structure  is  that  of  basal-cell  epithelioma.  Berkeley  saw  both  types  in  the 
same  tumor.  An  alveolar  arrangement  of  polygonal  cells  devoid  of  squamous 
characters  suggests  an  origin  of  some  tumors  from  ducts  of  mucous  glands 
(Steiner,  Hulsmeyer,  Kaufmann). 


FIG.  427. — Spindle-cell  epidermoid  carcinoma  of  tonsil. 

Embryonal  forms  of  epithelioma  arise  in  the  base  of  tongue,  tonsil,  and 
pharynx,  but  their  exact  source  is  undetermined.  The  cells  lack  squamous 
characters  and  they  grow  in  columns  or  indistinct  alveoli. 

In  all  types  of  structure  the  cells  infiltrate  surrounding  tissues,  following 
chiefly  the  lymph-vessels  and  nerve-trunks.  Goldmann  observed  the  inva- 
sion of  a  vein,  but  the  blood-vessels  are  usually  occluded  by  the  extensive 
new  connective  tissue  which  follows  the  process.  Secondary  infection  by  the 
streptococcus  complicates  or  dominates  the  later  stages  and  gives  rise  to 
suppuration  and  necrosis. 

The  clinical  course  of  buccal  cancer  is  usually  progressive  and  terminates 
fatally  in  an  average  period  of  2  years.  More  rapid  courses  are  commonly 
observed  in  lingual  cases  (6  to  12  months)  and  in  tonsillar  (6  to  10  months), 


EPIDERMOID  CARCINOMA  847 

and  pharyngeal  tumors  (4  to  10  months)  (Meller).  In  a  large  series  in  all 
locations  Meller  found  that  operation  prolonged  life  on  the  average  13.4 
months  and, cured  14.6  per  cent.,  while  the  operative  mortality  was  13  per 
cent.  While  the  duration  and  extent  of  the  disease  chiefly  determined  the 
result,  the  cured  list  includes  several  with  large  ulcers,  extensions  to  lymph- 
nodes,  and  some  with  local  recurrences. 

The  chief  causes  of  death  are  pneumonia,  septicemia,  edema  of  glottis, 
and  hemorrhage. 

It  seems  probable  that  the  prognosis  of  buccal  cancer  will  be  influenced 
in  the  future  by  the  introduction  of  radium.  This  agent,  either  alone  or  in 
combination  with  surgery,  has  produced  encouraging  results,  especially  in 
localized  cases  of  lingual,  tonsillar,  and  pharyngeal  cancers  in  inaccessible 
positions  and  in  advanced  stages. 

TUMORS  OF  THE  LARYNX 

Papilloma  of  Larynx. — Of  benign  tumors  of  the  larynx  epithelial  papilloma 
constitutes  39  per  cent.  (Juracz),  but  the  proportion  varies  with  different 
histological  criteria  from  59  to  8  per  cent.  (Janeway,  Schech).  The  chief 
location  is  the  anterior  and  middle  portion  of  the  under  surface  of  the  true 
vocal  cords,  but  the  epiglottis  and  various  mucous  folds  may  be  involved. 
All  ages  are  found  to  develop  papillomas,  especially  in  the  fourth  decade 
and  in  males  far  more  than  in  females.  An  hereditary  influence  is  rare,  but 
more  papillomas  appear  in  infants  and  children,  indicating  a  congenital  pre- 
disposition (Casnit,  Gerhardt).  Overuse  of  the  voice,  irritant  inhalations, 
the  sequelae  of  exanthems,  alcohol,  and  tobacco,  have  been  recognized  as 
etiological  factors,  and  all  probably  act  by  producing  some  form  of  chronic 
laryngitis.  Yet  some  cases  develop  without  a  demonstrable  trace  of  previous 
inflammation.  L.  Browne  attributes  many  laryngeal  polyps  to  the  influence 
of  nasal  and  pharyngeal  adenoids. 

The  tumors  appear  as  (i)  a  single  smooth  red  to  gray,  firm,  pea-sized 
nodule,  or  as  (2)  a  group  of  elongated  papillae  resembling  a  cock's-comb,  or 
(3)  a  more  bulky  cauliflower  tumor.  The  base  may  include  a  small  circum- 
scribed area,  or  much  of  the  mucosa  may  be  the  seat  of  papillary  outgrowth 
and  lead  to  suffocation,  or  stenosis  after  extirpation.  Laryngologists  generally 
agree  that  while  most  benign  papillomas  may  be  recognized  through  the 
laryngoscope,  yet  in  some  cases  a  full  microscopical  study  is  necessary. 

The  early  stages  have  been  traced  by  Werner  to  a  condition  first  of  hy- 
peremia  and  round-cell  infiltration  of  submucosa,  which  is  followed  by  nodular 
overgrowth  of  epithelium.  The  area  affected  by  these  changes  may  be  con- 
siderable and  a  basis  is  thus  furnished  for  the  appearance  of  multiple  tumors 
at  once  or  at  intervals.  In  the  condition  called  "singer's  nodes"  the  epithelial 
hypertrophies  become  chronic,  more  or  less  keratinized,  associated  with 
dilatations  of  blood-vessels,  and  sometimes  give  origin  to  papilloma. 

The  structure  shows  an  active  overgrowth  of  normal  or  slightly  altered 
epithelium,  in  many  projecting  folds  and  with  some  downward  elongation  of 
papillae,  but  with  an  intact  basement  membrane.  The  stroma  consists  of 
branching  strands  of  vascular  connective  tissue  which  may  be  very  scanty  or 
so  abundant  as  to  resemble  papillary  fibroma. 

The  epithelium  is  of  squamous  type  with  much  or  little  hornification. 
Small  concentric  cell  groups  and  mitotic  figures  may  be  found  in  benign 
growths,  but  when  these  features  are  prominent  they  should  be  regarded  with 
suspicion,  especially  when  combined  with  irregularity  in  the  form  and  arrange- 
ment of  the  cells.  Papillomas  removed  shortly  after  cauterization  or  imper- 
fect curetage  may  show  great  disorder  of  the  epithelium. 


848 


NEOPLASTIC  DISEASES 


In  the  diagnosis  of  malignancy  in  early  papillary  tumors  of  the  larynx 
chief  attention  should  be  given  to  atypical  cells  in  the  epithelial  layer.  I  have 
seen  a  fatal  course  in  so  many  apparently  simple  laryngeal  papillomas  in 
which  the  sole  sign  of  malignancy  consisted  in  atypical  hypertrophic  hyper- 
chromatic  cells  in  a  uniformly  thickened  layer,  that  I  am  compelled  to  regard 
this  appearance  as  of  grave  significance.  Reliance  on  this  criterion  leads  to 
the  conclusion  that  most  epithelial  papillomas  of  the  larynx^ttend  to  become 
malignant,  especially  in  adults,  and  this  conclusion  is  strengthened  by  the 
frequent  occurrence  of  long-existing  bulky  papillary  growths  which  have 
eventually  invaded  the  lymph-nodes. 


FIG.  428. — Atypical  epidermoid  carcinoma  of  tonsil. 

While  most  papillomas  are  completely  eradicable,  not  a  few  recur  locally, 
either  immediately  or  after  an  interval  which  may  be  as  long  as  9  (Curtis) 
or  even  22  years  (Lincoln).  Partial  extirpation  of  a  broad  base  is  responsible 
for  some  recurrences  which  appear  immediately  with  apparent  acceleration  of 
growth.  Or  a  new  tumor  may  slowly  develop  in  a  predisposed  mucosa.  There 
are  no  sufficient  grounds  for  assuming  a  local  infectiousness  of  these  tumors. 

Rapid  and  extensive  recurrence  in  histologically  benign  form  is  observed 
especially  in  children,  and  illustrates  the  remarkable  regenerative  powers  of 
the  laryngeal  epithelium.  Laryngotomy  and  excision  or  cauterization  has 
been  performed  three,  four,  and  even  seven  tunes  hi  a  relatively  short  period 
before  the  disease  could  be  arrested  (Wilkinson,  Lendon,  Clubbe).  In  this 
group  of  cases  radium  treatment  has  given  excellent  results. 

The  question  of  the  transformation  of  a  benign  papillomatous  into  a 


EPIDERMOID  CARCINOMA  849 

malignant  process  has  been  extensively  discussed.  Semon  could  find  only  45 
definite  reports  of  this  event,  12  spontaneous,  33  after  operation,  and  of  these 
he  discards  all  but  12.  It  is  difficult  for  the  laryngologist  to  secure  satisfactory 
material  for  histological  study,  which  must  include  a  considerable  portion  and 
especially  the  deeper  parts  of  the  growth.  Tissue  from  the  edges  of  a  car- 
cinoma may  show  the  structure  of  simple  papilloma.  Even  with  these  sources 
of  error  histological  data  have  often  proved  more  reliable  than  laryngoscopic 
appearance.  When  the  microscopical  study  can  be  made  of  satisfactory 
material  its  evidence  must  be  regarded  as  final,  and  on  such  evidence  it  seems 
probable  that  laryngeal  disease  not  infrequently  appears  first  as  simple  papil- 


FIG.  429. — Bulky  papillary  epidermoid  carcinoma  filling  larynx.    No  invasion  of  lymph- 
nodes. 

loma,  later  as  carcinoma.  I  have  examined  the  whole  of  an  excised  papilloma 
in  a  case  which  developed  carcinoma  3  years  later,  possibly  at  another  point. 
In  cases  in  which  such  a  transformation  appears  to  occur  there  are  several 
possible  explanations:  (i)  The  original  disease  is  a  simple  papilloma  which 
really  changes  its  clinical  character  and  develops  infiltrative  growth.  (2) 
The  original  disease  is  carcinoma,  but  the  examination  of  tissue  is  incompetent 
or  inadequate.  (3)  An  original  papilloma  is  removed,  but  the  disease  recurs 
elsewhere  as  carcinoma.  Such  events  are  observed  in  other  mucous  mem- 
branes. (4)  An  original  papilloma  is  imperfectly  removed  and  the  remnant 
is  stimulated  to  atypical  growth. 
54 


850 


NEOPLASTIC  DISEASES 


Miscellaneous  Benign  Tumors  of  the  Larynx. — Fibroma  is  a  frequent,  with  some 
authors  the  most  frequent,  tumor  of  the  larynx.  It  appears  on  the  true  or  false  cords, 
near  the  anterior  commissure,  or  on  the  epiglottis,  rarely  elsewhere.  Fibromas  are 
usually  single,  small,  and  pedunculated,  but  may  be  multiple,  and  present  a  broad  base 
and  reach  a  large  size.  Solis-Cohen  observed  six  in  one  case.  The  structure  varies  with 
the  consistence.  Hard  tumors  are  composed  of  adult  connective  tissue,  while  the  soft 
growths  are  edematous  or  mucoid  or  contain  an  excess  of  vessels.  The  surface  lining  of 
squamous  epithelium  may  be  quite  smooth  or  convoluted.  Very  small  fibromas  con- 
stitute a  portion  of  the  so-called  singer's  nodes  (A.  Chiari).  In  some  cases  the  structure 
shows  hornification  of  epithelium,  dilated  lymph-spaces,  dilated  gland  ducts,  and  collec- 
tions of  lymphocytes,  all  of  which  indicate  an  inflammatory  origin.  When  the  mucoid 
element  is  prominent  the  tumors  have  been  called  myxomas  (Fauvel,  Bruns). 

Chondroma. — Bruns  collected  14  reports  of  chondroma  of  the  larynx.  The  largest 
reached  the  size  of  a  walnut.  The  chief  location  was  in  the  cricoid  cartilage,  and  the 
structure  showed  hyaline  cartilage  often  with  calcification. 


FIG.  430. — Pachydermia  laryngis.     A  form  of  beginning  carcinoma  of  the  larynx. 

Lipoma  has  been  reported  in  and  about  the  larynx  in  9  cases  (Jurasz).  They  were 
usually  small  and  single,  but  Seyfert's  tumor  was  lobulated  and  of  considerable  bulk. 

Bruns  described  a  rather  large  adenoma  arising  from  the  vocal  cord  and  consisting  of 
alveoli  lined  by  cylindrical  cells.  A  few  other  cases  are  mentioned  by  Jurasz. 

Angioma  has  been  observed  by  many  authors.  Phillips  and  Ruh  collected  26  cases 
from  the  literature  and  report  I  case  in  a  child  following  measles,  in  which  there  was 
extensive  dilatation  of  vessels  below  the  cords  and  evidences  of  chronic  laryngitis.  The 
structure  indicates  a  close  relation  to  fibroma,  both  in  histogenesis  and  in  etiology. 
Many  of  these  tumors  consist  of  simple  varices,  capillary  or  cavernous,  and  are  not 
neoplastic.  Others  reach  considerable  size,  and  show  a  definite  overgrowth  of  new  ves- 
sels. In  Loomis'  case  there  were  also  angiomas  of  tongue,  pharynx,  and  neck. 

A  large  cavernous  lymphangioma  is  described  by  Koschier. 

A  primary  lymphoma  of  the  sinus  pyriformis  is  recorded  by  J.  Mackenzie,  and  lym- 
phosarcoma  of  pharynx  and  larynx  by  Stoerk.  Generalized  lymphosarcoma  may 
occlude  the  larynx.  Aberrant  thyroid  tissue  in  the  wall  of  the  larynx  may  be  the  source 
of  submucous  tumors  (Ziemssen,  Heise). 


EPIDERMOID  CARCINOMA  851 

Carcinoma  of  Larynx. — Carcinoma  and  sarcoma  of  the  larynx  form  i 
to  5  per  cent,  of  all  malignant  tumors  and  about  16  per  cent,  of  all  laryngeal 
tumors  (Jurasz). 

The  chief  age  of  incidence  is  the  fifth  decade,  but  many  cases  occur  between 
60  and  90  years,  and  several  cases  have  been  observed  in  children  of  3  to  6 
years  (Rehn,  Steiner).  The  evidence  suggesting  an  hereditary  influence 
in  cancer  of  the  larynx  is  probably  not  more  definite  than  with  other  forms 
of  cancer  in  the  adult  (Semon,  Lit.).  Syphilis  and  tuberculosis  seem  to  have 
no  definite  relation  to  the  disease,  although  a  few  cases  have  arisen  in  tuber- 
culous or  syphilitic  lesions  (Schmidt,  Wolfenden,  Crone).  Baumgarten  has 
observed  tubercle  diffused  throughout  a  laryngeal  carcinoma.  Males  are 
much  more  often  affected  than  females  (400  to  68,  Sendziak).  The  special 


FIG.  431. — Bulky  hornifying  papillary  carcinoma  of  larynx,  with  invasion  of  cervical 

lymph-nodes. 

factors  concerned  in  the  etiology  of  carcinoma  are  very  similar  to  those  of 
papilloma.  Chronic  laryngitis  and  the  misuse  of  alcohol  and  tobacco  prob- 
ably determine  the  great  predominance  of  the  disease  in  men. 

Molinie  emphasizes  the  combined  influence  of  syphilis,  alcoholism,  and 
tobacco. 

Pachydermia  laryngis  or  leukoplakia  is  a  condition  of  epithelial  hyper- 
trophy and  hyperkeratosis  affecting  the  posterior  portions  of  the  vocal  cords. 
The  mucosa  appears  smooth  or  warty  and  scaly.  The  papillae  are  elongated 
and  the  submucosa  is  infiltrated  with  round  cells,  while  the  glands  are  hyper- 
plastic  (Virchow,  Fraenkel).  It  is  not  known  to  precede  cancer  in  the  larynx, 
but  its  relation  to  cancer  in  other  tissues  renders  it  suspicious  in  all  situations. 
With  C.  Jackson  I  have  seen  one  characteristic  case  in  which  the  downward 
growth  of  papillae  and  atypical  qualities  of  the  cells  were  very  prominent. 


852 


NEOPLASTIC  DISEASES 


Anatomy. — The  earliest  stages  of  carcinoma  present  to  the  laryngoscope 
(a)  a  broad  but  circumscribed  thickening  of  the  mucosa,  or  (6)  a  projecting 
whitish  nodule,  (c)  a  broad  warty  excrescence.  Only  4  cases  of  carcinoma 
with  a  definite  pedicle  have  been  reported  (Schmidt).  These  lesions  are 
commonly  associated  with  signs  of  laryngitis  which  precedes  or  accompanies 
the  growth.  A  characteristic  light  opaque  color  may  or  may  not  be  prominent. 
The  early  carcinomas  may  not  differ  in  any  gross  feature  from  benign  papil- 
loma,  but  usually  they  are  broader,  more  dense  and  opaque,  and  more  firmly 
incorporated  in  the  submucosa. 

The  anterior  portion  and  commissure  of  vocal  cords  and  vicinity  are  the 
chief  seat  of  carcino'ma,  but  it  may  develop  in  any  part  of  the  organ  and  its 
various  folds  and  sinuses.  Immobility  of  the  vocal  cord  occurs  with  tumors 


FIG.  432. — A  flat  papillary  subglottic  carcinoma  which  gave  origin  to  bulky  metastases 

in  cervical  lymph-nodes. 

of  the  posterior  segment.  In  frequency  the  various  locations  stand  in 'the 
following  order:  true  vocal  cords,  false  cords,  posterior  surface  of  cricoid, 
epiglottis,  and  the  lateral  plicae  and  sinuses.  These  locations  suggest  the 
division  of  laryngeal  carcinoma  into  intrinsic  and  extrinsic  forms  (Krishaber). 
The  former  are  much  the  more  numerous  except  in  females  (Molinie). 

The  established  disease  takes  the  form  of  a  circumscribed  papillary  growth 
or  a  more  diffuse  infiltration.  The  cordal  tumors  long  remain  localized  to 
one  side,  but  diffuse  growths  spread  backward  and  to  the  opposite  side  (cir- 
cular carcinoma),  and  many  extrinsic  tumors  early  involve  both  sides.  Ulcera- 
tion  supervenes  in  the  second  year  in  nearly  all  cases,  greatly  altering  the 
gross  appearance  and  giving  rise  to  many  complications. 

Arising  in  the  submucous  tissues  of  the  ventricle  of  Morgagni  the  tumor 


EPIDERMOID  CARCINOMA 


853 


reaches  a  moderate  size,  displacing  the  false  cord  and  causing  a  protrusion  of 
the  overlying  mucosa.  Later  it  perforates  the  mucosa  and  reveals  itself  un- 
expectedly as  an  extensive  ulcerating  carcinoma  (Sendziak). 

Larval  Carcinoma. — M.  Schmidt  described  a  form  of  deep-seated  carcin- 
oma of  the  larynx  associated  with  superficial  benign  papillomas.  It  may 
cause  considerable  destruction  of  the  cartilages  before  it  appears  on  the  sur- 
face and  discloses  its  malignant  nature. 

The  advanced  disease  varies  considerably  in  its  form  and  mode  of  exten- 
sion. Many  reach  a  large  bulk  while  retaining  a  papillary  form.  Others 
infiltrate  early  and  cause  only  minor  laryngeal  symptoms.  Intrinsic  cancer 
long  remains  confined  to  the  larynx  and  is  slow  to  infiltrate  the  lymph-nodes, 


FIG.  433. — Epidermoid  carcinoma  involving  tonsil  and  pyriform  sinus  of  larynx. 

but  the  outlying  or  extrinsic  tumors  extend  to  esophagus,  tongue,  pharynx 
and  treachea,  and  to  the  neighboring  lymph-nodes.  Quite  bulky  tumors  may 
develop  in  the  late  stages,  and  the  extensions  may  be  remarkably  wide. 
Thiersch  observed  invasion  of  the  cervical  vertebrae,  Moure  saw  extension 
to  the  submaxillary  tissues,  and  Gougenheim  and  Gaston  reported  a  large 
secondary  thyroid  tumor. 

Contact  implantation  from  one  vocal  cord  to  the  other  has  several  times 
been  observed  (Butlin,  Newmann,  Semon,  Jurasz).  With  the  invasion  of 
the  soft  tissues  above  the  glottis  there  is  soon  involvement  of  the  submaxillary 
and  cervical  nodes  which  may  reach  large  dimensions  even  with  small  laryngeal 
growths.  In  some  cases  the  cervical  tumors  long  precede  definite  laryngeal 
symptoms.  Intralaryngeal  tumors  may  first  affect  the  prelaryngeal  nodes. 


854 


NEOPLASTIC  DISEASES 


FIG.  434. — Malignant  papillary  carcinoma  of  larynx. 


FlG.  435. — Epidermoid  carcinoma  of  larynx.     Extensive  hornification  and  calcification 

in  cervical  lymph-node. 

The  structure  is  usually  that  of  adult  acanthoma  with  abundant  kerato- 
sis  and  pearl  formation.    These  tumors  are  locally  destructive  but  of  slow 


EPIDERMOID  CARCINOMA 


855 


growth.  Many  laryngeal  cancers  exhibit  transitional  epithelial  characters 
with  cylindrical  or  cuboidal  cells,  free  from  keratosis.  They  arise  from  the 
folds  and  sinuses  of  the  larynx  and  are  the  source  of  extensive  tumors  in  the 
lymph-nodes  (Kosinski,  Maydl).  Glandular  carcinoma  arising  from  the 
alveoli  and  ducts  of  mucous  glands  is  rare  (Schmidt,  Schmiegelow,  B.  Fraen- 
kel,  Krieg).  Its  chief  location  is  in  the  ventricle  of  Morgagni. 

In  some  tumors,  probably  arising  from  the  stratified  cells  lining  the  crypts, 
the  cells  rapidly  become  changed  to  an  indifferent  rounded  or  polyhedral 
form  and  grow  in  very  small  groups  or  diffusely.  Such  a  structure  may  readily 
be  mistaken  for  sarcoma. 


FIG.  436. — Epidermoid  carcinoma  of  larynx  invading  the  lymphatics  of  the  thyroid. 

Lymphatic  Extension. — Based  on  Cuneo's  studies  of  the  laryngeal  lym- 
phatics, Molinie  shows  that:  (i)  Supraglottic  cancer  early  invades  the  supe- 
rior nodes  of  the  external  jugular  chain;  (2)  cancer  limited  to  the  vocal  cords 
rarely  invades  any  nodes;  (3)  subglottic  cancer  invades  the  deep  nodes  about 
larynx  and  trachea,  subcricoid,  and  peritracheal,  as  well  as  inaccessible  pos- 
terior groups  along  the  recurrent  nerves  and  behind  the  esophagus. 

The  course  of  laryngeal  carcinoma  is  much  influenced  by  the  type  and 
location  of  the  tumor.  Acanthoma  of  the  vocal  cords  is  of  relatively  slow 
development,  long  remains  confined  to  the  larynx,  but  in  the  ulcerative  stage 
extends  widely  and  involves  neighboring  tissues  and  nodes.  Periodic  remis- 
sions are  often  observed  and  2  or  3  years  may  elapse  before  a  small  carcinoma 
begins  to  grow  rapidly.  Extensive  perichondritis  may  become  established, 
in  which  the  carcinomatous  process  combined  with  secondary  infection  per- 


856  NEOPLASTIC  DISEASES 

forates  and  sequestrates  the  cartilage.  Diffuse  carcinoma  of  the  cords  may 
cause  asphyxia.  The  usual  termination  is  by  cachexia,  from  dysphagia,  sup- 
puration, and  hemorrhage  with  terminal  pneumonia.  The  extrinsic  carcinomas 
usually  progress  more  rapidly,  early  invade  lymph-nodes,  and  are  very  subject 
to  ulceration  and  extensive  suppuration.  Many  of  these  are  composed  of  cyl- 
indrical or  cuboidal  cells,  without  hornification.  Glandular  carcinoma  is  usually 
less  malignant.  In  advanced  stages  secondary  deposits  may  occasionally  appear 
in  distant  organs,  as  the  lungs,  liver,  kidney,  humerus,  dura  mater  (Shappers, 
Desnos,  Sands,  Virchow). 

Secondary  carcinoma  of  the  stomach,  probably  from  extension  through  the 
lymph-vessels,  is  recorded  by  Gougenheim. 

Sarcoma  of  Larynx. — Sarcomas  form  n  per  cent,  of  malignant  laryngeal 
growths  (Molinie).  The  series  of  117  cases  analyzed  by  Bergeat,  50  by  Send- 
ziak,  and  23  by  Butlin  show  that  sarcoma  arises  in  much  the  same  situations 
and  in  its  early  stages  closely  resembles  the  epithelial  tumor.  Thus  they 
are  extrinsic  or  intrinsic  in  location  and  polypoid  or  diffuse  in  form.  Some 
develop  a  long  pedicle  (McWhinnie). 

Many  histological  varieties  are  described,  most  frequently  spindle-cell, 
mucoid,  round-cell,  and  giant-cell  types.  Lymphosarcoma  is  described  by 
Koschier  and  Stoerk.  Spindle-cell  sarcoma  is  practically  limited  to  the  vocal 
cords  and  epiglottis,  while  the  so-called  alveolar  types  (carcinoma  ?)  appear 
in  the  folds  and  sinuses  (Sendziak).  The  surface  of  the  early  sarcoma  is  usually 
smooth.  In  late  stages  ulceration  occurs,  but  less  frequently  than  with  car- 
cinoma, the  lymph-nodes  may  be  invaded  (15  per  cent.),  and  the  conditions 
resemble  the  advanced  carcinomas.  It  is  probable  that  many  cases  recorded 
as  sarcoma  are  of  epithelial  origin. 


CHAPTER  XLIII 

EPIDERMOID  CARCINOMA  (Continued) 
CARCINOMA  OF  ESOPHAGUS 

Carcinoma  of  the  esophagus  is  characterized  by  the  variety  and  often 
by  the  obscurity  of  its  symptoms,  the  peculiarities  of  its  structure,  and  by 
its  high  mortality. 

Etiology. — Males  are  affected  in  75  per  cent,  of  the  cases  (Kraus),  and 
while  the  disease  occurs  chiefly  about  the  fiftieth  year,  Kaufmann  saw  a 
small  lesion  in  a  woman  of  90  and  Heirnan  reports  a  case  in  a  girl  of  19  years. 

Alcohol,  irritating  hot  foods,  tobacco,  and  wounds  of  various  kinds  stand 
as  contributing  factors.  Leukoplakia  and  tuberculous  ulcers  have  also  fur- 
nished the  basis  of  the  disease. 

The  anatomy  of  the  organ  has  a  prominent  bearing  on  the  location  and 
incidence  of  esophageal  cancer.  The  three  points  of  predilection,  (i)  upper, 
(2)  middle,  and  (3)  lower  thirds,  are  also  points  of  normal  constriction,  the 
narrowest  being  at  the  level  of  the  cricoid.  Mehnert  holds  that  there  are  13 
natural  constrictions  at  the  vertebrae.  Others  enumerate  narrowings  and 
points  of  election,  as  at  cricoid,  aorta,  tracheal  bifurcation,  left  bronchus,  and 
cardia.  At  these  points  also  diverticula  form  and  these  abnormalities  either 
on  their  edges  or  in  the  depth  may  be  the  seat  of  carcinoma  (Heller-Arndt, 
Ritter). 

Anomalies  of  structure  of  the  esophageal  mucosa  seem  to  be  an  important 
predisposing  factor  in  carcinoma,  but  their  exact  importance  has  not  been 
determined.  The  great  majority  of  subjects  exhibit  interruptions  in  the 
squamous  lining  of  the  mucosa  by  islands  of  mucous  glands  resembling  those 
of  the  stomach  (Schaffer).  The  most  notable  of  these  islands  appear  at  the 
level  of  th&  cricoid  to  fifth  tracheal  cartilage,  as  bilateral  spots  2  to  10  mm. 
in  diameter,  resembling  gastric  mucosa,  or  they  are  much  smaller,  irregularly 
distributed,  and  require  microscopic  identification.  The  cardiac  end  of  the 
esophagus  is  also  regularly  beset  with  similar  glands.  The  glands  are  of 
branched  tubular  type,  lined  by  cylindrical  cells,  containing  mucus  and  often 
becoming  cystic.  Mucous  and  parietal  cells  are  often  to  be  distinguished. 
Much  has  been  written  on  the  origin  and  significance  of  these  glands  and  their 
relation  to  carcinoma  (Hewlett,  Lit.).  They  doubtless  give  origin  to  the 
mucoid  and  adenoid  varieties  of  carcinoma,  and  the  sudden  transition  of 
epithelial  types  which  they  present  offers  a  predisposing  factor  for  epithelioma. 
They  are  probably  not  to  be  regarded  as  misplaced  islands  of  gastric  mucosa, 
but  as  a  type  of  normal  development  of  the  embryonal  esophageal  epithelium 
(Eberth,  Neumann).  The  general  incidence  of  carcinoma  does  not  seem 
definitely  related  to  these  structures,  Kraus  finding  158  cases  in  the  upper 
third  to  699  in  the  middle  and  lower  thirds. 

Another  series  of  abnormalities  of  importance  in  the  origin  of  esophageal 
cancer  is  described  by  Glinski,  Ciechanowski  and  Mosher,  and  consists  of 
(i)  canals  lined  by  cubical  or  squamous  cells  lying  hi  the  submucosa,  or  (2) 
deeper  canals  perforating  the  muscular  coat,  and  (3)  of  complete  tracheo- 

857 


858 


NEOPLASTIC  DISEASES 


esophageal  fistulae.  Many  of  these  canals  open  on  the  mucous  surface  of  the 
esophagus  and  always  on  the  anterior  surface  in  the  middle  line.  Stoeber, 
Kern,  and  others  describe  cysts  of  this  origin.  Kathe  found  in  a  case  of 
esophageal  cancer  an  opening  in  the  esophagus  in  the  above  position,  18  cm. 
below  the  laryngeal  orifice,  leading  into  a  canal  which  passed  in  the  sub- 
mucosa  downward  5.5  cm.,  where  it  again  opened  in  the  middle  line.  All  these 
structures  may  be  referred  to  incomplete  separation  of  trachea  and  esophagus 
at  an  early  embryonal  period.  That  epidermoid  carcinoma  may  arise  from 
such  structures  is  indicated  by  Grabowski's  case,  in  which  a  tumor  protruded 
into  esophagus  and  also  to  a  less  extent  into  the  trachea.  An  origin  from  such 
deep  structures  may  also  explain  the  common  failure  to  find  early  superficial 
lesions  of  the  lining  epithelium,  the  early  onset  of  deep  ulcerations,  the  wide 

vertical  extensions  of  the  disease,  and  prob- 
ably, also,  the  embryonal  character  of  certain 
very  malignant  cases. 

Gross  Anatomy. — The  tumor  appears  as 
(i)  a  flat  infiltrating  ulcer,  or  (2)  a  more  bulky 
polypoid  or  globular  mass,  or  (3)  a  diffuse 
infiltration. 

(1)  The  ulcer  may  encircle  the  tube,  causing 
constriction   and   invading   surrounding   tissues. 
Above,  it  invades  larynx ;  below,  gastric  wall,  and 
externally  it  permeates  lymph-nodes  and  rup- 
tures into  trachea,  bronchus,  lung,  aorta  (Stadel- 
mann,    Kaufmann),    and    mediastinum.      Fatal 
hemorrhage   results   also   from   erosion   of   pul- 
monary vessels,  or  carotid  and  thyroid  arteries. 
Infection  and  suppuration  constantly  supervene. 
In  many  cases  of  this  type  the  initial  lesion  is 
small  and  resembles  a  peptic  ulcer,  while  the 
invasion  of  nodes  and  tissues  is  extensive.    Thus 
there  may  be  bulky  tumors  in  the  neck,  or  ex- 
tending   down    the    mediastinum,    or    involving 
pleura  and  pericardium,  and  these  tumors  may 
cause    secondary    stenosis    or   perforations.      A 
second  ulcer  of  the  mucosa  may  appear,  prob- 
ably formed  in  this  manner  (Seelig). 

Pressure  on  the  recurrent  laryngeal  nerve 
is  a  frequent  and  early  symptom  recalling  aneu- 
rysm.  It  occurred  in  1 8  of  236  cases  (Sakata). 
Ehret  once  noted  hoarseness  as  the  initial  symp- 
tom. 

(2)  Globular  or  polypoid  tumors  are  usually 
of  the  adenocarcinomatous  type  (Coplin,  Lit.).     They  form  circumscribed 
growths  within  lumen,  wall,  or  lying  externally. 

(3)  A  diffuse  infiltration  of  much  of  the  esophagus  occurs,  of  which  Caesar 
describes  a  typical  case.  The  organ  from  larynx  to  cardia,  as  well  as  a  portion 
of  lesser  gastric  curvature,  was  uniformly  f  cm.  in  thickness,  stenosed,  but 
free  from  ulceration,  and  the  mediastinal  nodes  were  much  enlarged. 

The  early  and  extensive  metastases  of  esophageal  carcinoma  are  favored 
by  the  abundant  blood  and  lymphatic  supply  and  by  the  movements  of  the 
organ.  The  influence  of  the  latter  element  is  only  less  prominent  than  in 
the  stomach.  Of  the  lymphatics  Sakata  describes  a  rich  plexus  in  the  mucosa 
which  is  chiefly  longitudinal  and  a  plexus  of  much  finer  vessels  in  muscularis 


FIG.  437. — Congenital  fistu- 
lous  tracts  in  esophagus.  Prob- 
able sources  of  carcinoma. 
(After  Glinski,  V.  A.,  199.) 


EPIDERMOID  CARCINOMA 


859 


and  outer  coats.  Hence  growth  along  the  tube  is  readily  accomplished  and 
this  mode  of  extension  probably  accounts  for  the  multiple  growths  and  sup- 
posed implantations  in  lower  esophagus  and  stomach  (Borrmann).  Once 
beyond  the  fibrous  coat  extension  through  lymph-vessels  occurs  with  unusual 
rapidity,  giving  secondary  tumors  in  neck,  thyroid,  pleura,  lung,  and  liver. 
The  blood-vessels  appear  to  be  penetrated  in  rare  cases.  Diirr  found  a  large 
metastasis  in  the  muscles  over  the 
pubic  bone.  Francke  sectioned  a  case 
supposed  to  be  a  brain  tumor,  finding 
an  adenocarcinoma  of  esophagus  with 
metastases  in  lymph-nodes,  pericar- 
dium, pleura,  spleen,  ovaries,  pan- 
creas, and  brain. 

The  structure  is  usually  that  of 
acanthoma,  but  pearls,  hornification, 
and  prickle  cells  are  often  missing 
and  the  tumor  has  an  embryonal 
type.  The  adenocarcinomatous  va- 
rieties resemble  similar  tumors  of 
the  stomach  and  may  exhibit  an  al- 
veolar or  a  more  diffuse  structure. 
Mucous  production  may  be  abundant. 
The  structure  may  vary  in  different 
portions  of  the  same  tumor  and  Kauf- 
mann  mentions  mucous  production 
in  the  secondary  deposits  from  an 
acanthoma. 

Among  atypical  varieties  may  be 
mentioned  a  highly  embryonal  growth 
described  by  Norris.  In  this  case, 
with  an  ulcer  of  the  usual  gross  ap- 
pearance in  the  upper  esophagus, 
there  were  enormous  tumors  in  the 
liver.  In  both  the  cells  were  of  in- 
different large  polyhedral,  or  spindle, 
or  round  type. 

Extensive  involvement  of  cervical 
lymph-nodes  with  comparatively  small 
tumors  of  the  esophagus  occurs  in  an 
important  group  of  cases.  Large 
tumors  of  one  or  both  sides  of  the 
neck  may  form  when  esophageal 
symptoms  are  indefinite  or  absent. 
The  structure  of  the  tumors  in  the 
nodes  may  be  typical  acanthoma  or 
more  embryonal  and  atypical. 

Carcinosarcoma  of  the  esophagus 
is  an  atypical  growth  of  uncertain  sig- 
nificance, of  which  several  cases  have  been  reported.    In  some  of  them  there 
was  adult  acanthoma  in  sarcomatous  stroma  (Herxheimer,  Lit.,  Donath). 

The  very  early  stages  of  esophageal  carcinoma  are  rarely  encountered. 
Janeway  examined  in  this  laboratory  an  early  epithelioma  i  cm.  in  diameter. 
It  had  not  yet  broken  the  line  of  basal  cells,  but  the  cells  were  hypertrophic, 
nuclei  very  hyper  chromatic,  the  focus  was  rather  sharply  demarcated,  and 


FIG.  438. — Carcinoma  of  esophagus. 


860 


NEOPLASTIC  DISEASES 


the  whole  area  resembled  a  very  early  basal-cell  carcinoma.  Probably  many 
tumors  arise  from  embryonal  submucous  or  the  deeper  structures  previously 
described. 

EPITHELIAL  TUMORS  OF  BLADDER 

The  natural  history  of  epithelial  tumors  of  the  bladder  is  determined 
by  the  structure  of  its  mucosa,  and  the  physical  conditions  to  which  it  is 

exposed.  The  transitional  character  of  the 
vesical  epithelium,  which  exhibits  both  pave- 
ment and  glandular  properties,  accounts  for 
the  histological  varieties  of  tumors  arising 
from  it.  Thus  the  superficial  cells  are  chiefly 
of  the  squamous  type,  while  the  deeper  cells 
rapidly  become  polygonal  and  in  many  cases 
deep  lying  crypts,  often  called  Brunn's  follicles, 
are  present  and  exhibit  a  lining  of  polygonal 
or  cylindrical  cells.  Muscular  activity  and 
a  constant  bathing  in  fluid  explain  the  villous 
form  of  the  tumors.  The  villous  form  prob- 
ably, determines  the  long  confinement  of  the 
tumors  to  the  site  of  origin,  which  was  once 
wrongly  attributed  to  absence  of  lymphatics. 
Multiplicity  may  be  referred  to  ready  dif- 
fusion of  the  irritants  which  cause  inflam- 
matory and  then  neoplastic  overgrowth. 

There  are  two  common  varieties  of  these 
tumors:  (i)  Papilloma,  which  is  fibrous, 
benign,  or  malignant;  and  (2)  Carcinoma, 
which  may  be  of  adenoid  or  diffuse  type. 
Adenoma  is  very  rare.  Several  subvarieties 
are  mentioned  by  various  authors,  as  Al- 
barran  and  Fenwick.  The  bladder  furnishes 
between  0.96  per  cent,  of  all  carcinomas 
(Hadda)  and  0.25  per  cent.  (Albarran).  Rau- 
enbusch  finds  the  disease  three  times  as 
common  in  men  as  in  women.  Yet  Stein 
observed  16  simple  papillomas  in  women  to 
14  in  men.  Sarcomas  are  much  more  frequent 
in  women  and  children. 

Papilloma. — This  common  tumor  occurs 
usually  as  a  coarse  villous  growth  with  narrow 
pedicle,  or  the  papillae  may  be  feathery  or 
fleecy,  or  the  growth  may  be  rather  flat  and 
tabulated,  or  the  tumor  has  a  broad  flat  base 
and  is  sessile.  Rarely  long  cylindrical  papillomas  are  observed  (Albarran). 
The  surface  of  some  papillomas  may  be  of  low  warty  character  or  nearly  smooth, 
and  it  may  vary  in  different  portions  of  the  same  tumor.  Half  the  tumors  are 
multiple;  as  many  as  twenty  different  growths  may  be  scattered  over  a  wide 
area;  and  in  some  cases  much  of  the  bladder  wall  is  the  seat  of  very  numerous 
villous  outgrowths.  Hence  the  discovery  of  one  papilloma  indicates  a  search 
for  others  at  once  or  later.  The  multiple  villous  tumors  must  be  distinguished 
from  a  form  of  diffuse  low  papillary  inflammatory  hypertrophy  of  epithelium, 
which  has  been  known  to  cover  almost  the  entire  mucosa,  producing  a  velvety 
surface.  This  condition  is  a  curious  exhibition  of  the  regenerative  tendencies 


FIG.  439. — Double  ulcerating 
epitheliomas  of  esophagus.  (After 
Seelig,  A.  S.,  46.) 


EPIDERMOID  CARCINOMA 


861 


of  the  irritated  mucosa,  is  seen  in  exstrophy  of  the  bladder,  with  calculus, 
and  about  other  tumors,  and  may  be  arrested  by  curetage  (Keyes,  Fenwick) . 

The  size  of  the  papillomas  varies  extremely.  Some  long  remain  small, 
not  exceeding  2  cm.  in  length.  Others,  while  pedunculated,  attain  the  size  of 
a  small  orange.  The  more  solid  and  malignant  tumors  may  also  attain  con- 
siderable bulk.  A  very  large  pedunculated  myo-epithelioma  is  described  by 
Albarran.  The  chief  location  is  about  the  ureteral  orifices  and  along  the 
edges  of  the  trigone.  Fenwick  notes  a  relative  immunity  of  the  trigone  itself, 
where  the  mucosa  is  less  mobile. 

The  course  of  the  tumors  is  generally  prolonged.  Hadda  refers  to  cases 
lasting  1 8  years.  Guyon  observed  a  case  of  30  years'  duration,  and  Fenwick 


FIG.  440. — Advanced  carcinoma  of  esophagus  with  rupture  into  bronchus. 

attributed  to  i  case  a  duration  of  60  years.  They  arise  at  any  period  of 
life  from  i\  to  79  years  (Albarran,  Frisch),  but  are  most  common  after  middle 
life,  especially  in  the  sixth  decade.  The  life  of  most  papillomas  remains 
confined  chiefly  to  the  bladder.  Some  remain  benign  for  many  years,  and 
rarely  spontaneous  expulsion  occurs.  Others  (25  per  cent.)  become  malig- 
nant after  a  variable  period.  Some  are  malignant  from  the  first  (Albarran). 
Almost  75  per  cent,  reach  an  urgent  condition  or  are  fatal  in  3  years.  Albarran 
found  68  malignant  cases  to  13  benign  papillomas.  There  is  to  be  considered, 
in  addition,  the  tendency  of  the  benign  disease  to  become  malignant.  Most 
authors  are  agreed  that  the  macroscopic  appearance  is  no  safe  criterion  of 
clinical  course,  while  the  microscopic  structure  usually  indicates  considerable 


862  NEOPLASTIC  DISEASES 

growth  capacity  which  in  other  situations  would  always  prove  malignant. 
The  clinical  malignancy  is  also  influenced  by  the  tendency  of  new  tumors  to 
progressively  develop  in  a  predisposed  mucosa. 

In  many  cases  the  removal  of  the  original  tumor  is  followed  by  recurrence 
at  another  site.  It  is  probable  that  the  recurrence  usually  represents  a  de- 
velopment of  a  new  tumor  from  preexisting  lesions,  but  not  a  recrudescence 
or  implantation  of  the  old  growth.  Frankly  malignant  cases,  however,  doubt- 
less exhibit  a  growth  of  retained  cell  groups  in  the  submucosa.  Of  103  simple 
papillomas  Frisch,  after  suprapubic  cystotomy,  saw  21  recurrences  in  53  cases 
which  he  could  follow.  Of  49  papillomas  which  gave  microscopical  signs  of 


FIG.  441. — Bulky  papillary  carcinoma  of  bladder. 

malignancy,  29  recurred,  3  in  the  form  of  flat  carcinomas.  Of  95  definite  can- 
cers, 62  recurred  and  the  others  were  not  traced.  In  3  cases  a  simple  papilloma 
recurred  as  single  or  multiple  carcinoma. 

Extensions  occur  through  the  wall  of  the  bladder  to  the  pelvic  tissues, 
up  the  ureters  toward  the  kidneys,  along  the  pelvic  lymphatics  to  the  pre- 
vertebral  lymph-nodes.  Rarely  there  is  a  superficial  extension  of  a  papillary 
cancer  of  the  urethra  into  the  bladder  (Fluss,  Lit.),  or  vice  versa  (Adenot). 
Metastases  are  not  common,  but  have  been  observed  in  liver,  lung,  pleura, 
kidney,  and  inguinal  and  axillary  lymph-nodes. 

Albarran  saw  a  pulmonary  metastasis  2  years  after  removal  of  a  solitary 


EPIDERMOID  CARCINOMA  863 

papilloma,  the  bladder  remaining  free.  He  accepts  frequent  propagation  by 
contact,  but  does  not  insist  on  the  actual  implantation  of  tumor-cells.  The 
bulky  wide-spread  metastases  of  prostatic  cancer  are  regularly  wanting. 

The  complications  of  malignant  papillomas  and  of  other  cancers  are  hem- 
orrhage with  anemia,  infection  with  cystitis  and  pericystitis,  hydronephrosis, 
renal  suppuration,  and  septicemia.  Extension  occurs  late  and  true  cancerous 
cachexia  from  generalization  is  rare. 

The  structure,  of  the  vesical  papilloma  is  rather  simple  and  uniform.  It 
consists  of  a  series  of  branching  tufts  of  stroma  covered  by  multiple  layers 
of  epitheluim  resembling  that  of  the  bladder.  The  variable  element  is  the 
stroma,  which  may  consist  of  a  single  delicate  capillary  sometimes  in  imme- 
diate contact  with  the  epithelium,  more  often  supported  by  delicate  strands 
of  connective  tissue,  occasionally  accompanied  by  smooth  muscle-fibers.  The 
muscular  stroma  may  be  quite  abundant  and  in  Albarran's  myo-epithelioma  it 


A 
FlG.  442. — Spindle-cell  epidermoid  carcinoma  of  bladder. 

composed  the  bulk  of  a  large  malignant  tumor.  Fibrous  polyps  are  described, 
consisting  chiefly  of  localized  overgrowth  of  submucous  tissue.  They  are  of 
inflammatory  nature.  Stein  found  mucous  polyps  almost  as  common  as 
papilloma.  True  fibromyxomas  are  rare,  but  may  reach  large  dimensions 
(Stein,  Albarran).  The  epithelium  is  usually  overnourished,  with  hyper- 
chromatic  nuclei,  but  mitoses  are  rare.  The  cell  form  may  exactly  reproduce 
that  of  the  bladder,  or  the  cells  may  be  elongated,  or  rounded,  or  extensively 
vacuolated.  Albarran  describes  as  the  "allantoid  type"  a  simple  papilloma  of 
which  the  villi  are  capped  with  cylindrical  cells  as  in  the  intestine.  Venulet 
described  a  structure  resembling  chorioma.  The  papillae  are  closely  packed 
together  in  the  more  solid  tumors,  so  that  the  section  may  resemble  alveolar 
carcinoma. 

Signs  of  malignancy  in  papillomas  include  much  variation  in  the  size  and 
type  of  the  cells  and  extensive  and  irregular  overgrowth,  but  the  most  im- 


864  NEOPLASTIC  DISEASES 

portant  indications  may  be  found  only  in  the  pedicle  which  is  seldom  accessible 
in  operative  material.  Downward  growth  of  the  convoluted  epithelium  in- 
vading the  pedicle  and  subajcent  tissue  is  the  chief  factor  in  local  recurrence 
and  malignancy.  There  is  reason  to  believe  that  chronic  inflammation  with 
edema  and  round-cell  infiltration  facilitates  this  downward  growth  and  renders 
it  possible  without  any  great  change  in  the  growth  capacities  or  morphology 
of  the  cells.  Yet  in  some  papillomas  the  invasive  tendency  is  present  from  the 
first.  That  a  slowly  growing  and  originally  benign  papilloma  may  become 
malignant  is  abundantly  attested  (Albarran,  Fenwick,  Frisch).  Frankly, 
malignant  papillomas  exhibit  throughout  the  atypical  and  lawless  growth  of 
carcinoma. 

Buerger  places  the  proportion  of  carcinomas  preceded  by  papilloma  at 
30  to  36  per  cent.  While  it  is  impossible  to  determine  from  the  structure 
which  papillomas  will  become  malignant,  the  actual  presence  of  malignant 
characters,  he  finds,  may  be  determined  from  examination  of  portions  acces- 
sible to  the  cystoscope.  The  changes,  as  usual,  consist  in  atypical  qualities  of 
the  cells  and  nuclear  hyperchromatism. 

Degenerative  changes  in  papillomas  include  fragmentation,  infection, 
and  ulceration,  edema,  necrosis,  cellular  infiltration,  and  calcific  incrustation. 

Adenoma. — The  literature  contains  isolated  reports  of  adenoma  and  ade- 
nocarcinoma  of  the  bladder  (Albarran,  Fenwick).  These  tumors  are  usually 
small,  single  or  multiple,  located  on  trigone  or  other  portion  of  wall,  and 
they  may  be  flat  or  pedunculated.  They  are  composed  of  large  alveoli  lined 
by  multiple  layers  of  cells  some  of  which  are  usually  cylindrical.  They  show 
a  tendency  to  mucous  degeneration,  as  in  Kaltenbach's  case.  Some  of  the 
large  glandular  cysts  of  the  bladder  are  probably  related  to  adenoma. 

The  occurrence  of  cylindrical  cell  and  mucoid  adenoma  and  carcinoma 
in  the  bladder  suggests  an  origin  from  mucous  glands,  which  are  not  always 
attributed  to  the  structure  of  this  organ.  Yet  short  tubular  glands  are  reg- 
ularly found  in  the  bladder  mucosa,  especially  in  the  trigone  and  about  the 
urethral  orifice  (Albarran,  Aschoff).  They  have  been  variously  interpreted 
as  aberrant  prostatic  glands  (Virchow),  or  urethral  glands  (Aschoff),  or  as  the 
result  of  snaring  off  of  papillae  of  epithelium  by  thickened  connective-tissue 
septa  (v.  Brunn's  follicles).  In  cystitis  cystica  many  of  the  invaginated 
epithelial  tubules  are  lined  by  cylindrical  cells  and  the  modified  epithelium 
develops  secretory  tendencies.  Albarran  describes  in  the  trigone  tubular 
glands  in  the  submucosa  lined  by  cylindrical  and  cuboidal  cells  and  simpler 
tubular  crypts  scattered  over  the  bladder  wall.  No  true  secretory  processes 
have  been  established  in  these  glands,  but  the  lumina  are  filled  with  des- 
quamated cells.  It  is  probable  that  such  glandular  structures  increase  in 
number  with  increasing  age  and  in  cases  of  chronic  cystitis  (Prezwosky). 

Glandular  Carcinoma. — A  rare  type  of  carcinoma  of  the  bladder  takes 
the  form  of  a  diffuse  infiltration  of  the  wall,  with  extensive  mucoid  degenera- 
tion. Rauenbusch  has  collected  10  cases  of  this  type  and  offers  a  description 
which  indicates  that  such  tumors  may  result  from  an  extensive  malignant 
growth  of  the  same  type  as  the  mucoid  adenomas.  Yet  the  well-known  diffi- 
culty of  distinguishing  secondary  and  primary  carcinoma  of  the  bladder,  and 
the  occurrence  of  somewhat  similar  conditions  from  secondary  invasion  by 
intestinal  cancer,  leaves  a  reasonable  doubt  as  to  the  exact  origin  of  some  of 
the  colloid  carcinomas.  Montfort,  for  example,  was  able  to  find  only  4 
primary  glandular  cancers  of  the  bladder  in  83  cases  fully  examined.  The  ob- 
servations of  many  authors  indicate  the  importance  of  this  point  of  view. 

Secondary  invasion  of  the  bladder  by  carcinoma  may  closely  simulate 
primary  tumors.  Carcinoma  of  the  prostate  frequently  invades  the  bladder 


EPIDERMOID  CARCINOMA  865 

at  the  trigone,  and  Klebs  once  thought  that  all  carcinomas  of  the  bladder 
arose  in  the  prostate.  The  differential  diagnosis  is  often  difficult  and  at  times 
impossible.  Many  observers  have  found  that  only  a  small  proportion  of 
true  carcinomas  involving  the  bladder  are  primary  in  that  organ.  Besides 
the  prostate,  the  uterus  and  rectum  furnish  a  considerable  proportion  of 
the  invading  tumors  (Fere).  The  invasion  of  the  trigone  from  the  prostate 
may  take  the  form  of  a  fungating  mass  or  a  flat  ulceration;  or  the  urethral 
orifice,  trigone,  and  prostatic  urethra  may  be  the  seat  of  hard  projecting 
nodules;  or  the  growth  originating  in  the  anterior  portion  of  the  prostate 
may  invade  and  thicken  the  anterior  wall  of  the  bladder  (Fenwick).  Sar- 
comas of  the  prostate  or  vagina,  especially  in  children,  may  grow  extensively 
in  the  bladder.  From  the  seminal  vesicle  a  carcinoma,  described  by  Fenwick, 
invaded  prostate  and  bladder  wall,  forming  a  hard  cup-shaped  ulcer  involving 
one-half  of  the  trigone  and  ureteral  opening. 

Primary  ureteral  carcinoma  has  occurred  in  rare  cases  (Voelcker,  Rundle), 
and  downward  growth  of  this  tumor  may  yield  a  tumor  mass  at  the  urethral 
orifice  (Drew).  Yet  it  is  difficult  to  exclude  a  primary  growth  at  the  ure- 
teral orifice,  as  in  Fenwick's  case  (1.  c.,  p.  18).  The  cases  in  which  the  renal 
pelvic  mucosa,  ureter,  and  ureteral  orifice  are  involved  by  nodular  or  villous 
carcinoma  probably  signify  the  development  of  multiple  primary  tumors 
over  a  wide  area.  The  possible  extent  of  this  predisposed  territory  is  in- 
dicated by  various  cases  of  pyelitis,  ureteritis,  and  cystitis  cystica  (Stow, 
Lit.).  A  similar  explanation  probably  applies  to  the  alleged  cases  of  im- 
plantation of  renal  carcinoma  along  ureter  and  in  bladder.  This  view  is 
strengthened  by  the  occurrence  of  benign  papillomas  in  the  bladder  in  cases 
of  malignant  renal  or  ureteral  growths  (Fenwick,  Lit.).  Several  observers 
have  noted  that  the  invasion  of  the  bladder  by  malignant  tumors  of  other 
organs  may  excite  the  growth  of  villous  papillomas  in  the  adjacent  mucosa. 

Etiology. — The  great  majority  of  bladder  cancers  can  be  traced  to  a 
previous  or  coexistent  cystitis.  In  one  group  the  cystitis  long  antedates 
the  tumor  and  may  be  forgotten.  Vesical  calculus  is  associated  with  car- 
cinoma in  a  rather  small  proportion  of  cases,  varying  greatly  with  different 
authors.  It  is  especially  common  when  stones  form  in  Bilharzia  cystitis 
(Goebel). 

Stoerk  has  traced  a  definite  relation  between  cystitis  cystica  and  its  fore- 
runners with  multiple  papilloma,  and  he  and  Cohen  report  cases  of  cystitis 
cystica  developing  into  carcinoma.  I  have  observed  one  case  in  which  a 
large  portion  of  the  bladder  was  the  seat  of  low,  nodular,  and  cystic  outgrowths, 
from  many  points  of  which  carcinoma  had  developed.  The  multiple  tend- 
ency of  villous  carcinoma  and  the  heterotopic  recurrences  indicate  the  exist- 
ence of  wide-spread  lesions  in  the  mucosa  from  which  tumors  may  develop. 

In  Bilharzia  disease  there  is  a  series  of  changes,  including  venous  and 
lymph  stasis,  catarrhal  cystitis,  irritation  by  ova,  and  lithiasis,  which  have 
been  shown  by  Goebel  and  others  to  lead  in  many  instances  to  epithelial 
and  other  tumors.  The  frequency  of  chronic  cystitis,  papilloma,  carcinoma, 
and  even  sarcoma  among  anilin  workers  has  been  pointed  out  by  Rehn, 
Wendel,  Leichtenstern,  and  lately  by  Nassauer.  Here  the  cystitis  and  the 
tumors  are  often  located  at  the  ureteral  orifices.  A  large  proportion  (50  per 
cent.,  Seyberth)  of  these  tumors  are  malignant. 

Miscellaneous  Tumors  of  Bladder. — Among  the  rare  tumors  sarcoma 
of  the  bladder  is  of  chief  interest.  Albarran  collected  51  cases.  They  occur 
chiefly  in  young  subjects.  They  produce  a  large  globular  or  polypoid  in- 
travesical  growth  or  diffusely  invade  the  wall.  The  structure  varies,  round, 
spindle,  and  mixed  cells  predominating.  Vascular  myxosarcomas  of  large 
55 


866 


NEOPLASTIC  DISEASES 


size  are  reported  by  Kaufmann.  Osteochondrosarcoma  is  reported  by  Beneke 
and  W.  Fischer.  Secondary  invasion  of  the  bladder  by  the  myxosarcoma  of 
the  vagina  in  children  is  a  well-recognized  condition. 

Rhabdomyoma  has  been  described  in  a  few  cases  (Monckberg).     Leio- 
myomas  appear  as  polypoid  tumors,  sometimes  of  large  dimensions  (Terrier, 


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FIG.  443. — Cystitis  cystica.     A  lesion  often  followed  by  carcinoma  of  bladder. 

Hartmann).  Various  mixed  tumors  of  the  bladder  occurring  chiefly  in  chil- 
dren are  described  by  Husler  and  R.  F.  Miiller.  Probable  sources  of  these 
tumors  and  their  interpretations  are  discussed  under  Teratology. 

TUMORS  OF  PENIS 

Epithelioma  of  the  penis  forms  from  i  to  3  per  cent,  of  all  cancers  in 
males  (Paget,  Billroth)  and  occurs  most  frequently  in  the  sixth,  fifth,  and 
seventh  decades  of  life  (C.  Kaufmann).  Curtis  refers  to  a  case  of  epithe- 
lioma  at  1 8  years,  and  Demarquay  saw  9  cases  between  20  and  30  years. 
Creite  describes  an  atypical  embryonal  carcinoma  of  the  corpora  cavernosa 
of  undetermined  origin  in  a  child  of  2  years. 

The  disease  arises  chiefly  on  the  glans  (69  per  cent.,  Barney)  and  on  the 
dorsal  aspect  nera  the  corona  (Thomson).  Kaufmann  found  it  more  fre- 
quently on  the  prepuce.  Cancer  arises  from  the  normal  or  chronically  in- 
flamed urethral  mucosa.  Hottinger  collected  20  cases  of  this  type,  which 


EPIDERMOID  CARCINOMA 


867 


took  the  form  of  epithelioma  or  carcinoma  with  mucoid  degeneration  and 
occasionally  with  alveoli  lined  by  cylindrical  cells.  Cowper's  glands  were 
the  source  of  carcinoma  in  3  cases  described  by  Kaufmann.  Contributing 
factors  are  chiefly  phimosis  and  syphilis.  Demarquay  and  Barney  noted 
phimosis  in  80  to  85  per  cent,  of  their  cases,  and  Kaufmann  found  a  chronic 
balanitis  with  warty  vegetations,  the  result  of  irritating  secretions,  in  29 
of  33  cases.  Hebrews  are  practically  free  from  the  disease.  Thomson  de- 
scribes as  a  precancerous  condition  of  the  penis  a  catarrhal  balanitis  with 
desquamation  or,  later,  epithelial  hypertrophy  with  overgrowth  of  sub- 
epithelial  connective  tissue.  Schuchardt  calls  this  condition  "psoriasis  pre- 
putialis." 


FIG.  444. — Spindle-cell  epidermoid  carcinoma  of  penis. 

Syphilitic  scars  and  venereal  warts  are  not  infrequently  the  starting-points 
of  epithelioma,  and  the  trauma  of  circumcision  is  occasionally  mentioned. 
Buday  reports  a  urethral  carcinoma  following  elephantiasis  of  the  penis. 

Implantation  by  contact  with  a  cancerous  cervix  has  been  maintained  as  a 
source  of  penile  carcinoma  by  Demarquay,  Martin,  and  others,  but  without 
satisfactory  data. 

The  initial  lesion  is  usually  regarded  as  a  simple  wart,  or  it  appears  as 
an  eroded  papule,  more  dense  and  pearly  than  a  chancre,  or  as  a  smooth 
lump  or  thickening  of  the  epithelium,  or  finally,  as  a  definite  ulcer.  Many 
cases  are  not  recognized  until  an  irritating  purulent  discharge  calls  for  the 
relief  of  phimosis  and  discloses  an  established  lesion,  and  most  cases  have 
progressed  for  months  or  years  before  recognition. 

The  established  disease  regularly  takes  the  form  of  a  papillary  epithelioma 


868 


NEOPLASTIC  DISEASES 


and  may  long  remain  a  relatively  warty  tumor  of  considerable  dimensions, 
but  ulceration  commonly  supervenes,  excavates  the  central  portions,  and 
kads  to  infection  and  suppuration.  Early  ulceration  and  infiltration  of 
tht  base  may  obscure  the  papillary  character  from  the  first  and  lead  to  a 
more  rapid  and  malignant  course.  C.  Kaufmann  speaks  of  bulky  non-papillary 
lobulated  tumors  arising  fiom  the  glans.  Papillary  tumors  of  the  glans  are 
nearly  always  malignant. 

Local  extensions  of  the  disease  occur  late,  but  eventually  the  glans  is 
destroyed,  the  corpora  cavernosa  are  invaded,  and  the  whole  penis  may  be 
infiltrated,  especially  in  the  ulcerative  form.  In  most  cases,  however,  the 
corpora  cavernosa  long  resist  invasion  and  the  corpus  spongiosum  remains 
free,  so  that  urination  through  the  urethra  or  a  fistulous  tract  is  maintained. 


f;;.v:;y^.v<...^  -.'I 


FIG.  445.  —  Carcinoma  of  penis.    Suppurating  carcinomatous  inguinal  lymph-node 


Lymphatic  extension  occurs  through  the  superficial  vessels  to  the  inguinal 
nodes  and  through  the  deep  lymphatics  of  the  urethra  and  along  the  dorsal 
vein  to  the  pelvic  nodes.  The  inguinal  nodes  are  commonly  involved  and 
often  on  both  sides.  Kaufmann  found  the  inguinal  nodes  free  in  only  8  of 
48  cases.  Martin  found  30  out  of  40  invasions  bilateral.  Kuttner  proved 
that  many  swollen  nodes  were  free  from  cancer.  He  records  invasion  of 
pelvic  nodes  and  in  prevesical  region  in  2  cases  without  the  affection  of  in- 
guinal nodes,  and  emphasizes  the  connections  of  the  deep  urethral  and  dorsal 
vein  lymphatics  with  the  iliac  vessels.  A  notable  case  is  that  of  Taylor  who 
amputated  the  penis  without  removing  the  nodes  in  the  sixth  year  of  the 
disease,  the  patient  remaining  well  for  10  years.  Permeation  along  the  dorsal 


EPIDERMOID  CARCINOMA  869 

lymphatics  is  the  rule,  and  continuous  cords  have  been  traced  up  to  groin, 
pubes,  and  even  to  umbilicus.  Localized  nodules  may  develop  in  the  course 
of  the  lymphatics  and  break  through  the  skin.  Highly  infected  cancerous 
ulcers  develop  in  this  way  and  hasten  cachexia.  In  advanced  cases  there 
may  be  wide-spread  ulceration  and  extensions  with  metastases  in  pelvic 
and  abdominal  nodes  and  internal  organs.  The  liver  is  a  favorite  seat  of 
metastases  from  carcinoma  of  penis,  which  may  occur  early  in  the  disease. 
The  lungs,  heart,  stomach,  and  central  nervous  system  have  also  been  in- 
vaded. Rarely  the  disease  appears  to  become  implanted  by  contact  from 
glans  to  prepuce  or  scrotum. 

The  course  of  penile  carcinoma  is  relatively  slow,  especially  in  cases  which 
remain  papillary  and  escape  ulceration.    Barney  shows  that  most  cases  run 


FIG.  446. — Beginning  epidermoid  carcinoma  of  female  urethra  involving  a  superficial 

area  of  2  sq.  cm. 

i  to  3  years  before  reaching  a  critical  condition,  but  he  reports  n  cases  of  over 
5  years'  duration  and  i  case  living  n  years  without  operation.  The  gross 
mortality  was  32  per  cent.,  while  15  per  cent,  developed  visceral  metastases, 
the  others  succumbed  to  local  and  pelvic  lesions,  and  of  all  types  of  cases  38 
per  cent,  were  cured.  Recurrences  are  usually  observed  in  the  first  year, 
but  often  develop  after  5  years.  Ten  of  Barney's  26  recurrent  cases  died  of 
cancer  after  an  average  duration  from  the  beginning  of  the  disease  of  about 
8  years. 

The  structure  of  epithelioma  of  the  penis  is  uniformly  that  of  adult  acan- 
thoma  of  papillary  type  and  with  abundant  development  of  pearls  and  horni- 
fication.  This  structure  is  usually  maintained  in  the  secondary  growths  and 
may  be  very  prominent  even  in  hepatic  metastases. 


870  N EOF  LAST  1C  DISEASES 

Urethral  carcinoma  presents  the  structure  of  epithelioma  of  the  bladder 
(Hall,  Lit.).  It  is  quite  possible  that  the  endothelioma  intravasculare  of  the 
corpora  cavernosa  is  a  urethral  carcinoma  (cf.  Borrmann).  The  malignant 
tumors  arising  from  Cowper's  glands  show  the  structure  of  glandular  car- 
cinoma (Beck). 

Melanoma  of  the  glans  penis  is  described  by  Payr  (Lit.). 

Scrotal  cancer  is  interesting,  especially  because  of  the  variety  of  specific 
exciting  factors  to  which  it  has  been  attributed.  Chimney-sweeps'  cancer 
figured  frequently  in  the  literature  from  1820  to  1870,  but  has  now  largely 
disappeared  from  observation.  It  was  attributed  to  the  irritation  of  carbon 
and  oils  derived  from  the  soot.  It  was  first  recognized  by  Pott  and  fully 
described  by  Curling.  It  first  appears  as  a  "soot- wart"  which  may  long 
remain  innocent  and  may  long  grow  as  a  harmless  process,  or  with  ulcera- 
tion  may  develop  malignant  features.  The  lesion  may  develop  in  the  cuta- 
neous glands  and  produce  a  subcutaneous  nodule.  Creighton  states  that 
the  epitheliomatous  nature  of  chimney-sweeps'  cancer,  although  always 
assumed,  is  far  from  clear  in  the  recorded  cases.  He  notes  that  the  lesions 
appear  first  as  subcutaneous  nodules,  that  there  are  visceral  metastases  in 
fatal  cases,  that  the  structure  is  not  that  of  adult  acanthoma,  and  he  traces 
the  origin  to  the  sweat-glands  of  the  skin.  Many  parts  of  the  body  have 
been  affected.  Curling  relates  several  histories  indicating  that  the  disease 
may  develop  long  after  exposure.  It  has  been  observed  chiefly  in  England. 

Paraffin  cancer  of  the  scrotum  has  occupied  a  somewhat  less  definite  posi- 
tion. V.  Volkmann  was  chiefly  responsible  for  the  view  that  irritation  by 
products  occurring  in  the  manufacture  of  paraffin  gives  rise  to  scrotal  cancer. 
He  described  the  chronic  irritation  of  the  skin  of  the  genitals  in  paraffin  work- 
ers and  stated  that  the  lesions  had  a  notable  tendency  (90  per  cent.)  to  run 
into  epithelioma. 

J.  K.  Mitchell  and  Lewin  studied  the  cutaneous  eruptions  among  workers 
in  petroleum,  but  found  no  cases  of  carcinoma.  Lewin  describes  a  form  of 
chronic  acne  which  in  advanced  cases  leads  to  diffuse  chronic  inflammation 
with  crusting.  It  was  observed  especially  among  the  handlers  of  the  by- 
products of  petroleum  refining. 

That  cancer  of  the  scrotum  often  develops  in  subjects  that  are  free  from 
exposure  to  bituminous  products  is  generally  recognized.  Exposure  to  trauma 
and  irritating  secretions  are  probably  important  factors  in  its  genesis.  While 
many  of  the  cases  are  of  slow  progress,  very  active  and  malignant  forms 
occurring  at  an  early  age  (8  to  15  years)  are  reported  by  Curling  and  Heath. 


CHAPTER  XLIV 
MELANOMA 

Melanoma  is  a  pigmentiferous  tumor  arising  from  a  specific  mesoblastic 
cell,  the  chromatophore,  and  possibly  also  from  epithelial  cells  which  have 
been  modified  by  pigment  production.  It  arises  chiefly  in  the  skin  and  the 
choroid  coat  of  the  eye,  less  frequently  in  the  meninges,  rectum,  and  other 
organs.  In  the  skin  its  origin  is  connected  with  a  congenital  abnormality 
consisting  of  overgrowth  and  pigmentation  of  epidermis  and  often  of  the 
cutaneous  glands,  occasionally  with  angiomatous  processes,  and  especially 
by  the  presence  of  many  peculiar  abnormal  cells  in  the  derma,  forming  a 
lesion  known  as  the  congenital  nevus.  In  many  cases  the  process  terminates 
in  wide-spread  extension  of  the  proliferating  cells,  giving  a  highly  malignant 
tumor  process.  The  peculiar  and  obscure  conditions  of  its  origin,  the  re- 
markable physiological  properties  of  the  chromatophores  in  the  animal  king- 
dom, the  eccentricities  of  its  clinical  course,  and  its  interesting  history  as  a 
field  of  debate  render  this  tumor  one  of  the  most  notable  topics  in  oncology. 

History. — The  congenital  character,  the  origin  from  various  forms  of 
pigmented  moles,  and  the  numerous  clinical  peculiarities  were  fully  recog- 
nized by  the  early  writers  before  Virchow  (1864,  Lit.),  while  their  views 
concerning  the  exact  position  of  the  process  were  about  equally  divided. 
Virchow  recognized  both  a  sarcomatous  and  a  carcinomatous  melanoma, 
the  former  exhibiting  a  diffuse  structure  of  spindle-cells,  the  latter  an  alveolar 
structure,  and  he  employed  the  term  "melanoma"  for  the  entire  group.  Dem- 
ieville  in  1880  traced  the  origin  of  nevus  cells  to  the  perithelium  and  endothe- 
lium  of  blood-vessels,  and  in  1882  Recklinghausen  discussed  the  origin  of 
melanoma  in  connection  with  multiple  fibroma  of  the  skin.  He  accepted  by 
exclusion  the  endothelial  origin,  but  could  not  trace  any  transitions  of  cap- 
illary endothelium  into  nevus  cell  masses.  He  dealt  especially  with  the  older 
fibrous  nevi  which  may  resemble  fibroma. 

In  1893  Unna  presented  in  substantial  form  the  evidence  in  favor  of  the 
epithelial  origin  of  nevus  cells,  and  while  at  first  his  views  received  little 
support  (Delbanco,  Hodara,  Scheuber,  Gilchrist),  or  were  actively  combated 
(Bauer,  Jadassohn,  Lubarsch,  Hansemann,  Borst),  they  have  been  actively 
supported  by  many  later  writers  up  to  the  present  time  (Favera,  Lit.). 

According  to  Unna  "All  pigmented  and  non-pigmented  flat  or  wart-like 
nevi  of  newborn  infants  and  children  exhibit  a  direct  connection  between  the 
cutaneous  epithelium  or  hair  follicles  or  ducts  of  sweat-glands  and  the  cell 
cords  of  the  nevus.  In  these  structures  there  is  a  progressive  transformation 
of  prickle-cells  into  clumps  of  pliable  ameboid  cells  without  spines  or  fibrils, 
whose  epithelial  origin  and  nature  is  still  attested  by  their  clear  oval  vesicular 
nuclei  and  their  immediate  contact  with  each  other  and  with  the  neighboring 
epithelium  without  the  intervention  of  intercellular  substance.  This  meta- 
plastic  process  shows  a  constant  tendency  toward  the  complete  isolation  of 
groups  of  altered  epithelial  cells  which  are  completely  surrounded  by  the 
connective  tissue  of  the  derma." 

Definite  limitations  to  this  explicit  doctrine  were  soon  encountered,  con- 
cerning especially  the  relation  of  the  nevus  cells  to  the  abundant  connective 

871 


872  NEOPLASTIC  DISEASES 

tissue  in  older  nevi,  and  their  behavior  toward  the  lymph-  and  blood-vessels 
of  the  cutis. 

The  rather  definite  indications  that  the  nevus  cells  actively  participate 
in  the  formation  of  the  cellular  and  fibrous  tissue  which  surrounds  them 
have  been  interpreted  by  Kromayer  as  evidence  of  the  desmoplastic  property 
of  epithelium  and  this,  phase  of  the  subject  has  been  pursued  by  Kromayer 
in  a  series  of  studies  1898  to  1905  and  by  others,  with  interesting  results.  Jud- 
alewitsch  especially  has  confirmed  Kromayer's  views  and  depicts  the  gradual 
loss  of  fibrils,  pigmentation  followed  by  depigmentation,  and  isolation  of 
epithelial  cells  and  their  transformation  into  fusiform  cells  with  fibrillar 
prolongations.  Yet  there  is  a  strong  probability  favoring  the  conclusion 
of  Favera  and  others  that  this  fibrous  tissue  is  a  product  derived  from  the 
preexisting  tissue  of  the  derma.  Riecke  and  Pini,  however,  consider  the 
nevus  cells  to  be  modified  fibroblasts.  The  relation  of  the  nevus  cells  to 
the  endothelium  of  vessels  has  remained  a  difficult  question  and  a  few  more 
recent  observers  have  clung  to  theory  of  endothelial  origin  of  certain  nevi, 
while  admitting  that  many  are  derived  from  epithelium  (Lowenbach,  Walsch, 
Herxheimer,  Borrmann,  Moller,  Fox,  Johnston).  The  particular  form  which 
this  compromise  takes,  and  the  grounds  for  it,  vary  considerably  with  the 
authors,  and  specific  features  distinguishing  the  two  types  of  tumors  have 
not  been  demonstrated.  According  to  Soldan  the  endothelium  of  the  nerve 
sheaths  gives  origin  to  nevus  cells. 

The  presence  of  many  large  polygonal  or  multipolar  heavily  pigmented 
cells  in  nevi  and  melanomas  and  certain  considerations  bearing  on  the  ques- 
tion of  pigment  production  in  general,  as  well  as  observations  on  melanoma 
of  the  uveal  tract,  have  led  Ehrmann  and  Ribbert  to  maintain  the  origin 
from  the  highly  specialized  mesodermal  cell,  the  melanoblast  or  chromato- 
phore,  and  to  attribute  the  nevus  and  its  tumors  to  aberrations  of  this  cell 
(Ribbert's  chromatophoroma). 

The  evidence  accumulating  in  recent  years  from  the  comparative  study 
of  the  physiology  of  the  color  function  in  the  animal  kingdom  is  a  very 
formidable  argument  in  favor  of  the  specific  mesoblastic  nature  of  the 
chromatophore.  It  is  much  less  cogent  evidence  that  all  melanomas  are 
derived  from  mesoblastic  chromatophores.  Melanoma  undoubtedly  arises 
from  nevus  cells  and  the  histological  signs  point  very  strongly  toward  the 
origin  of  nevus  cells  from  the  epidermis.  The  relation  of  chromatophores 
to  the  nevomelanoma  is  not  yet  clear.  The  theoretical  considerations 
favor  the  origin  of  all  melanomas  from  the  mesoblastic  chromatophore, 
while  the  histology  of  human  tumors  favors  the  origin  from  epithelial  cells 
which  have  taken  on  pigmentary  functions.  The  established  tumors  ex- 
hibit either  carcinomatous  or  sarcomatous  structure,  or  both. 

Under  these  circumstances  the  writer  confesses  his  inability  to  reach  a 
conclusion  regarding  the  nature  of  melanomas,  and  he  will  therefore  present 
the  data  regarding  them  as  impartially  as  possible,  awaiting  further  elucida- 
tion of  the  many  subjects  involved. 

Although  the  chromatophore  is  a  mesoblastic  cell,  it  arises  very  early  in 
the  formation  of  this  germ  layer  and  exhibits  many  specific  properties  some 
of  which  resemble  those  of  epithelium,  so  that  the  identification  of  this  tumor 
with  carcinoma  or  sarcoma  seems  undesirable.  The  term  "melanoma"  should 
be  employed  to  emphasize  the  specific  character  of  the  tumor  and  its  cells 
of  origin.  The  possible  origin  from  epidermal  cells  may  be  indicated  by  the 
term  "melanocarcinoma,"  and  the  sarcomatous  character  of  other  tumors  is 
indicated  as  "melanosarcoma." 

Clinical  Characters. — Modes  of  Origin. — The  pigmented  mole  or  nevus 


MELANOMA  873 

which  is  the  source  of  cutaneous  melanomas  occurs  chiefly  on  face,  neck, 
and  back,  but  may  be  found  on  any  portion  of  the  body.  It  may  even  appear 
on  the  sole  of  the  foot,  and  in  this  and  other  exposed  positions  is  more  liable 
to  malignant  change.  A  relation  to  nerve-trunks  has  sometimes  been  noted, 
as  well  as  a  unilateral  or  symmetrical  distribution.  It  appears  as  a  minute 
pigmented  spot  (n.  spilus),  or  soft,  flat  elevation,  and  often  grows  to  a  warty 
excrescence  (n.  verrucosus),  or  papillary  tumor  (n.  papillaris).  Many  exhibit 
a  growth  of  soft  or  coarse  hairs,  pointing  to  the  implication  of  hair  follicles 
(n.  pilosus),  and  larger  tumors  may  contain  much  loose  connective  tissue  and 
fat  tissue  suggesting  a  complex  disturbance  of  dermal  structure  (n.  lipoma- 
todes). 

Remarkably  wide  extension  over  much  of  the  body  occurs  in  rare  cases 
of  "bathing  trunk"  type,  of  which  Fox  has  collected  25  cases.  The  color 
varies  from  a  light  brown  to  black,  but  not  a  few  notable  cases  of  pigment- 
free  moles  have  been  described  (Moullin).  The  consistence  is  usually 
soft,  in  older  fibrous  lesions  firm,  and  the  vascularity  slight.  Eventually 
they  may  become  hard  and  pedunculated  (molluscoid  degeneration).  The 
clinical  distinction  from  capillary  nevi,  port- wine  stains,  and  lentigines 
(freckles)  is  usually  obvious,  but  other  pigmented  tumors  and  processes 
in  the  skin  may  require  microscopical  study. 


FIG.  447. — Extensive  hairy  nevus.     Bathing  trunk  type.     (After  Fox,  J.  A.  M.  A.,  58.) 

Pigmented  moles  are  sometimes  associated  with  vascular  nevi  and  with 
molluscum  fibrosum.  These  various  lesions  may  be  wholly  distinct  in  the 
same  region,  or  so  intimately  combined  as  to  greatly  complicate  the  question 
of  their  essential  relations. 

Melanotic  whitlow  (Hutchinson)  is  a  heavily  pigmented  malignant  epi- 
thelioma  which  begins  as  a  swelling  of  the  lateral  nail  fold  of  finger  or  toe. 
The  lesion  soon  ulcerates  and  early  involves  the  regional  lymph-nodes.  The 
disease  has  all  the  essential  features  of  melanoma  (Faguet,  Plantier,  Galloway). 
The  process  may  take  origin  in  the  flat  pigmented  lesions  called  lentigo,  which 
may  or  may  not  show  irritation  or  ulceration  (Bayet). 

Finally,  in  rare  cases  no  local  point  of  origin  of  the  disease  can  be  demon- 
strated clinically  or  at  autopsy. 

In  the  lower  animals  moles  and  melanomas  are  relatively  frequent.  Their 
occurrence  in  white  horses  was  noted  by  Virchow  as  evidence  of  a  constitu- 
tional dyscrasia. 

Course. — The  natural  history  of  the  vast  majority  of  pigmented  nevi 
includes  a  long  period  of  slow  growth,  a  stage  of  inertia,  followed  by  a  process 
of  regression.  A  congenital  disturbance  of  the  structure  of  the  derma 
must  be  assumed  for  all  cases,  and  some  moles  are  visible  at  birth.  Many 
more  appear  in  early  life,  and  according  to  Unna  these  always  show 


874  NEOPLASTIC  DISEASES 

evidences  of  progressive  growth.  Having  reached  the  limit  of  growth,  which 
is  commonly  restricted  to  small  innocuous  tumors,  they  tend  to  undergo 
fibrosis  and  atrophy.  Some  become  hard,  flat,  and  circumscribed  (fibro- 
matous  degeneration),  others  become  pedunculated,  fissured,  or  extruded 
(molluscoid  degeneration).  Repeated  trauma  often  causes  a  limited  over- 
growth. 

Malignant  melanoma  develops  in  a  small  proportion  of  cases,  usually 
after  trauma  or  incomplete  extirpation.  Familiarity  with  these  apparently 
insignificant  lesions  constantly  invites  meddlesome  interference  by  patient, 
surgeon,  dermatologist,  and  other  specialists.  A  slight  enlargement  or  in- 
crease of  pigmentation  of  the  tumor  may  be  the  first  signs  of  malignant 
change,  which  may  be  checked  by  wide  extirpation.  Following  operation  or 
without,  there  may  be  rapid  local  growth  and  extension,  but  some  cases 
remain  localized,  with  repeated  excisions,  for  many  years.  In  another 
group  of  cases  there  is  immediately  or  after  years  wide-spread  dissemination 
with  invasion  of  regional  nodes,  or  more  often  of  the  blood-stream.  The 
skin  is  the  chief  seat  of  the  first  metastatic  tumors,  which  may  be  extremely 
numerous.  Painless  firm  nodules  or  larger  hemorrhagic  masses  appear  in 
many  regions,  grow  larger  for  a  time,  and  then  may  tend  to  become  circum- 
scribed, hard,  or  even  pedunculated.  Successive  series  of  superficial  tumors 
may  develop  before  visceral  metastases  occur  in  lungs,  liver,  kidney,  brain, 
bone-marrow,  serous  membranes  and  other  tissues,  with  melanemia, 
melanuria,  and  cachexia.  The  duration  of  the  generalized  disease  is  about 
3  years,  but  10  years  may  intervene  between  the  extirpation  of  a  primary 
tumor  and  the  appearance  of  secondary  lesions  (Dobbertin).  Fisher  and 
Box  observed  a  large  melanoma  of  liver  14  years  after  removal  of  a  primary 
intra-ocular  tumor,  and  Albert  reported  a  local  recurrence  24  years  after 
excision  of  a  primary  tumor. 

The  melanemia  may  be  an  early,  pronounced,  and  persistent  symptom, 
and  the  serous  membranes,  meninges,  and  intima  of  blood-vessels  may  be- 
come diffusely  pigmented. 

A  very  acute  course  is  observed  in  rare  cases  in  which  localized  tumors 
do  not  appear  in  the  skin,  but  the  disease  proves  fatal  in  a  few  weeks  with 
melanemia,  melanuria,  and  cachexia. 

The  melanuria  has  been  attributed  to  the  excretion  of  pigment  grains 
or  the  passage  of  tumor-cells  through  the  glomeruli  (Eberth).  Johnston 
found  the  cortex  sparsely  dotted  with  small  metastases  and  light  pigmenta- 
tion of  endothelium,  Bowman's  capsule  and  epithelium  of  Henle's  loop, 
but  no  evidences  of  emigration  of  pigment  cells.  In  the  early  stages  of 
dissemination  the  urine  is  usually  of  deep  brownish  color,  probably  from 
dissolved  melanogen.  Later  it  may  become  nearly  black  (Eiselt). 

Histology. — The  structure  of  pigmented  moles  varies  in  different  stages 
of  their  natural  history. 

(i)  In  the  congenital  mole  of  infants  and  young  children  one  finds  chiefly 
the  early  stages  of  development  and  a  process  limited  chiefly  or  exclusively 
to  the  epidermis  and  the  immediately  adjacent  derma.  The  first  change 
is  a  clearing  of  the  cytoplasm,  swelling  of  the  cell  body,  and  nuclear  hyper- 
chromatism  in  foci  of  cells  in  the  deeper  layers  of  the  epidermis.  Sharply 
isolated  groups  of  such  cells  thus  appear  in  the  epidermis  and  similar  groups 
in  the  adjacent  derma  represent  cross-sections  of  columns  of  cells  that  seem 
to  have  pushed  their  way  downward  and  appear  beneath  the  basal  epithelium 
(Fig.  448).  These  same  changes  may  be  more  diffuse  and  affect  mostly  the 
basal  layer,  from  which  single  cells  appear  to  break  off  and  penetrate  the 
derma.  The  epithelium  of  hair  follicles  and  sweat-glands  often  participates 


MELANOMA 


875 


in  the  process.  Pigmentation  usually  accompanies  these  early  changes,  but 
may  be  absent.  It  appears  uniformly  in  all  affected  cells,  or  single  elongated, 
polyhedral  or  multipolar  epithelial  cells  may  usurp  the  chief  part  of  this 
function.  This  mode  of  origin  of  pigmented  cells  can  readily  be  followed. 
As  these  proliferating  cells  become  more  and  more  displaced  they  may  lose 
their  polygonal  form,  spines,  and  fibrils,  and  become  converted  into  rounded 
coherent  clear  staining  cells  with  dense  nuclei,  lying  in  alveolar  groups  or 
elongated  columns.  Depigmentation  proceeds  with  the  isolation  of  the  cells 
and  usually  is  complete  when  the  cells  become  quiescent  in  a  matrix  of  fibrous 
tissue.  Pigment  may  then  be  found  in  this  fibrous  tissue,  in  the  surround- 
ing loose  tissue  cells,  and  in  walls  of  capillaries.  It  must  be  noted,  however, 
that  all  these  interpretations  of  the  epithelial  origin  of  nevus  cells  are  regarded 
by  Ribbert  and  others  as  erroneous.  These  authors  regard  all  the  peculiar 
cells  as  inwandering  chromatophores. 

In  the  congenital  mole  the  blood-  and  lymph-vessels  play  a  passive 
part.  The  endothelium  is  usually  normal,  sometimes  hypertrophic,  and  the 
lumen  patent.  About  the  vessels  one  often  finds  pigmented  cells  and  the 
endothelium  may  be  laden  with  pigment.  Neither  the  lumen  nor  the 


FIG.  448. — Structure  of  quiescent  pigmented  nevus  in  an  infant.     Notice  apparent  con- 
tinuity of  one  nest  of  nevus  cells  with  rete  peg. 

peri  vascular  spaces  seem  to  serve  as  channels  for  the  advancing  epithelium. 
I  have  been  unable  to  trace  any  connection  between  the  endothelium  and  the 
nevus  cells  of  congenital  moles.  Capillary  nevi  and  capillary  angioma  or 
endothelioma  may  be  associated  with  pigmented  mole.  In  these  cases  the 
two  processes  remain  distinct  and  the  separation  of  endothelium  from  epi- 
thelium is  unusually  sharp. 

(2)  In  adults  the  structure  of  the  pigmented  mole  varies  with  the  stage 
of  development.  Many  such  moles  become  elevated,  warty  or  papillary, 
and  in  these  one  finds  groups  or  elongated  vertical  cords  of  clear  rounded 
cells  lying  in  acellular  fibrous  tissue.  Scanty  blood-  and  lymph-vessels 
of  normal  structure  traverse  these  areas.  I  have  not  been  able  to  find  any 
connection  between  endothelium  and  adult  nevus  cells.  All  connections 
of  the  cell  cords  with  the  epidermis  are  missing.  The  deeper  cells  become 
spindle  shaped  and  are  intimately  incorporated  with  the  fibrous  tissue  and 
fine  fibrils  usually  pass  between  the  cells  (Favera) . 

In  not  a  few  cases  the  pigmented  mole  of  adults  continues  to  exhibit 
appearances  suggesting  a  focal  or  diffuse  process  of  swelling  and  splitting 
off  of  basal  epithelium.  These  moles  are  usually  of  large  size  and  of  slow 


876 


NEOPLASTIC  DISEASES 


but  progressive  growth.  The  structure  then  fails  to  show  the  clear  cells 
of  the  quiescent  nevus,  but  presents  small  groups  or  alveoli  or  a  diffuse 
growth  of  larger  opaque  polygonal  cells  with  hyperchromatic  vesicular 


FIG.  449. — A  quiescent  papillary  pigmented  nevus.      (After  Johnston.) 


:.:•« 


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FIG.  450. — Cells  in  a  resting  congenital  nevus. 

nuclei.  Pigmented  cells  are  scanty  in  the  quiescent  adult  mole  and  appear 
chiefly  in  the  outskirts  of  the  cell  masses.  The  basal  cells  of  the  epidermis 
may,  however,  be  deeply  pigmented  and  swollen. 

In  rare  cases  the  mole  may  be  entirely  free  from  pigment. 


MELANOMA 


877 


(3)  Fibromatous   and  molluscoid   regression   overtakes   many   moles   in 
their  late  history.    Much  new  fibrous  tissue  replaces  the  cellular  areas  and 
surrounds  sweat,  sebaceous,  and  hair  glands,  and  this  tissue  may  be  cellular 
and  mucinous.    The  nevus  cells  become  atrophic,  compressed,  and  disappear. 
Pigmentation  is  scanty  or  absent.    The  included  fat  lobules  may  be  enlarged. 
The  mole  may  be  much  elongated,  pedunculated,  or  extruded. 

(4)  Malignant   changes    supervene   spontaneously   or   after   trauma    or 
incomplete  extirpation.     The  apparently  innocent  histological  character  of 
certain  moles  which  have  given  rise  to  secondary  tumors  is  one  of  the  mysteri- 
ous features  of  this  disease,  but,  as  a  rule,  the  dangerous  lesions  give  gross 
and   microscopical  evidence  of  active  growth  and  especially  of  increased 
vascularity.    The  vigorous  preparation  of  the  skin  is  perhaps  responsible  for 
some  unsuccessful  operations  on  these  vascular  growths.    Deep  pigmentation 
is  commonly  observed  to  belong  to  dangerous  moles. 

The  histological  signs  of  malignant  tendencies  are  readily  detected  and 
consist  of  increased  vascularity,  hypertrophy  of  cells,  with  nuclear  hyper- 


FIG.  451. — Section  of  a  flat  heavily  pigmented  mole  on  skin  of  forearm,  which  had  given 
rise  to  metastases  in  axillary  lymph-nodes. 

chromatism  and  occasional  mitotic  figures.  An  alveolar  grouping  of  poly- 
hedral cells  with  prominence  of  epithelioid  characters  are  observed  in  many 
moles  which  prove  malignant.  Fibrous  lesions  containing  only  cords  of 
clear  cells  are  seldom  dangerous.  Pigmentation  usually  increases  with  the 
advent  of  new  growth,  but  this  rule  has  shown  exceptions.  The  local  growth 
of  nevi  is  usually  the  result  of  multiplication  of  the  cells  originally  isolated. 
In  some  cases,  however,  there  is  evidence  of  a  progressive  involvement 
of  previously  normal  rete  pegs.  The  histological  appearances  indicate  that 
this  secondary  process  begins  in  the  basal  epithelium,  is  often  accompanied 
by  pigmentation  of  these  cells,  but  is  not  associated  with  the  presence  of 
specific  chromatophores. 

The  extensions  of  melanoma  pass  through  either  lymph-  or  blood-vessels. 
In  the  former  case  the  regional  nodes  are  involved,  the  generalization  is 
relatively  slow,  and  repeated  local  extirpation  may  accomplish  a  cure  or 


878 


NEOPLASTIC  DISEASES 


long  delay  the  fatal  termination.  Preceding  the  invasion  of  the  nodes  there 
may  be  pronounced  hyperplastic  lymphadenitis.  Through  the  blood-vessels 
dissemination  is  usually  general.  There  is  little  histological  indication  of 
the  factors  which  determine  the  mode  of  extension,  but  the  accumulation 
of  tumor-cells  about  blood-vessels  often  reveals  an  imminent  danger  of 
rupture  into  the  vessels.  Numerous  dilated  blood  sinuses  are  occasionally 
present  and  offer  a  ready  access  to  the  general  blood-stream.  In  some  malig- 
nant moles  I  have  found  great  variations  in  the  size  and  grade  of  anaplasia 
of  the  cells,  some  reassuming  their  epithelioid  characters,  others  multiplying 
in  the  form  of  small  indifferent  round  cells. 

The  structure  of  metastatic  tumors  presents  the  same  wide  variations. 
The  tumor  may  appear  as  an  alveolar  or  diffuse  carcinoma,  as  a  large  spindle- 
cell  sarcoma,  often  as  perithelioma,  and  even  as  lymphosarcoma.  Well 


FIG.  452. — Melanoma  of  pseudoperitheliomatous  type. 

circumscribed  groups  of  characteristic  large  round  or  polyhedral  clear  cells 
are  often  seen  in  cutaneous  metastases,  pigmented  or  not,  and  at  once 
suggest  their  true  origin.  The  appearance  of  such  tumors  may  be  the  first 
indication  of  the  existence  of  an  offending  mole.  Metastatic  nodules  may  at 
first  be  surrounded  by  hemorrhage  from  dilated  blood-vessels  and  the  ab- 
sorption of  the  blood  may  be  followed  by  cicatrization  and  marked  regres- 
sion of  the  tumor.  In  some  cases  there  are  very  numerous  pigmented  points 
and  spots  in  skin  and  mucous  and  serous  membranes.  These  lesions  may 
contain  so  much  pigment  and  so  few  traces  of  tumor-cells  as  to  suggest  that 
pigment  emboli  have  formed.  The  assumption  that  such  pigment  may 
incite  tumor  growth  of  normal  cells  is  without  definite  support,  but  there  is 
no  satisfactory  explanation  of  the  great  number  of  small  metastatic  tumors 
arising  from  some  very  small  primary  tumors. 


MELANOMA 


879 


In  the  organs  the  metastatic  tumor  may  contain  the  common  large  poly- 
hedral cells,  or  smaller  round  cells  of  highly  anaplastic  type.  In  a  large 
hepatic  tumor  I  found  the  cells  all  of  spindle  form  resembling  sarcoma.  In 
another  case  all  the  numerous  visceral  metastases  contained  small  polyhedral 
cells  whose  desmoplastic  properties  yielded  the  structure  of  alveolar  carci- 
noma. In  2  cases  I  have  found  adenomatoid  hypertrophy  and  hyperplasia 
of  polyhedral  non-pigmented  cells  in  the  medulla  of  the  adrenal. 

The  pigmentation  of  metastatic  tumors  varies  greatly,  being  excessive 
in  some  tumors  or  parts  of  tumors,  entirely  absent  or  scanty  in  others. 
When  excessive  it  may  lead  to  destruction  of  tissue  and  the  formation  of 
cysts  containing  black  fluid.  There  is  no  constant  relation  between  the 
degree  of  pigmentation  of  primary  and  metastatic  tumors.  Heavily  pig- 
men  ted  primary  tumors  may  give  origin  to  pigment-free  metastases. 
The  absence  of  pigment  is  observed  in  some  of  the  most  rapid  and  malig- 


FIG.  453. — Structure  of  metastatic  melanoma  in  lymph-node.     Note  the  limitation  of 
pigment  to  invaded  stroma  cells. 

nant  cases.  Not  infrequently  the  pigment  is  limited  to  the  large  fusiform 
cells  in  the  connective  tissue  about  tumor  nodules.  In  large  areas  of  non- 
pigmented  cells  small  foci  may  contain  swollen,  apparently  hydropic,  and 
heavily  pigmented  cells.  The  conditions  of  pigment  formation  appear  to 
be  very  delicately  balanced. 

The  Pigmentation  of  Melanoma. — The  origin  and  nature  of  the  pigment 
in  melanoma  have  been  the  subjects  of  long  and  elaborate  investigation 
Furth  (Lit.).  Special  interest  attaches  to  this  study  since  variations  in  this 
substance  offer  a  very  delicate  indicator  of  the  functional  activity  of  the 
cells  and  a  unique  opportunity  to  trace  the  relation  between  a  functional 
activity  and  the  growth  capacity  of  tumor-cells.  In  fact,  it  is  not  unlikely 
that  a  complete  elucidation  of  the  pigment  problems  may  reveal  at  the  same 
time  the  secret  of  the  excessive  nutrition  and  overgrowth  of  this  particular 
tumor-cell. 


880  NEOPLASTIC  DISEASES 

Morphology.— The  earliest  indications  of  pigment  deposit  in  nevi  appear 
in  the  form  of  fine  yellowish  granules  in  the  swollen  basal  cells  of  the  mole, 
and  these  appearances  are  nearly  identical  with  those  of  normal  pigmentation. 
As  the  epithelial  proliferation  progresses  the  foci  of  new  cells  continue  to 
exhibit  increasing  pigmentation  and  single  cells  in  the  groups  may  develop 
excessive  deposits  of  pigment,  increase  in  size,  and  become  elongated  or  mul- 
tipolar.  Multipolar  chromatophores  are  usually  present  in  pigmented  moles, 
lying  beneath  the  epidermis,  passing  between  the  basal  cells  and  occasionally 
lying  within  the  Malpighian  layer.  When  absent  it  is  permissible  to  assume 
that  they  have  yielded  their  pigment  to  the  epithelium  and  then  disappeared. 

With  the  further  progress  of  the  cell  growth  the  pigment  may  appear  in 
very  large  quantities,  and  in  these  cases  evidences  of  intranuclear  forma- 
tion of  pigment  appear  and  it  becomes  scattered  widely  in  neighboring  cells 
and  tissues.  The  intranuclear  formation  has  been  described  by  several 
authors  (Ritter,  Mertsching,  Kromayer,  Jarisch),  and  is  frequently  observed. 
A  parallel  formation  of  pigment  from  the  chromidia  of  protozoa  has  been 
described  by  Hertwig.  The  nuclear  origin  led  Bohn  to  assume  that  the 
pigment  granule  is  a  biological  entity  with  nuclear  properties.  Rossle 
noted  an  excess  of  nucleolar  material  in  pigmented  tumor-cells  and  traced 
its  escape  into  the  cytoplasm  in  the  form  of  pigment  grains.  He  concluded 
that  the  production  of  pigment  reduced  the  regenerative  capacity  of  the 
cell.  This  relation  of  the  nucleoli  to  pigment  production  has  been  elaborated 
by  Staffel  and  by  Meirowsky. 

The  dissemination  of  pigment  to  neighboring  cells  may  be  very  exten- 
sive and  in  metastatic  nodules  it  may  be  almost  exclusively  present  in  the 
stroma  of  invaded  tissues  while  scanty  or  absent  in  the  tumor-cells.  This 
condition  may  be  attributed  to  the  phagocytosis  of  free  pigment,  to  the 
assumption  of  pigment  production  by  normal  cells  (Fuchs),  or  to  absorption 
of  extravasated  blood.  Pigment  streaks  leading  from  cutaneous  tumors, 
patches  of  pigment  in  serous  membranes,  extensive  deposits  in  lymph- 
nodes  and  bone-marrow,  and  englobed  granules  in  the  vascular  endothelium 
of  many  organs,  melanemia,  and  melanuria  mark  the  advanced  stages  of 
the  process.  Invaded  organs  may  show  much  diffuse  pigmentation.  Kat- 
surada  observed  diffuse  pigmentation  of  cerebral  capillaries  without  cere- 
bral tumor.  The  extensive  pigmentation  of  lymph-nodes  led  Gierke  to  con- 
clude that  the  tissue  cells  must  be  induced  to  elaborate  pigment  by  some  agent 
derived  from  the  tumor-cells.  Berdez  and  Nencki  have  calculated  that 
as  much  as  500  gr.  of  pigment  may  be  produced  in  one  case. 

That  the  pigment  of  melanoma  is  the  product  of  a  special  metabolic 
function  of  the  cell  is  the  conclusion  of  the  great  majority  of  observers. 
Virchow  regarded  the  local  deposits  as  the  expression  of  a  general  dyscrasia. 
Many  find  a  close  parallel  between  the  physiological  formation  of  pigments, 
that  occurring  in  Addison's  and  other  metabolic  diseases,  and  that  of  melan- 
oma. Lubarsch  concludes  that  melanomas,  contrary  to  the  rule  with  many 
tumors,  contain  no  glycogen  and  that  from  a  specific  disturbance  of  metabo- 
lism they  convert  protein  material  into  pigment.  Nevertheless  many  facts 
have  been  interpreted  in  favor  of  the  direct  hematogenous  origin  of  the  pig- 
ment. Langhans  has  described  the  englobement  of  red  cells  by  tumor-cells, 
but  this  event  must  be  rare.  The  perivascular  position  of  many  chroma- 
tophores may  be  explained  as  an  adaptation  in  the  interests  of  nutrition 
and  appears  in  a  wide  variety  of  non-pigmented  tumors.  The  view  that 
ameboid  chromatophores  carry  the  pigment  to  the  nevus  cells  is  in  conflict 
with  some  definite  histological  appearances  in  early  nevi.  Their  movement 
is  probably  in  the  opposite  direction. 


MELANOMA  881 

The  evidence  of  microchemical  reactions  favors  the  view  that  the  pig- 
ment is  essentially  of  metabolic  origin,  but  that  secondary  pigmentation 
from  the  absorption  of  extravasated  blood  is  of  frequent  occurrence.  In 
the  early  mole  pigment  almost  constantly  fails  to  give  Perls'  reaction  for 
free  iron,  but  in  more  advanced  cases  this  reaction  may  often  be  obtained 
(Vossius,  Hamburger,  Walter),  although  not  always  (Perls,  Rindfleisch, 
Lubarsch,  Ravenna).  Melanin  stains  with  some  basic  dyes,  as  polychrome 
methylene-blue,  after  which  careful  treatment  by  tannic  acid  leaves  melanin 
colorless,  hemosiderin  greenish  blue  (Unna).  Barlow  finds  that  the  pigment 
granules  blacken  with  osmic  acid.  The  comparative  study  of  pigment 
production  in  lower  animals  points  to  its  metabolic  nature  (Furth,  Lit.). 

Chemical  studies  have  thrown  much  light  on  the  nature  and  origin  of 
tumor  pigments,  while  leaving  many  questions  still  unsettled.  The  black 
pigment  of  the  hair,  choroid,  melanotic  tumors,  and  sepia  pigment,  known 
as  melanin,  usually  contains  C,  H,  N  while  S  is  by  no  means  constant. 
The  elements  C,  H,  N  occur  in  the  general  proportions  of  i,  5,  5  (Hoff- 
meister).  The  presence  of  Fe  also  appears  to  be  variable  and  inconstant 
(Berdez,  Nencki),  so  that  one  may  conclude  that  melanin  is  essentially  free 
from  S  and  Fe,  but  possesses  a  strong  tendency  to  unite  with  these  elements. 
It  may  be  dissolved  slowly  by  strong  alkalies,  and  bleached  by  H2O2,  chlorin, 
and  by  Whitefield's  method,  which  includes  laying  sections  some  hours  in 
potassium  permanganate  10  per  cent.,  followed  by  dilute  sulphurous  acid. 

Heated  with  strong  alkali  melanin  from  tumors  yields  indol,  skatol, 
volatile  fatty  acids,  and  an  ether-soluble  acid  which  gives  a  dark  blue  color 
with  ferric  chlorid.  The  chief  product  is  the  melanic  acid  of  Nencki.  Under 
dry  heat  melanin  gives  off  pyrrhol. 

Thormahlen  found  that  the  urine  of  advanced  cases  of  melanoma  gives 
a  characteristic  reaction  with  sodium  nitroprusside.  When  -this  reagent  is 
added  with  KOH  a  deep  reddish-violet  color  appears,  which  on  acidification 
becomes  blue.  The  reaction  occurs  in  other  diseases  and  is  given  by  indol, 
and  probably  depends  on  the  presence  of  the  pyrrhol  ring  in  the  reacting 
substance  (Eppinger).  Melanin  appears  in  the  urine  of  advanced  cases 
either  constantly  or  periodically.  Stiller  observed  it  only  during  febrile 
periods,  and  Ganghofner  noted  an  increase  during  regression  of  cutaneous 
tumors.  The  urine  may  be  very  dark  on  passage,  but  usually  darkens  only 
on  standing.  Hence  the  pigment  is  chiefly  in  the  form  of  dissolved  melanogen 
which  oxidizes  to  melanin  on  exposure  to  the  air.  Various  oxidizing  agents 
hasten  the  reaction. 

Many  investigators  have  attempted  to  determine  the  construction  of 
melanin  and  its  relation  to  the  protein  molecule.  Nencki  concluded  that  the 
protein  molecule  contains  a  heterocyclic  chromogenic  radicle  which  is  the 
source  of  both  melanin  and  hemoglobin,  and  may  be  split  off  by  pancreatic 
digestion.  Hopkins  and  Cole  isolated  from  pancreatic  digestive  products  a 
crystalline  tryptophan  which  they  regarded  as  the  mother  substance  of  the 
chromogen.  The  demonstration  that  the  ferment  tyrosinase  is  concerned  in 
the  remarkable  pigments  of  many  insects  and  in  the  cuttlefish  (Furth)  led 
to  the  search  for  this  ferment  in  melanoma.  Gessard  first  demonstrated 
the  presence  of  tyrosin  and  tyrosinase  in  melanoma  of  the  horse,  and  he  con- 
cluded that  the  pigment  of  tumors  and  that  of  the  cuttlefish  are  produced 
in  the  same  way  by  the  action  of  tyrosinase  on  tyrosin  and  other  aromatic 
compounds.  Eppinger  isolated  from  the  urine  of  a  case  of  melanoma  of  the 
liver  a  crystalline  melanogen  which  he  regards  as  a  derivative  of  tryptophan. 
On  dry  distillation  it  yielded  pyrrhol,  treated  with  strong  alkali  it  gave 
indol  and  skatol,  blackened  with  oxidizing  agents,  and  gave  a  blue  color 
56 


882  NEOPLASTIC  DISEASES 

with  sodium  nitroprusside  (Thormahlen's  reaction).  He  concluded  that  the 
disturbance  of  metabolism  in  melanoma  consists  essentially  in  the  inability 
to  split  the  pyrrhol  ring  and  thus  destroy  the  excessive  pigment  produced 
by  the  tumor-cells.  He  would  regard  the  excess  of  pigment  and  its  products, 
especially  indol  and  skatol,  as  the  cause  of  the  overgrowth  of  the  cells.  Stoe- 
ber  and  Wacker  observed  that  indol  and  skatol  cause  marked  proliferation 
of  epithelial  cells.  In' a  melanoma,  regarded  by  Orth  as  originating  in  the 
adrenal,  Neuberg  demonstrated  a  ferment  which  failed  to  act  on  tyrosin, 
but  split  adrenalin.  Alsberg  in  a  melanoma  of  liver  found  a  ferment  which 
acted  on  pyrocatechin  and  hydrochinon,  but  not  on  tyrosin.  In  all  of  these 
fields,  as  Furth  remarks,  the  various  hypotheses  require  further  substantiation. 

O.  Adler  by  treating  tryptophan  or  tyrosin  with  strong  H2SO4  secures 
black  pigments  which  he  regards  as  very  similar  to  those  occurring  in  mela- 
noma. He  devised  a  color  test  which  seemed  to  be  specific  of  melanoma. 

That  the  pigment  or  its  derivatives  exert  a  toxic  action  in  the  disease, 
while  probable,  is  without  definite  proof.  Rosenfeld  increased  the  excre- 
tion of  pigment  by  administering  iodid  of  potash,  without  causing  any 
toxic  symptoms.  Most  of  the  pigments  artificially  produced  or  extracted 
from  tumors  or  urine  are  toxic  for  animals,  but  it  is  difficult  to  trace  these 
effects  in  the  cachexia  of  the  disease.  The  antigenic  properties  of  choroid 
pigments  have  been  studied  by  Elschnig. 

Orbital  Melanoma. — Pigmented  nevi  and  melanomas  occur  in  the  con- 
junctiva, iris,  choroid,  and  in  the  sheath  of  the  optic  nerve  and  surrounding 
tissue.  In  each  of  these  situations  they  present  characteristic  features  of 
origin  and  course,  and  variations  in  the  aspect  of  the  problem  of  histogenesis, 
all  of  which  have  been  very  fully  studied  by  ophthalmopathologists  (Winter- 
steiner,  Lit.). 

In  the  eye  there  occur  processes  which  correspond  to  the  cutaneous  nevus 
and  to  the  malignant  tumors  derived  from  them,  as  well  as  pigment-free 
tumors  which  are  difficult  to  separate  from  the  pigmented  forms. 

In  the  conjunctiva  pigment  spots  appear  at  birth  or  later  and  may  re- 
main unchanged  throughout  life  or  become  the  source  of  malignant  tumors. 
Parsons  describes  them  as  of  epithelial  origin  reproducing  the  picture  of 
cutaneous  pigmented  moles.  There  is  epithelial  hyperplasia,  shallow  ex- 
tensions into  the  deeper  tissues,  and .  appearance  of  chromatophores.  The 
lesions  may  gradually  extend  over  conjunctiva  and  eyelid  and  when  incom- 
pletely removed  may  be  followed  by  the  usual  wide-spread  dissemination 
through  blood-vessels.  I  have  followed  one  congenital  case  for  10  years 
which  gradually  extended,  was  twice  excised,  and  eventually  became  dis- 
seminated. 

In  the  iris  Fuchs  and  Parsons  describe  brownish  nodules  which  appear 
on  the  pupillary  margin,  in  the  horse  nearly  constantly,  and  are  said  to  be 
derived  from  the  pigmented  epithelium.  They  also  describe  brownish 
tumors  of  the  iris  which  grow  into  the  anterior  chamber,  and  are  derived 
from  the  chromatophores  of  the  iris.  Both  begin  as  slow  benign  tumors 
which  may  become  malignant. 

The  ciliary  body  is  a  frequent  seat  of  melanomas,  of  which  Groenouw 
has  collected  50  cases.  The  tumor  first  appears  as  a  protuberance  on  the 
ciliary  body  and  extends  in  various  characteristic  forms  as  a  flat  tumor 
involving  a  segment  of  the  ciliary  body  and  contiguous  choroid,  as  a  pro- 
jecting mass  displacing  the  lens,  or  as  a  diffuse  growth  of  entire  ciliary 
body,  the  so-called  ring  sarcoma  of  Evetsky.  It  may  infiltrate  the  iris  in 
various  ways  (Verhoeff),  extend  over  the  choroid  throughout  most  of  the 
eyeball,  or  appear  as  discontinuous  multiple  foci  in  the  choroid  (Meyerhoff ) , 


MELANOMA 


or  perforate  the  cornea  along  the  ciliary  vessels.  The  variety  of  histological 
structure  is  considerable,  spindle-,  rounded,  and  polyhedral  cells  appearing 
diffusely  or  in  alveoli,  or  in  perithelial  form,  while  pigment  may  be  scanty 
or  absent  (Rogman).  An  alveolar  structure  with  pronounced  epithelial 
character  is  described  by  Groenouw,  and  appears  in  one  of  my  cases.  In  a 
very  early  case  Derby  claims  to  have  traced  the  origin  to  the  pigmented 
cells  of  the  intermuscular  connective  tissue. 

The  choroid  is  the  most  frequent  site  of  ocular  melanoma,  yet  the  disease 
is  relatively  rare,  occurring  in  0.58  per  cent,  of  ophthalmic  patients  (Winter- 
steiner).  About  one- third  of  all  melanomas  originate  in  the  choroid  (John- 
ston). The  earliest  stages  of  the  growth  have  seldom  been  observed.  Fuchs 
encountered  several  isolated  elongated  pigmented  spots  near  the  macula. 
On  section  these  consisted  of  groups  of  proliferating  cells  between  the  large 
vessels  of  the  choroid  and  apparently  from  cells  lining  the  elastic  lamella* 


FIG.  454. — Flat  infiltrating  melanoma  of  choroid,  with  epibulbar  nodule.     (A.  Knapp.} 

The  pigmented  epithelium  of  retina  and  the  choriocapillaris  were  normal. 
Very  similar  tumors  are  described  by  Wintersteiner  and  by  Purtscher. 

In  more  developed  stages  the  tumor  takes  various  forms.  Usually  a 
globular  mass  forms  in  the  choroid,  which  displaces  the  basal  lamella  (Bauch) 
and  retina  into  the  vitreous.  Perforation  of  the  basal  lamella  is  followed  by 
extension  along  the  retina.  -  A  flat  growth  long  confined  by  the  basal  mem- 
brane, on  perforating  this  structure,  grows  more  rapidly,  producing  a  globular 
tumor  connected  by  a  narrow  pedicle  with  the  flat  base.  Rarely  the  flat 
growth  in  choroid  is  maintained  until  almost  the  entire  eyeball  is  encircled  by 
a  diffuse  tumor  (Evetsky).  About  the  entrance  of  the  optic  nerve  the  tumor 
may  encircle  the  nerve,  in  which  position  early  extension  along  the  nerve  must 
be  feared  (Fehr).  The  intrabulbar  extensions  are  usually  by  continuity. 
The  retina  is  detached,  infiltrated,  split  up  by  layers  of  tumor-cells,  and  de- 
stroyed. Reaching  the  anterior  chamber  free  cells  or  pigment  may  become 
loosened  and  deposited  on  the  iris  or  cornea  or  choke  the  canal  of  Schlemm 
(Kamocki,  Michel).  The  ciliary  body  and  iris  are  invaded  and  the  ciliary 


884 


NEOPLASTIC  DISEASES 


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vessels  may  be  penetrated  by  tumor-cells  (Gutman),  thus  opening  the  way  to 
intravascular  dissemination.  The  sclerotic  may  be  perforated  by  the  same 
channels  or  along  the  optic  nerve,  producing  a  retrobulbar  tumor  which 
extends  even  to  the  chiasm.  Focal  or  extensive  necrosis  of  the  tumor  may 
result  from  occlusion  of  blood-vessels,  or  complete  phthisis  bulbi  may  result. 
In  such  cases  extensive  arteritis  has  usually  been  found,  which  Evetsky 
refers  to  toxic  products  derived  from  the  disintegrating  tumor.  The  com- 
plicating sympathetic  ophthalmia  has  been  referred  to  the  same  factor. 

Fuchs  divides  the  natural  history  of  the  tumor  into  four  stages,  including 
the  periods  before  and  after  the  onset  of  glaucoma,  the  stage  of  extra-ocular 
growth,  and  that  of  general  dissemination.  Excision  in  the  first  stage  has 

been  followed  by  cure  in  60  to  80  per  cent,  of 
the  cases  (Stock,  Hirschberg),  after  which  the 
prognosis  becomes  rapidly  worse.  Local  re- 
currence is  rare  after  removal  of  intra-ocular 
tumors.  Virchow  observed  a  local  "carcino- 
matous"  recurrence  after  removal  of  a  "sar- 
comatous"  primary  tumor.  In  all  stages, 
especially  after  extension  through  the  capsule, 
metastases  through  the  blood-vessels  develop 
in  liver,  brain,  stomach,  lungs,  skin,  lymph- 
nodes,  bones,  and  other  tissues,  frequency  in 
the  order  named.  The  dissemination  may  be 
extremely  wide-spread  or  limited  to  one  organ, 
as  the  liver.  As  with  cutaneous  melanoma, 
the  appearance  of  metastases  may  be  long 
delayed,  and  generalization  may  occur  with 
apparently  insignificant  primary  lesions. 

The  structure  of  melanoma  of  the  choroid 
is  somewhat  varied,  a  fact  which  complicates 
the  problem  of  histogenesis,  but  hardly  justifies 
the  present  confusion  in  nomenclature.  The 
tumors  may  be  pigmented  or  non-pig- 
mented  in  the  same  patient,  or  in  different 
tumors  of  the  same  organ,  or  in  different 
metastases.  Among  the  pigmented  growths 
Kerschbaumer  has  made  a  notable  attempt 
to  distinguish  true  primary  melanomas  from 
those  with  secondary  hematogenous  pig- 
mentation. Focal  accumulation  of  coarse 
yellow  pigment  giving  the  reaction  for 
free  iron,  in  cells  of  variable  form  dis- 
tributed along  blood-vessels,  are  characters 
of  hematogenous  type,  while  diffuse  dis- 
tribution of  fine  brownish-black  pigment,  not  yielding  the  hemosiderin 
reaction  and  with  cells  chiefly  of  spindle  form,  belongs  to  the  primary 
pigmentation.  Yet  since  hematogenous  pigment  may  be  diffuse  and  may 
lose  the  reaction  for  free  iron,  and  since  hemorrhage  may  occur  in  true  mela- 
noma, these  distinctions  cannot  be  applied  rigidly.  They  may  perhaps  serve 
to  eliminate  certain  pigmented  tumors  which  have  no  relation  to  melanoma. 
The  arrangement  of  the  tumor-cells  varies.  The  majority  of  the  tumors 
in  early  stages  appear  superficially  as  large  spindle-cell  sarcomas,  but  on 
careful  study  an  alveolar  arrangement  of  large  polyhedral  cells  may  often 
be  detected  in  small  tumors.  A  concentric  arrangement  about  vessels  has 


FIG.  455. — Metastatic  mela- 
noma of  choroid.  Spindle  tumor- 
cells  growing  among  atrophic  liver 
cords. 


MELANOMA 

led  many  to  employ  the  term  "perithelioma,"  and  an  extensive  growth  of  blood- 
vessels has  received  the  designation  "angiosarcoma."  Each  of  these  struc- 
tures has  been  called  by  some  endothelioma.  None  of  them  offers  any  definite 
indication  of  histogenesis.  After  penetrating  the  retina  and  after  passing 
the  eyeball  the  tumors  grow  more  rapidly,  the  cells  enlarge,  pigment  is  less 
abundant,  and  the  structure  soon  duplicates  that  of  melanoma  from  other 
sources. 

In  the  etiology  of  ocular  melanoma  hereditary  influence  rarely  appears, 
but  Silcock  observed  the  disease  in  three  generations.  A  frequent  traumatic 
origin  has  been  claimed  by  Leber  and  Krahnstover,  but  on  uncertain  data. 
Sex  is  without  influence.  The  age  incidence  is  chiefly  between  40  to  60  years, 
but  a  few  cases  have  occurred  in  infants  (Wintersteiner). 


FIG.  456. — Primary  melanomatosis  of  cerebral  pia.    (After  Schopper,  Frank/.,  Z.  P.,  13.) 

Melanoma  of  Brain  and  Cord. — In  a  series  of  cases  which  now  number  at 
least  9,  primary  melanoma  of  brain  or  cord  has  been  observed  (Boit,  Lit.). 
Beginning  with  the  normal  chromatophores  which  are  sometimes  found  along 
the  vessels  of  pia  and  even  in  the  brain  tissue,  a  considerable  increase  of  these 
cells,  producing  definite  pigment  spots  and  streaks,  has  repeatedly  been 
observed  (Obertsteiner,  Rokitansky).  In  a  notable  case  of  Grahl's  an  exten- 
sive skin  nevus  of  the  bathing  trunk  type  was  associated  with  profuse  pig- 
ment spots  of  pia  mater,  and  Oberndorfer  saw  the  same  extensive  cutaneous 
nevus  with  symmetrical  pigment  spots  and  tumors  of  cerebral  pia.  Thorel 
observed  diffuse  pigmentation  of  the  pia  of  brain  and  upper  cord,  which 


886  NEOPLASTIC  DISEASES 

merged  into  a  tumor  process  only  at  the  cauda.  Some  of  the  tumors  have 
been  multiple  (Virchow,  Stoerk),  others  single  (Minelli).  Boit's  tumor  arose 
from  the  outer  side  of  the  spinal  dura,  Hirschberg's  developed  in  the  sub- 
stance of  the  lumbar  cord,  and  Minelli's  in  the  centrum  ovale. 

Although  intracranial  metastases  of  cutaneous  or  orbital  melanoma  are 
frequent,  in  several  of  the  above  cases  a  careful  autopsy  eliminated  the  pos- 
sibility of  a  primary  tumor  elsewhere.  There  is,  therefore,  no  doubt  that 
primary  melanoma  of  the  central  nervous  system  occurs  and  that  it  arises 
from  the  pigmented  cells  often  found  along  the  cerebral  vessels. 

The  origin  of  the  cerebral  chromatophores  appears  more  difficult  to  estab- 
lish than  in  any  other  situation.  The  structure  of  the  simple  pigment  spots 
and  areas  has  suggested  to  many  that  these  cells  are  specialized  perithelial 
cells  of  mesodermal  origin,  and  in  this  field  Ribbert's  views  find  their  best 
support.  The  structure  of  the  tumors  is  that  of  a  diffuse  growth  of  elongated 
or  polyhedral  heavily  pigmented  cells  without  intervening  fibrils,  often 
sheathing  blood-vessels  as  in  perithelioma. 

In  a  remarkable  case  described  by  Berblinger,  in  an  infant  of  o.  months, 
multiple  melanomas  of  the  skin  and  neurofibromatosis  were  associated  with 
a  melanotic  tumor  of  the  gyrus  hippocampus,  multiple  pigmented  spots 
in  various  portions  of  the  brain,  glioma  of  pons,  diffuse  perithelial  sarcoma 
of  cerebrospinal  pia  with  secondary  deposits  of  pigment  and  a  true  accessory 
adrenal.  The  author's  interpretation  of  the  diffuse  sarcoma  as  an  independent 
process  may  be  questioned,  since  many  observers  have  regarded  such  peri- 
thelial growths  as  derived  from  peri  vascular  chromatophores.  The  chromat- 
ophores were  very  widely  distributed  throughout  the  brain,  sheathing  the 
larger  vessels,  lining  the  endothelium  of  capillaries,  and  forming  rosettes 
resembling  those  of  neuro-epithelium.  The  case  presents  a  universal  disease 
of  the  fetal  pigment-producing  function,  and  involving  disturbances  in  skin, 
central  nervous  system,  and  even  the  adrenal  gland. 

Melanoma  of  intestine. — Diffuse  melanosis  of  the  colon  is  not  an  uncom- 
mon condition  in  elderly  subjects  and  is  generally  referred  to  the  elaboration 
of  blood  extravasated  in  the  mucosa.  I  have  observed  it  in  pernicious  ane- 
mia as  well  as  in  many  other  conditions.  Its  extent  recalls  the  diffuse  pig- 
mentation by  chromatophores  in  the  intestinal  tract  of  lower  vertebrates. 
Pigmented  tumors  of  the  rectum  are  relatively  common  in  horses  (Eiselt). 

Melanoma  of  the  intestine,  occurring  almost  exclusively  in  the  rectum, 
was  recognized  by  Virchow,  has  been  described  in  isolated  reports  by  various 
observers,  as  Paneth,  Dietrich,  Tuffier,  Wiener,  while  recently  Chalier  and 
Bonnet  have  collected  and  fully  analyzed  64  cases.  They  form  about  2  to 
3  per  cent,  of  all  melanomas. 

The  tumors  occur  chiefly  in  adults,  but  I  have  examined  a  cecal  melanoma 
from  a  child  of  8  years.  They  arise  from  the  anal  orifice  or  from  the  rectal 
ampulla,  and  produce  circumscribed  nodules  or  bulky  masses  as  large  as  a 
child's  head.  A  polypoid  form  is  very  common,  but  Meurier  found  the 
rectum  encased  in  ;a  cylindrical  mass.  I  found  the  ileocecal  orifice  sur- 
rounded by  a  lobulated  tumor.  The  growth  originates  and  expands  within 
the  submucosa  so  that  the  mass  is  movable  and  only  later  do  ulceration  and 
fixation  supervene.  Metastases  in  pelvic  nodes,  liver,  and  other  organs  are 
extremely  common.  Only  2  of  64  cases  were  reported  free  after  operation. 

The  structure  presents  the  usual  appearance  of  melanoma.  Chalier  and 
Bonnet  emphasize  the  resemblance  to  epidermoid  carcinoma  and  they  de- 
rived their  tumor  from  the  anal  epidermis.  Yet  most  tumors  occupy  the 
ampulla  and  some  lie  5  to  6  cm.  above  the  anus,  necessitating  an  origin,  if 
epidermal,  from  a  misplaced  tissue  rest.  Most  authors  have  been  unable  to 


MELANOMA  887 

trace  the  origin,  so  that  the  observations  on  intestinal  melanoma  do  not 
strengthen  the  epithelial  theory  of  the  nature  of  chromatophoromas. 

Melanoma  of  Uncertain  Origin. — In  a  series  of  fatal  melanomas  careful 
search  at  autopsy  has  failed  to  demonstrate  the  origin  of  the  tumor.  In  some 
of  these  the  presence  of  a  large  tumor  of  the  adrenal  has  suggested  a  primary 
melanoma  of  this  organ.  In  Orth's  case  the  structure  of  some  metastases 
resembled  the  adrenal  cortex,  and  Neuberg,  finding  in  them  a  ferment  acting 
on  adrenalin  with  the  production  of  a  black  pigment,  suggested  that  disturb- 
ance of  adrenal  function  might  be  concerned  in  the  pigmentation  of  mel- 
anoma. In  Davidsohn's  case  there  were  many  tumors  of  brain  and  colon 
and  a  large  growth  in  the  adrenal.  Reiman  found  a  large  growth  in  adrenal 
with  small  tumors  elsewhere.  Wietmg  and  Hamdi  described  a  supposed  pri- 
mary melanoma  of  gall-bladder.  In  Johnston's  case  Elser  was  quite  unable 
to  fix  any  point  of  origin  for  a  massive  hepatic  tumor.  I  have  studied  a  large 
melanoma  of  the  spleen  in  which  the  structure  presented  very  large  poly- 
hedral cells  in  perithelial  and  alveolar  arrangement.  There  were  no  other 
tumors  in  the  body. 

Histogenesis  of  Melanoma. — The  extant  theories  of  the  origin  of  melan- 
oma are  as  follows: 

(1)  Exclusively  from  mesoblastic  chromatophores  (Ribbert). 

(2)  Exclusively  from  epithelial  cells  and  epithelial  chromatophores  (Post, 
Wieting  and  Hamdi,  Favera). 

(3)  From  epithelial  nevus  cells  in  the  skin,  and  mesoblastic  chromato- 
phores in  choroid  and  meninges. 

(4)  From  endothelial  cells  of  blood-  and  lymph-vessels,  or  of  nerve-trunks. 
It  is  of  first  importance  to  determine  the  origin  and  function  of  chromato- 
phores before  considering  their  probable  relation  to  tumors. 

Origin  and  Function  of  Chromatophores. — A  competent  opinion  regarding 
the  nature  of  chromatophores  must  be  based  on  a  knowledge  of  the  color 
function  in  the  whole  animal  kingdom.  This  comprehensive  point  of  view 
will  inevitably  influence  the  interpretation  of  phenomena  observed  in  man. 
The  comparative  physiology  and  morphology  of  the  color  function,  as  pre- 
sented by  R.  Fuchs,  strongly  supports  the  view  that  pigment  production 
belongs  essentially  to  a  specific  mesoblastic  cell,  the  chromatophore.  Only 
in  the  highly  pigmented  vertebrates,  as  the  frogs  and  reptiles,  in  which  the 
ova  are  pigmented  and  pigment  is  required  in  unusual  quantities,  is  there  any 
reasonable  doubt  of  the  mesoblastic  origin  of  chromatophores  and  of  the 
exclusive  relation  of  this  cell  to  pigment  production  and  transport.  In  these 
animals,  however,  there  is  some  evidence  to  show  that  pigment  production 
may  overflow  to  epithelial  cells.  Yet  the  conditions  here  are  not  favorable 
for  a  ready  solution  of  the  problem  of  pigment  production  by  epithelium. 
Even  in  the  frog  Ehrmann  concluded  that  pigmentation  is  controlled  exclu- 
sively by  the  wandering  chromatophores.  In  the  higher  vertebrates  the 
evidence  swings  distinctly  in  favor  of  the  mesoblastic  chromatophore. 

In  fundulous  embryos,  48  hours  old  without  a  circulation,  Stockard  has 
watched  with  the  binocular  microscope  the  first  appearance  of  pigment  in 
large  mesoblastic  wandering  cells  of  such  huge  size  that  they  can  be  traced 
with  great  certainty.  These  cells  have  a  notable  tendency  to  gather  along 
blood-vessels  and  they  can  be  readily  followed  in  the  act  of  depositing  pig- 
ment in  the  ectoderm.  In  cephalopods  the  migratory  movements  and 
changes  in  form  of  the  chromatophores  are  facilitated  by  muscular  processes. 
Many  of  them  are  provided  with  rich  connection  with  sympathetic  nerve 
fibers  (Hoffmann).  In  some  species  the  chromatophores  exhibit  many  prop- 
erties of  protozoa  (Chun).  In  Amphioxus  chromatophores  exist  only  in  the 


888  NEOPLASTIC  DISEASES 

central  nervous  system,  and  in  crustaceans  intestinal  chromatophores  are  the 
rule.  In  man  the  prominence  of  the  chromatophore  was  demonstrated  by 
Kolliker,  and  has  been  maintained  by  an  unbroken  line  of  subsequent  observ- 
ers. These  observations  establish  the  mesoblastic  origin  of  the  primitive 
pigment  cells,  and  they  are  especially  significant  in  emphasizing  certain  char- 
acters which  reappear min  human  melanoma,  viz.,  extreme  motility,  peculiar 
relations  to  blood-vessels,  and  distribution  throughout  central  nervous  sys- 
tem, choroid,  and  intestinal  tract. 

This  extensive  chapter  of  .natural  history  must  unquestionably  incline  the 
student  of  tumors  to  regard  all  manifestations  of  melanoma  in  terms  of  the 
chromatophore.  It  forms  a  strong  theoretical  basis  for  Ribbert's  view  of  the 
origin  of  melanoma  exclusively  from  chromatophores. 

On  the  other  hand,  there  has  always  been  a  considerable  number  of 
observers,  occupied  chiefly  with  the  direct  study  of  pigment  processes  in  man, 
who  have  maintained  the  epithelial  origin  of  the  pigment.  Post  attributed 
pigment  production  in  mammals  almost  exclusively  to  the  epithelium. 
Pigmented  connective-tissue  cells  he  regarded  as  carrying  off  excess  pigment 
from  the  epithelium.  Caspary  and  Kaposi  maintained  the  epithelial  origin 
of  pigments  in  skin  and  hair.  It  is  generally  agreed  that  chromatophores 
cannot  be  traced  in  the  hair  follicles.  The  great  majority  of  close  histolog- 
ical  studies  of  nevi  and  early  melanoma  have  led  to  the  conclusion  that 
epidermal  pigment  arises  in  the  epithelial  cells  (Abesser,  Wieting  and  Hamdi, 
Favera).  It  must  be  admitted  that  the  course  of  pigment  production  in  man 
is  not  as  clearly  denned  as  in  lower  mammals  and  that  the  doctrine  of  specific 
chromatophores  may  not  be  rigidly  applicable  to  man. 

Results  of  the  Studies  of  Nevi. — The  minute  studies  of  nevi  by  many  observ- 
ers have  told  strongly  hi  favor  of  the  epithelial  origin  of  nevus  cells  and  their 
pigmented  derivatives.  Unna's  derivation  of  the  resting  nevus  cell  from  the 
rete  pegs  has  been  verified  in  detail  by  Judalewitsch,  Favera,  and  many 
others,  who  have  traced  every  stage  of  the  passage  of  cell  groups  from  the  Mal- 
pighian  layer  into  the  derma,  where  they  lose  their  fibrils  and  become  con- 
verted into  the  glassy  rounded  nevus  cells.  Kromayer  has  further  traced 
these  cells  into  fusiform  cells  with  intercellular  fibrils,  a  process  which  he 
interprets  as  the  transformation  of  basal  epithelium  into  fibroblastic  elements. 
These  intercellular  fibrils  Ribbert  regards  as  an  indication  of  a  mesoblastic 
origin  of  nevus  cells  which  he  identifies  with  depigmented  chromatophores. 
The  sharp  circumscription  of  the  pigmented  cells  in  the  Malpighian  layer,  he 
interprets  as  the  result  of  inwandering  of  superfluous  chromatophores. 

I  believe  that  the  histological  data  do  not  permit  a  final  decision  between 
these  contending  hypotheses.  The  histological  data  appear  to  me  strongly 
but  not  decisively  in  favor  of  the  epithelial  origin,  while  the  theoretical  con- 
siderations are  all  against  the  epithelial  theory. 

Subordinating  the  evidence  drawn  from  comparative  morphology,  the 
following  conception  of  the  origin  of  moles  and  cutaneous  melanoma  might  be 
suggested:  The  deposit  of  excessive  pigment  by  mesoblastic  chromato- 
phores in  certain  cells  of  the  fetal  epidermis  excites  these  cells  to  prolifera- 
tion and  causes  them  to  assume  the  function  of  pigment  production,  thus 
producing  the  early  congenital  nevus.  This  process  is  favored  by  excess  of 
blood-vessels  in  the  derma,  and  possibly  by  some  abnormality  in  the  innerva- 
tion  of  the  part.  Chromatophores  are  attracted  by  blood-vessels  and  prob- 
ably somewhat  controlled  by  the  nervous  system,  and  some  nevi  are  asso- 
ciated with  capillary  angioma,  and  some  appear  to  be  in  relation  to  peripheral 
nerve-fibers. 

The  congenital  nevus  tends  to  regress  or  remain  quiescent,  the  cells  de- 


MELANOMA  889 

scending  into  the  derma  and  losing  their  pigment  as  in  the  adult  nevus. 
Through  irritation  of  simple  traumatic,  or  nervous,  or  more  complex  origin 
the  quiescent  nevus  cells  may  be  incited  to  overgrowth  and  renewed  pigment 
production,  developing  a  malignant  localized  tumor.  The  overlying  epider- 
mis soon  participates  in  this  tumor  process,  developing  pigment,  the  presence 
of  which  still  further  stimulates  growth  and  often  the  extension  of  the  tumor 
process  along  the  basal  cells  of  previously  normal  rete  pegs.  From  both 
these  sources  actively  proliferating  epithelial  cells,  bearing  pigment  and 
devoid  of  fibrils,  become  disseminated  by  lymph-  or  blood-vessels.  In  this 
scheme  the  part  assigned  to  chromatophores,  while  initial  and  essential,  is 
subordinate.  Histological  appearances  do  not  indicate  that  these  cells  are 
more  than  camp  followers  during  the  advance  of  the  tumor  process.  On  the 
other  hand,  assuming  that  the  nevus  cell  is  a  mesoblastic  chromatophore,  the 
tumor  process  becomes  simply  a  neoplastic  overgrowth  of  a  specific  cell, 
while  the  appearances  suggesting  participation  of  rete  pegs  and  hair  follicles 
must  signify  invasion  of  these  structures  by  tumor-cells.  In  this  dilemma 
one  may  turn  to  evidence  presented  by  melanoma  in  other  situations. 

In  the  eye  much  the  same  obscure  histological  pictures  as  in  the  skin 
present  themselves  for  interpretation.  Although  Wieting  and  Hamdi  claim 
that  embryological  studies  indicate  the  epithelial  origin  of  all  ocular  pig- 
ments, yet  the  mesoblastic  origin  of  the  choroidal  chromatophores  must  be 
conceded.  The  origin  of  the  tumors  from  these  cells  is  somewhat  less  certain. 
Leber  found  the  retinal  epithelium  in  active  proliferation  and  from  them  he 
derived  the  uveal  melanoma.  Very  early  melanomas  have,  however,  been 
traced  by  Fuchs,  Wintersteiner,  and  Purtscher,  to  the  pigmented  cells  of 
the  choroid,  while  the  retinal  epithelium  was  intact.  In  the  iris  and  ciliary 
body  exactly  the  same  relations  between  pigment  cells  and,  epithelium  are 
encountered  as  in  the  skin,  and  here  many  authors  have  derived  their 
tumors  from  the  epithelium  (La  Grange,  Bard,  Griffith,  Mitrolsky,  Weui- 
baum,  Kerschbaumer).  In  very  early  artificially  depigmented  ciliary 
melanomas  I  find  the  usual  indications  of  the  splitting  off  of  heavily  pig- 
mented basal  epithelial  cells. 

In  primary  ocular  melanoma  spindle-cells  are  more  prominent  than  with 
cutaneous  tumors,  but  in  metastatic  growths  the  structure  of  each  type  shows 
identical  variations.  The  occurrence  of  melanoma  in  the  sheath  of  the  optic 
nerve  is  difficult  to  reconcile  with  an  epithelial  origin,  but  is  quite  consistent 
with  the  distribution  of  chromatophores. 

The  melanomas  of  the  central  nervous  system  arise  from  the  wandering 
chromatophores  which  are  scattered  over  the  meninges,  about  the  vessels, 
along  nerve  sheaths,  and  in  the  subependymal  tissue.  That  these  cells  are 
homologues  of  the  mesoblastic  chromatophores  appearing  abundantly  in  the 
meninges  of  lower  animals  there  can  be  no  reasonable  doubt.  The  associa- 
tion of  these  tumors  with  extensive  cutaneous  nevi  strongly  indicates  that  in 
both  situations  the  process  is  identical  in  nature.  While  the  melanomas  of 
the  nervous  system  resemble  sarcoma  or  perithelioma  in  structure,  these 
features  are  frequently  seen  in  cutaneous  tumors  and  their  metastases. 

The  series  of  intestinal  melanomas  may  safely  be  referred  to  groups  of 
chromatophores  located  in  the  submucous  tissue.  Their  presence  recalls  the 
great  abundance  of  intestinal  chromatophores  in  crustaceans. 

For  the  rare  cases  of  melanoma  occurring  in  the  internal  organs  as  in  the 
spleen,  an  origin  from  aberrant  chromatophores  is  the  most  reasonable 
assumption.  Pigmented  adrenal  tumors  belong  in  a  special  group  which  need 
not  be  considered  hi  this  connection. 

Thus  the  review  of  the  different  forms  of  melanoma  reveals  a  direct  con- 


890  NEOPLASTIC  DISEASES 

flict  between  the  histological  data  derived  from  cutaneous  melanomas  on  the 
one  hand,  and  on  the  other  the  occurrence  of  melanoma  in  several  situations 
where  an  epithelial  origin  is  a  strained  hypothesis,  as  well  as  the  formidable 
body  of  evidence  presented  by  comparative  morphology.  If  the  epithelial 
derivation  of  nevus  cells  were  not  so  strongly  supported  by  observation  and 
argument  there  would-  no  longer  be  any  reason  for  delay  in  accepting  Rib- 
bert's  theory,  to  which  the  author  inclines.  Until  more  light  is  thrown  on  the 
nature  of  the  supposed  epithelial  changes  in  congenital  nevi,  a  final  decision 
may  be  withheld. 

The  endothelial  origin  of  the  nevus  has  received  little  new  support  in 
recent  years.  The  general  behavior  of  malignant  tumors  arising  from  nevi 
is  strongly  against  their  endothelial  nature.  No  other  known  endothelioma 
approaches  melanoma  in  its  cell  forms,  peculiar  course,  and  malignancy.  The 
endothelial  theory  can  best  be  pursued  in  old  quiescent  nevi,  where  it  is  quite 
impossible  to  reach  any  conclusion  regarding  the  origin  of  the  cells  which  have 
lost  their  original  form,  while  their  relations  are  disturbed  by  fibrosis  and 
atrophy.  From  the  study  of  sections  in  which  others  have  claimed  to  find 
lymph-  and  blood-vessels  terminating  in  nests  of  nevus  cells,  I  have  been 
impressed  with  the  unsuitable  nature  of  the  material  for  such  analysis.  The 
cell  columns  of  epithelial  tumors  have  been  found  canalized  and  filled  with 
blood.  Where  angioma  is  associated  with  nevi  I  find  the  two  processes 
invariably  distinct. 

Adrenal  Melanoma. — Small  brownish  benign  cortical  tumors  of  the  adrenal 
are  described  by  Lucksch.  They  occur  in  adults  and  are  composed  of  corti- 
cal cells  containing  pigment  resembling  melanin,  and  they  seem  to  form  a 
probable  source  of  the  malignant  pigmented  tumors  of  the  adrenal.  Not  a 
few  of  the  typical  adrenal  carcinomas  contain  areas  of  pigmented  cells  of  the 
adrenal  type. 

Primary  bilateral  melanotic  malignant  tumors  of  the  adrenal  are  de- 
scribed by  Davidsohn,  Goldzieher,  Tuczek,  and  MacLachlan.  The  tumors 
occurred  in  adults,  were  of  moderate  size,  and  sometimes  produced  extensive 
metastases,  but  primary  sources  in  skin  or  choroid  were  missing. 

The  origin  of  the  tumors  it  is  difficult  to  determine.  Davidsohn  thought 
he  recognized  the  zona  fasciculata  in  a  mesenteric  metastasis,  claims  to  have 
demonstrated  adrenalin  in  this  tissue,  and  derives  the  tumor  from  pigmented 
adrenal  cortex  cells.  Tuczek  found  the  pigment  a  true  melanin  and  not  a 
lipochrome,  as  is  found  in  the  adrenal  cortex.  He  derived  the  tumor  from 
the  pigmented  ganglion  cells  of  the  medulla,  which  contain  melanin.  Mac- 
Lachlan concluded  that  the  adrenal  melanoma  arises  from  the  wandering 
chromatophores  which  are  said  to  exist  in  the  loose  tissue  about  the  adrenal. 
Yet  the  tumors  seem  to  involve  the  whole  organ,  which  long  preserves  its 
form. 


CHAPTER  XLV 

V 

TUMORS  OF  THE  THYROID 

Epithelial  overgrowth  in  the  thyroid  occurs  in  three  main  conditions: 

(1)  Simple  goiter,  and  the  benign  tumors  or  tumor-like  processes  asso- 
ciated with  it. 

(2)  Graves'  disease. 

(3)  True  tumors. 

These  conditions  are  not  sharply  separated  from  each  other,  simple  goi- 
ter may  assume  the  characters  of  the  exophthalmic  type,  and  true  tumors 
may  develop  in  the  course  of  either  form. 

The  correct  interpretation  of  hyperplastic  processes  in  the  thyroid 
demands  special  standards  dependent  upon  the  development,  structure,  and 
functions  of  this  gland,  and  not  applicable  elsewhere. 

In  the  development  of  the  organ  there  is  progressive  centrifugal  growth  of 
separate  new  vesicles  from  central  embryonal  foci  which  produce  independent 
lobules.  Hence  the  central  portions  of  lobules  contain  the  older  vesicles,  a 
relation  which  is  specially  apparent  in  certain  fetal  adenomas.  The  inde- 
pendence of  the  vesicles  and  lobules  is  most  clearly  shown  in  the  wide  dis- 
semination of  thyroid  acini  in  the  fish  (Gudernatsch),  and  of  accessory  thy- 
roids in  man.  More  striking  evidence  of  unusual  capacity  of  independent 
growth  is  seen  in  the  cases  of  structurally  benign  but  metastasizing  goiter. 
Dissociated  thyroid  alveoli  tend  to  grow  rather  than  to  regress,  a  fact  demon- 
strated more  recently  by  the  survival  of  thyroid  tissue  in  transplants  and 
cultures. 

A  second  important  principle  governing  pathological  processes  in  the 
thyroid  is  the  remarkable  response  to  functional  stimulus,  and  the  wide 
variations  in  the  functional  activity  and  structure  of  the  gland  in  different 
physiological  states.  Marked  cellular  hyperplasia  may  readily  be  induced 
by  changes  in  diet  and  by  drugs,  and  correspondingly  reduced.  The  excessive 
hyperplasia  of  severe  Graves'  disease,  which  is  probably  the  result  of  func- 
tional stimulus,  equals  that  of  some  malignant  tumors,  but  may  promptly 
regress  under  suitable  treatment.  No  other  gland,  and  only  the  lymphoid 
tissues,  exhibit  such  adaptations. 

A  third  dominating  factor  is  found  in  the  structure  of  the  gland.  The 
vascularity  is  enormous  and  subject  to  wide  variations,  owing  to  the  great 
capacity  of  the  venous  sinuses.  Capillaries  encircle  the  alveoli  and  the  blood- 
current  is  separated  from  the  epithelium  only  by  an  endothelial  barrier.  A 
basement  membrane  is  absent  in  the  thyroid  gland,  and  the  mobility  of  the 
epithelium  is  thereby  increased.  The  colloid  secretion  of  the  organ  varies 
rapidly  in  quantity  and  in  composition  and  exerts  a  marked  influence  on  the 
structure  of  the  diseased  organ. 

Simple  Goiter. — Under  this  term  are  included  self-limiting  but  often 
bulky  enlargements  of  the  thyroid  of  congenital  or  spontaneous  origin  and 
usually  unattended  by  other  than  pressure  symptoms.  Two  chief  forms  are 
observed:  (i)  colloid,  and  (2)  parenchymatous. 

(i)  Colloid  goiter  is  a  very  common  disease  of  sporadic,  endemic,  and  even 
epidemic  occurrence,  and  is  commonly  referred  to  some  influence  residing  in 

891 


892 


N  EOF  LA  STIC  DISEASES 


drinking-water.     Reference  to  the  extensive  discussion  of  its  etiology  may 
here  be  omitted  (Bircher,  Lit.). 

The  enlarged  gland  reaches  considerable,  sometimes  enormous,  dimen- 
sions, the  growth  affecting  single  nodules,  or  one  lobe,  or  the  isthmus,  or  the 


FIG.  457. — Cross-section  through  a  simple  goiter. 


FIG.  458. — Cystic  adenoma  of  thyroid.     A  form  of  encapsulated  cystic  goiter. 

entire  gland,  or  accessory  glands  in  many  situations.  The  chief  accessory 
goiters  are  substernal,  intratracheal,  retropharyngeal  and  esophageal,.  and 
lingual  (Payr,  Martina,  Lit.,  Meerwein). 


TUMORS  OF  THE  THYROID 


893 


On  section  the  gland  presents  distended  spaces  filled  with  colloid  to  which 
the  enlargement  is  due,  and  which  yields  a  translucent,  shiny,  brownish, 
honeycomb  appearance.  Cysts  of  all  sizes  may  form  by  fusion  of  adjoining 
spaces,  liquefaction,  and  hemorrhage  (cystic  goiter).  The  appearance  is 
greatly  altered  by  hemorrhage,  pigmentation,  fatty  degeneration,  and  by 
late  fibrosis  and  calcification.  Smooth  shiny  areas  may  be  produced  by 
hyaline  changes  in  the  stroma.  Amyloid  deposits  in  stroma  and  blood- 
vessels may  be  very  prominent  (v.  Eiselberg).  Bone  deposits  are  often 
observed  in  late  stages  (Sehrt,  Heinziger,  Pfister).  The  blood-vessels  may 
be  overdeveloped,  at  times  so  much  that  the  gland  pulsates. 

The  structure  of  colloid  goiter  presents  chiefly  normal  alveoli  distended 
with  colloid.  The  lining  cells  are  flattened,  the  walls  of  adjoining  alveoli 


FIG.  459. — -Benign  cystic  adenoma  of  thyroid.     Tissue  from  wall  of  cyst. 

melt  away  and  large  spaces  and  cysts  form.  New  alveoli  are  commonly 
observed  in  small  foci  in  the  stroma  and  abundantly  beneath  the  capsule. 
Wolfler  finds  an  increase  of  alveoli  in  all  cases  of  colloid  goiter  and  hence 
speaks  of  the  process  as  adenoma  gelatinosum. 

The  colloid  is  of  normal  appearance,  or  more  often  soft  or  fluid.  It  may 
infiltrate  the  stroma,  collecting  in  lymphatics,  vessels,  and  tissue  spaces, 
often  in  great  abundance.  Small  capillary  hemorrhages  or  bulky  extrav- 
asations are  common,  producing  cysts  and  leaving  pigment.  Into  these 
hemorrhagic  areas  new  alveoli  sprout,  and  gradually  fill  with  colloid  as  the 
blood  is  absorbed.  Fatty  and  hyaline  degeneration,  calcification,  and  fibrosis 
regularly  mark  the  advanced  stages. 


894 


NEOPLASTIC  DISEASES 


Notwithstanding  the  great  size  of  colloid  goiter  the  process  lacks  any 
definite  neoplastic  character,  and  consists  in  a  functional  hyperplasia,  reten- 
tion of  colloid,  simple  regenerative  growth,  and  regressive  and  inflammatory 
changes.  Yet  true  tumors  may  arise  in  its  course,  as  papillary  adenomas 
growing  out  into  cysts,  and  the  low-grade  interacinous  adenomas.  Malig- 
nant tumors  if  they  arise  in  colloid  goiter  usually  develop  early,  but  the  great 
majority  of  colloid  strumas  maintain  their  individual  character  for  many 
years.  A  few  cases  develop  Graves'  symptoms  and  structure. 

Interacinous  Adenoma. — In  many  cases  of  colloid  goiter  the  overgrowth 
of  epithelium  reaches  considerable  proportions,  many  alveoli  are  lined  by 
clusters  of  small  round  or  cubical  cells,  many  new  alveoli  form  between  the 
older  acini  and  the  condition  suggests  a  low  grade  of  neoplastic  process.  Such 
areas  may  occur  in  circumscribed  portions  of  the  gland  and  recur  after 
extirpation.  In  all  cases  they  are  of  slow  growth  and  after  reaching  variable 


FIG.  460. — Wall  of  a  cystic  adenoma  of  thyroid.     Active  growth  of  alveoli  with  very 
small  cells,  and  formation  of  cholesterin  crystals  in  cyst  contents. 

dimensions  they  remain  stationary.  The  new  alveoli  thus  formed  tend  to 
develop  into  normal  colloid-holding  vesicles.  Wolfler  derives  these  focal  and 
diffuse  overgrowths  from  the  same  superfluous  cell  groups  which  give  origin 
to  the  fetal  adenoma.  Interacinous  adenoma  is  distinguished  from  fetal 
adenoma  chiefly  by  the  more  adult  character  of  the  cells,  and  by  its  occurrence 
in  colloid  goiters. 

(2)  Parenchymatous  goiter  is  less  frequent,  but  of  wider  significance  than 
the  colloid  form.  It  is  congenital  or  acquired. 

(a)  Congenital  Goiter. — In  the  newborn  infant  the  thyroid  may  be  much 
enlarged,  pressing  upon  the  trachea  and  causing  death  by  asphyxia.  In 
many  instances  there  has  been  a  history  of  chronic  goiter  or  idiocy  in  the 
parents  (Demme).  It  is  rather  common  in  goitrous  regions  (Escherich). 
The  infants  are  often  stillborn  or  survive  only  a  few  hours,  but  occasionally 
there  is  a  gradual  regression  and  the  goiter  disappears  after  some  years 
(Kamann). 


TUMORS  OF  THE  THYROID  895 

Wolfler  divides  the  congenital  strumas  into  parenchymatous,  angio- 
matous,  cystic,  and  adenomatous.  The  anatomical  condition  is  usually  a 
diffuse  parenchymatous  hypertrophy,  with  overgrowth  of  well-formed  alveoli 
lined  with  cells  somewhat  larger  than  in  the  normal  fetus,  and  without  any 
collection  of  colloid  (Demme,  Fabre,  Therenot).  In  a  case  of  the  writer's 
this  condition  was  remarkably  uniform.  Hewetson  reports  a  very  large  goiter 
in  which  parenchymatous  hypertrophy  with  desquamation  of  cells  was  com- 
bined with  extensive  development  of  blood-vessels.  Cysts  and  nodular 
hypertrophy  are  usually  wanting.  Simple  distention  of  the  blood-vessels  in 
face  presentation  may  give  a  marked  swelling  of  the  fetal  thyroid  which 
disappears  in  a  few  hours  or  days.  The  existence  of  a  true  angiomatous 
condition  is  doubtful.  Berry  describes  congenital  circumscribed  adenoma 
and  sarcoma,  and  Zahn  a  case  of  congenital  osteochondrosarcoma.  In  a 
few  cases  the  congenital  parenchymatous  goiter  has  given  origin  to  a  very 
early  carcinoma  (O.  Ehrhardt,  Lit.). 

(b)  Acquired  parenchymatous  goiter  is  less  frequent  than  the  colloid  form, 
from  which  it  is  distinguished  by  the  prominence  of  new  alveoli  and  the  rela- 


FIG.  461. — Circumscribed  follicular  adenoma  of  thyroid. 


tive  diminution  of  colloid.  -  The  new  growth  of  alveoli  is  diffuse  or  nodular. 
The  diffuse  type  gives  a  uniform  or  focal  distribution  of  alveoli  containing 
little  or  no  colloid,  intermingled  with  alveoli  filled  or  distended  with  colloid. 
The  structure,  therefore,  may  approach  that  of  colloid  goiter.  The  nodular 
masses  usually  exhibit  the  structure  of  Wolfler's  fetal  adenoma. 

Fetal  Adenoma. — This  condition  appears  in  the  form  of  small  or  large 
opaque  nodules  in  one  or  both  lobes.  They  develop  slowly,  reach  consider- 
able dimensions,  form  nodular  projections  of  the  capsule,  but  eventually 
become  stationary.  The  larger  tumors  may  reach  the  size  of  the  fist,  re- 
placing nearly  the  entire  lobe.  They  are  often  the  seat  of  hemorrhage  which 
alters  the  gross  appearance  and  structure.  The  structure  presents  numerous 
small  alveoli  lined  by  low  cubical  epithelium,  and  without  colloid.  Or  the 
cells  are  small  and  round  with  densely  staining  nuclei,  while  a  definite  lumen 
is  wanting.  The  growth  is  centrifugal,  so  that  the  center  of  the  nodules  often 
show  alveoli  with  colloid  and  abundance  of  stroma,  while  on  the  periphery 


896 


NEOPLASTIC  DISEASES 


there  are  many  small  closely  packed  cell  groups  in  scanty  stroma.  The 
embryonal  character  of  the  cells  is  quite  prominent,  and  when  they  become 
closely  packed  the  structure  resembles  sarcoma.  When  interstitial  hemor- 
rhage occurs  the  structure  is  disordered.  The  alveoli  sprout  with  renewed 
energy  into  the  blood  mass,  which  undergoes  hyaline  transformation  and 
absorption,  or  it  becomes  mucoid  and  gradually  replaced  by  new  growth  of 
fetal  alveoli  (secondary  adenoma).  Small  cysts  may  appear,  into  which  the 
epithelium  grows  in  low  papillary  form  (papillary  fetal  adenoma).  The  circu- 
lation in  the  fetal  adenoma  is  of  the  lacunar  type  with  many  pouched  blood 
sinuses,  a  structure  which  favors  hemorrhage  on  moderate  congestion. 
-^  Wolfler  traces  the  fetal  adenoma  to  somewhat  ill-defined  groups  of 
superfluous  embryonal  thyroid  epithelium  which  he  finds  throughout  the 


FIG.  462. — Follicular  adenoma  of  thyroid,  with  very  small  cells.     Benign  course. 

organ.  The  existence  of  these  cell  groups  is  not  easily  demonstrated. 
The  diffuse  colloid  goiter  he  refers  to  the  same  sources,  more  diffusely  dis- 
tributed, and  not  to  proliferation  of  adult  follicles.  In  this  latter  view  he  is 
not  confirmed  by  the  majority  of  observers.  The  fetal  adenoma  may  give 
origin  to  adenocarcinoma,  carcinoma  and,  as  I  believe,  to  many  so-called 
sarcomas.  It  arises  in  early  life,  and  appears  as  a  definite  tumor  usually 
before  the  twentieth  year.  Both  colloid  and  parenchymatous  goiter  may 
develop  Graves'  symptoms,  in  which  case  the  structure  assumes  the  peculi- 
arities of  exophthalmic  goiter. 

(c)  Exophthalmic  Goiter. — The  relation  of  the  symptoms  of  Graves'  disease 
to  the  structure  of  the  thyroid  gland  is  variable,  complex,  and  in  many  respects 
obscure.  These  symptoms  in  mild  form  are  rather  frequently  observed  in 


TUMORS  OF  THE  THYROID 


897 


the  course  of  simple  colloid  goiter,  and  less  frequently  a  colloid  goiter  precedes 
the  development  of  progressive  Graves'  disease  (Moebius).  In  the  course 
of  relatively  benign,  as  well  as  with  certain  malignant  tumors,  Graves'  symp- 
toms may  also  appear  (Koeber,  Ehrhardt). 

In  the  great  majority  of  cases  Graves'  disease  is  associated  with  a  series 
of  structural  changes  in  the  thyroid  which  signifies  functional  overgrowth. 
While  in  the  early  stages  these  changes  may  occasionally  be  duplicated  in 
other  conditions,  yet  in  nearly  all  stages  the  changes  are  peculiar  and,  taken 
as  a  whole,  the  series  is  distinctly  characteristic  of  the  disease  (Greenfield, 
Ewing). 


FIG.  463. — Miliary  adenoma  of  thyroid  in  exophthalmic  goiter. 


Several  phases  of  the  natural  history  of  the  exophthalmic  goiter  may  be 
traced.  Not  all  cases  pass  through  every  stage  of  the  disease.  Some  are 
mild  and  early  arrested;  others  are  fatal  at  the  height  of  cellular  activity; 
not  a  few  pass  a  critical  period  and  become  chronic:  while  the  remainder 
pursue  a  very  chronic  course,  ending  in  glandular  atrophy  and  myxedema. 
The  determining  factor  seems  to  be  the  intensity  of  the  process. 

Four  somewhat  distinct  stages  may  be  recognized  in  the  exophthalmic 
goiter. 

(i)  Hyperemia  with  increased  secretion  of  colloid  showing  diminished 
staining  reaction  with  eosin.    In  these  cases  the  disease  is  early  and  the  symp- 
toms are  mild. 
57 


898  NEOPLASTIC  DISEASES 

(2)  Increased  vascularity,  abundance  of  abnormal  colloid,  and  beginning 
cellular   hyperplasia.      These   changes   are   observed   in   established   cases, 
often   of   considerable   duration   and   intensity.     Some   of   them   are   long 
preceded  by  simple  goiter  and  the  lesions  differ  from  those  of  simple  colloid 
goiter  in  the  greater  vascularity,  reduction  of  colloid,  and  greater  cellular 
activity. 

(3)  Varicosities   of   large   vessels   with   diminished   capillary   circulation, 
comparative  or  complete  absence  of  colloid,  extensive  cellular  hyperplasia, 
and  interstitial  thyroiditis  or  fibrosis  may  be  present. 

(4)  In  chronic  cases  of  long  duration  cellular  hyperplasia  is  succeeded 
by    atrophy,    arteriosclerosis,    cyst    formation,    and    calcification,    and    the 
structure  approaches  that  of  myxedema.     These  cases  are  of  long  duration, 
with  urgent  symptoms,  and  often  fatal. 

There  is  much  variation  in  the  structure  of  the  gland  in  the  advanced 
disease,  but  the  lesions  regularly  present  the  most  pronounced  types  of 
parenchymatous  goiter.  The  follicles  proliferate,  forming  many  new  alveoli 
without  colloid  and  almost  diffuse  cellular  areas.  The  cells  are  hyper- 
trophied,  nuclei  are  hyperchromatic,  and  giant-cells  may  form.  Or  the  out- 
lines of  follicles  are  better  preserved,  but  the  lining  cells  are  enlarged  and 
appear  in  multiple  layers  often  filling  the  lumen.  Dilated  spaces  may  appear 
in  which  there  are  papillary  projections  of  epithelium  lying  on  thickened 
septa.  In  a  bulky  thyroid  of  this  type  the  cellular  hyperplasia  far  exceeds 
that  of  some  true  tumors,  but  the  Graves  process  is  not  neoplastic.  The 
chief  histological  distinction  is  the  preservation  of  a  more  or  less  typical  cell 
form  and  orderly  arrangement.  The  capsule,  septa,  lobules,  and  alveoli 
remain  intact,  the  course  of  the  disease  is  prolonged,  and  the  natural  tend- 
ency of  the  lesion  is  toward  regression,  atrophy,  and  fibrosis. 

True  tumors  rarely  develop  in  the  Graves  thyroid.  When  miliary 
adenomas  appear  their  structure  is  at  once  distinguished  from  that  of  the 
hyperplastic  gland.  When  malignant  tumors  are  associated  with  Graves' 
symptoms  it  is  possible  that  the  initial  hyperplasia  belonging  to  the  general 
disease  passes  rapidly  into  a  malignant  overgrowth,  which  thereafter  domi- 
nates the  clinical  picture.  In  several  cases  marked  Graves'  symptoms 
continued  throughout  the  course  of  thyroid  carcinoma  (Ehrhardt,  Lit.). 
I  have  observed  Graves'  symptoms  with  a  fetal  adenoma  of  the  thyroid 
during  a  period  in  which  the  thyroid  tumor  was  invaded  by  mammary 
carcinoma. 

Adenocarcinoma.  Malignant  Adenoma. — This  tumor  appears  in  the 
form  of  a  rather  large,  solid,  well-encapsulated  growth  presenting  a  nodular 
or  lobulated  texture.  The  lobules  show  a  soft  obaque  periphery  and  a  firmer 
or  fibrous  central  area.  The  red  color  indicates  an  abundant  or  excessive 
blood-supply,  and  hemorrhage  is  frequent.  Yellowish  opaque  or  pigmented 
areas  represent  fatty  and  cellular  portions  and  the  sites  of  hemorrhage.  On 
section  the  tumor  may  yield  a  mucinous  exudate,  and  colloid  portions  may 
resemble  the  normal  thyroid.  Papillary  cystadenocarcinoma  is  a  well- 
definied  subvariety,  in  which  small  cysts  and  a  papillary  structure  may  be 
detected  in  the  gross  examination. 

-  The  appearance  of  the  tumor  is  usually  preceded  by  a  period  of  slow 

enlargement  of  the  gland  which  may  extend  over  several  years. 

The  rate  of  growth  is  active,  but  not  often  rapid,  2  to  3  years  being  re- 
quired for  the  appearance  of  serious  pressure  symptoms.  Local  recurrence  is 
frequently  observed,  as  a  single  tumor  arising  from  remnants  of  the  old,  or  in 
the  form  of  primary  multiple  nodules.  Metastases  are  observed  in  some 
cases,  but  less  frequently  than  with  carcinoma. 


TUMORS  OF  THE  THYROID  899 

The  structure  is  much  the  same  in  each  of  the  constituent  lobules,  which 
present  a  peripheral  cellular  zone  of  small  alveoli  without  definite  lumina,  or 
cellular  cords  of  secondary  alveoli,  and  a  central  zone  in  which  alveoli  are 
more  adult  and  may  contain  colloid,  while  the  stroma  is  more  abundant.  This 
structure  has  often  been  interpreted  as  representing  a  centrifugal  growth 
from  an  original  focus  of  embryonal  thyroid  tissue,  passing  through  the  natu- 
ral course  of  development  of  the  thyroid  lobule.  Hence  the  peripheral 
alveoli  are  the  youngest.  There  is  much  variation  in  the  size  of  the  cells, 
the  distinctness  of  alveoli,  and  the  presence  of  colloid,  but  there  are  always 
signs  of  an  alveolar  tendency.  The  cells  are  sufficiently  atypical  to  indicate 
the  presence  of  a  true  neoplasm.  They  are  regularly  larger  and  usually  more 
adult  in  type  than  the  fetal  adenoma,  from  which,  however,  this  tumor  may 
arise. 

The  stroma  is  usually  very  vascular,  the  vessels  showing  the  characters 
of  sinusoids,  a  definite  adventitia  is  often  lacking,  and  in  the  usual  absence 
of  membrana  propria  the  tumor-cells  lie  on  the  vascular  endothelium.  Or 
convoluted  columns  of  tumor-cells  surround  thick-walled  veins.  A  perithe- 


FlG.  464. — Embryonal  follicular  adenocarcinoma  of  thyroid. 

lial  arrangement  may  be  assumed  and  has  led  some  observers  to  seek  a  specific 
origin  for  these  particular  forms  of  adenocarcinoma. 

In  some  of  these  very  vascular  tumors  the  alveolar  structure  is  reduced 
to  a  minimum  or  entirely  lost  and  the  tumor  is  composed  of  a  network  of 
columns  of  round  or  spindle-cells  surrounding  the  blood  spaces  and  resem- 
bling angiosarcoma.  Many  of  these  growths  pulsate. 

In  different  portions  of  the  same  tumor  the  structure  of  simple  goiter,  of 
adenocarcinoma,  and  of  solid  carcinomatous  cell  masses  may  appear.  In  the 
metastases  the  structure  is  usually  of  the  more  adult  type  and  many  alveoli 
contain  colloid.  Hence  this  type  of  growth  contributes  some  of  the  so-called 
benign  metastasizing  strumas. 

In  rare  cases  the  original  tumors  contain  alveoli  lined  by  cylindrical  cells. 
Some  authors  regard  such  growths  as  belonging  in  a  separate  class  and  the 
very  peculiar  structures  sometimes  observed,  as  by  Wolfler,  suggests  a  specific 
origin.  Yet  the  thyroid  cells  often  assume  a  cylindrical  form,  no  specific 
origin  has  been  demonstrated  for  these  growths,  and  it  seems  necessary  to 
assume  that  they  arise  from  the  thyroid  alveoli  by  metaplasia. 

Papillary  epithelial  tumors  of  the  thyroid  form  a  well-defined  subgroup 
which  usually  takes  the  form  of  adenocarcinoma.  Yet  some  are  relatively 
simple  and  benign  (adenoma),  while  others  are  atypical,  malignant,  and 


900  NEOPLASTIC  DISEASES 

carcinomatous.  They  arise  as  single  or  multiple  nodular  tumors  which  fuse 
in  a  single  lobulated  mass  usually  of  moderate  dimensions.  They  are  soft  in 
the  early  stages,  but  later  there  is  fibrosis,  thickening  of  stroma,  and  calcine 
deposits.  Small  cysts  (i  to  2  mm.)  and  a  papillary  structure  are  visible  in  the 
gross  and  occasionally  the  cysts  are  of  larger  dimensions.  In  Rose's  case  the 
cyst  contained  650  c.c.  of  fluid.  Hinterstoisser  makes  a  separate  group  of 
large  cystic  papillary  cystadenomas.  The  papillary  tumors  are  usually  pre- 
ceded by  chronic  enlargement  of  the  thyroid  and  growth  is  relatively  slow, 
but  the  malignancy  and  rate  of  progress  vary  with  the  structure.  Local 
recurrence  is  common  and  probably  results  from  the  development  of  new 
independent  tumors.  Barker  observed  five  recurrences  in  one  case. 

The  adenomas  are  slow  to  infiltrate  capsule  or  nodes,  while  the  adeno- 
carcinomas  recur  locally,  infiltrate  the  capsule,  and  generalize.  A  common 
history  is  that  the  original  tumor  recurs  after  operation,  becoming  more  and 


FIG.  465. — Papillary  adenocarcinoma  of  thyroid. 

more  malignant,  and  eventually  generalizing.  Graves'  symptoms  are  associ- 
ated with  many  papillary  adenomas. 

The  structure  presents  a  complex  network  of  vascular  stroma  enclosing 
alveoli  and  small  cystic  cavities  into  which  there  are  many  papillary  pro- 
jections. The  papillae  are  low  and  composed  of  epithelial  buds,  or  higher, 
with  connective-tissue  strands,  inclosing  groups  of  epithelium  and  lined  by 
one  or  more  layers  of  epithelial  cells.  These  cells  are  cubical,  cylindrical  or 
syncytial,  and  the  cytoplasm  may  be  clear  or  acidophile.  The  cylindrical 
character  is  prominent  and  uniform  in  a  group  of  cases  which  many  authors 
are  inclined  to  separate  from  the  others  (Langhans,  Kocher,  Ehrhardt). 
The  connective  tissue  of  the  papillae  may  become  very  thick  and  hyaline, 
while  the  lining  cells  desquamate.  Colloid  is  scanty  or  absent.  Calcific 
granules  may  appear  in  stroma  or  alveoli.  In  3  of  5  cases  Langhans  found 
numerous  lymph-follicles  in  the  surrounding  gland  tissue. 

Papillary  adenoma  in  one  of  the  thyroid  tumors  that  may  readily  be  traced 
to  an  origin  from  the  adult  gland  tissue,  and  the  structure  is  throughout  that 
of  an  adult,  though  often  atypical  and  malignant  neoplasm.  In  one  early 


TUMORS  OF  THE  THYROID  901 

case  I  find  very  numerous  foci  where  the  normal  alveoli  throughout  a  large 
portion  of  the  lobe  are  becoming  transformed  by  a  pronounced  neoplastic 
overgrowth  of  epithelium.  In  this  case  also  there  were  transitions  from  regu- 
lar adenomatous  to  infiltrating  carcinomatous  growth.  In  some  cases 
the  tumor  process  becomes  established  on  the  hyperplastic  gland  of  Graves' 
disease,  the  symptoms  of  which  long  precede  the  appearance  of  a  neoplasm. 
A  certain  papillary  tendency  may  also  be  observed  in  tumors  of  embryonal 
type.  In  a  series  of  cases  papillary  cystic  tumors  of  the  neck  have  been  traced 
to  accessory  thyroids  (Madelung,  Plauth,  Kapsamer). 

Struma  Postbranchialis  (Getzowa).  Small  Alveolar,  Large  Cell  Adeno- 
carcinoma  (Langhans). — In  a  group  of  thyroid  tumors,  which  in  other  respects 
do  not  differ  from  malignant  adenocarcinoma,  the  highly  specific  structure 
suggests  a  peculiar  origin.  These  tumors  are  composed  of  relatively  small 
well-formed  alveoli  lined  by  one  or  more  layers  of  very  irregular  cells.  Some 
are  clear,  cuboidal  or  cylindrical,  or  irregularly  polyhedral.  Others  are 
large,  sometimes  of  giant  size,  finely  granular,  eosinophile  and  opaque,  and 
resemble  granular  adrenal  or  liver-cells.  The  nuclei  are  small,  vesicular, 
with  visible  nucleoli.  In  some  alveoli  the  cells  are  twisted  about  one  another 
with  concave  and  convex  borders,  or  separated  by  clefts,  and  occasionally 
syncytial  masses  appear.  Rather  numerous  globules  of  colloid  are  usually 
present,  and  the  original  structure  reappears  in  metastases.  The  cells  contain 
neither  fat  nor  glycogen. 

Langhans  considers  the  possibility  of  the  origin  of  these  tumors  from 
parathyroid  or  carotid  gland,  but  concludes  that  they  arise  from  certain 
cell  groups  in  the  thyroid,  identified  by  Getzowa  as  remnants  of  the  lateral 
thyroid  anlage  (postbranchial  body).  I  have  examined  two  tumors  answer- 
ing this  description  and  suggesting  that  the  acidophile  cells  might  represent 
hypertrophic  Hurthle's  cells  of  the  thyroid  alveoli. 

Carcinoma. — The  separation  between  adenocarcinoma  and  carcinoma  of 
the  thyroid  is  very  imperfect  and  many  transitional  tumors  are  observed. 
Langhans  finds  that  the  great  majority  of  tumors  which  he  would  class  as 
carcinoma  still  show  a  tendency  to  produce  alveoli  which  sometimes  contain 
colloid.  The  same  tendency  appears  in  many  of  Wolfler's  carcinomas.  Aside 
from  these  pure  carcinomatous  growths  which  produce  solid  groups  of  atypical 
infiltrating  cells,  the  class  of  thyroid  carcinoma  must  take  account  of  the 
gross  anatomical  characters,  such  as  infiltration  of  stroma,  capsule,  and 
blood-vessels,  invasion  of  neighboring  tissues  and  lymph-nodes,  as  well  as 
the  formation  of  local  and  distant  metastases. 

Thyroid  carcinoma  is  a  disease  of  advanced  life,  50  to  60  years,  but  has 
been  observed  between  10  and  90  years.  Berry  described  a  round-cell  sar- 
coma in  a  boy  of  3  years  and  Demme  a  carcinoma  in  a  boy  of  5  years.  This 
tumor  is  slightly  more  frequent  in  females  than  in  males  (85  to  65,  Ehrhardt). 
Three  cases  were  imputed  to  trauma  (Braun,  Cornil,  Suskind).  Not  a  few 
are  attributed  to  or  aggravated  by  gestation.  Most  cases  arise  in  goiterous 
glands,  Ehrhardt  finding  this  history  in  104  of  200  cases,  the  goiter  dating 
from  i  to  50  years. 

The  average  duration  is  about  2  years.  Very  acute  and  usually  febrile 
courses  are  occasionally  seen  (Braun,  Hochstetter,  Karst).  I  have  observed 
2  such  cases  in  young  women.  The  structure  was  alveolar  or  diffuse,  with 
local  and  general  metastases.  Adenocarcinoma  progresses  more  slowly, 
v.  Eiselsberg  recording  a  duration  of  8  years.  Papillary  and  cystic  adeno- 
carcinomas  are  even  more  prolonged,  as  in  Wolfler's  case  (18  years)  and 
Smoler's  (27  years). 

In  the  gross  thyroid  carcinoma  produces  a  single,  firm,  opaque,  encap- 


902 


NEOPLASTIC  DISEASES 


sulated  tumor  mass  which  grows  steadily  until  it  invades  capsule,  gland, 
and  surrounding  tissues.  A  multicentric  origin  in  five  separate  nodules  is 
described  by  Langhans  and  is  probably  not  infrequent.  Or  the  growth  may 
begin  as  a  diffuse  infiltration,  of  which  Hinterstoisser  has  collected  17  cases. 
Friedland  describes  carcinoma  without  enlargement  of  the  gland.  Most 
carcinomas  grow  to  considerable  size  and  yield  symptoms  from  pressure, 
local  invasion,  and  metastasis.  Occasionally  the  original  tumor  remains 
small  while  metastases  develop,  and  in  a  few  cases  the  thyroid  tumor  has 
been  overlooked  and  a  metastatic  tumor  in  bone  or  lungs  has  first  attracted 
attention.  The  trachea  is  displaced,  constricted,  or  flattened.  Billroth's 
scirrhous  cancer  encircled  this  organ  like  a  band.  The  wall  becomes  infiltrated 
or  perforated,  and  polypoid  masses  may  appear  in  the  lumen  or  fill  a  bronchus 
(Herb,  Semon) .  A  diffuse  carcinomatous  lymphangitis  of  the  tracheal  mucosa 
is  described  by  Mermet  and  Lecour.  Beneath  the  obstructing  growth  the 
bronchi  may  be  dilated,  and  some  have  assumed  that  pulmonary  metastasis 
may  arise  from  inspired  particles.  The  esophagus  suffers  in  much  the  same 
manner  as  the  trachea.  The  blood-vessels  are  early  invaded  by  malignant 
as  well  as  by  some  histologically  benign  tumors.  The  thyroid  veins  may 


FIG.  466. — Solid  carcinoma  of  thyroid. 

contain  tumor  thrombi,  and  in  Ehrhardt's  case  the  thrombus  extended  to 
the  jugular  and  the  innominate. 

Invasion  along  the  vessel  sheaths  extends  further,  to  the  base  of  the  skull, 
to  the  axilla,  and  to  the  heart.  The  recurrent  laryngeal  nerve  is  frequently 
compressed  or  infiltrated,  the  vagus  and  sympathetic  less  often.  Thus  of 
34  malignant  tumors,  Meyer  noted  laryngeal  paralysis  in  20.  Direct  invasion 
of  muscles  of  neck,  cervical  spine,  mediastinum,  and  lungs  are  commonly 
observed. 

Metastases  pass  chiefly  through  the  blood-vessels  (47  cases),  by  lymph- 
paths  (16),  or  by  both  channels.  Metastases  were  absent  in  14  of  94  cases. 
The  organs  in  238  cases  of  carcinoma  and  sarcoma  were  affected  as  follows: 
lungs,  129  cases;  bones,  66;  liver,  36;  kidneys,  20;  pleura,  16;  brain,  12;  other 
organs,  13  (Ehrhardt). 

The  main  lymphatics  of  the  thyroid  are:  (i)  the  deep  jugular  plexus, 
which  drains  the  organ  laterally  and  continues  downward  in  the  inferior 
cervical  nodes  into  mediastinum;  (2)  posterior  trunks  which  run  between 
trachea  and  esophagus;  (3)  superior  vessels  leading  to  submaxillary  and 
lingual  nodes;  and  (4)  inferior  vessels  leading  directly  to  the  mediastinal 
nodes:  The  blood-vessels  first  invaded  are  the  main  thvroid  veins. 


TUMORS  OF  THE  THYROID  903 

The  pulmonary  tumors  are  large  or  small  and  disseminated.  The  bronchi 
may  be  surrounded  and  perforated  by  polypoid  masses.  Hemorrhage  is 
early  excited  in  the  pulmonary  parenchyma  and  hemoptysis  is  a  frequent 
result. 

The  bones  are  involved  only  less  frequently  than  with  mammary  and 
prostatic  cancer,  and  in  the  following  order:  skull,  sternum,  spine,  ribs, 
humerus,  femur,  and  pelvis.  The  metastatic  growths  appear  at  epiphyses 
or  along  sutures,  and  produce  large  encapsulated  tumors  or  diffuse  central 
or  periosteal  infiltrations.  The  process  may  be  osteoplastic  and  the  fractures 
occurring  may  heal  (v.  Eiselsberg).  The  claim  that  bone  metastases  may 
appear  at  points  of  hemorrhage  following  trauma,  must  be  received  with 
caution  (Ehrhardt,  Lit.).  Pulsating  bone  tumors  have  in  several  instances 
been  identified  as  metastatic  thyroid  growths  (Coats,  Feurer,  Middledropf, 
Morris).  Swelling  of  such  a  tumor  was  interpreted  by  v.  Eiselsberg  as  a 
menstrual  phenomenon.  Retrosternal  pulsating  tumors  were  regarded  as 
aneurysms  and  treated  by  appropriate  arterial  ligatures,  by  Cramer,  Langen- 
beck,  and  Sheen.  Solitary  benign  bone  metastases  have  been  observed  by  v. 
Eiselsberg  and  others.  Here  a  thyroid  adenocarcinoma  produces  a  single 
benign  metastasis  (sternum),  which  may  be  successfully  extirpated,  although 
the  patient  dies  with  later  metastases  in  other  organs.  Ehrhardt  shows  that 
many  reputed  cases  of  this  type  exhibit  multiple  bone  metastases.  In  either 
case  the  surgical  procedure  is  of  little  avail. 

Comparing  the  structure  of  primary  and  secondary  thyroid  tumors  Jaeger 
finds  the  following  relations:  (i)  both  are  benign;  (2)  primary  tumor  malig- 
nant, secondary  benign;  (3)  primary  tumor  benign,  secondary  malignant; 
(4)  both  malignant. 

That  many  metastatic  thyroid  tumors  functionate  is  indicated  by  the 
presence  of  colloid  and  has  been  proved  experimentally  by  v.  Eiselsberg. 
His  patient  suffered  from  tetany  after  extirpation  of  a  large  carcinomatous 
thyroid,  but  was  gradually  relieved  upon  the  appearance  of  an  adenomatous 
tumor  in  the  sternum,  after  the  removal  of  which  the  tetany  reappeared. 
The  influence  of  the  parathyroids  seems  to  have  been  ignored  in  the  numerous 
citations  of  this  case.  The  presence  of  iodin  in  metastatic  adenocarcinoma, 
demonstrated  by  K.  Ewald,  is  a  further  indication  of  functional  activity,  and 
since  the  original  tumor  was  free  from  iodin  the  result  indicates  a  partial 
restoration  of  function  in  the  metastases. 

Metastasizing  Colloid  Goiter. — That  a  simple  colloid  goiter,  presenting  a 
structure  that  usually  remains  harmless  for  years,  may  give  rise  to  metastatic 
tumors  of  benign  or  malignant  type  is  one  of  the  striking  anomalies  of  the 
pathological  thyroid.  Such  a  case  was  first  described  by  Cohnheim,  who 
found  the  structure  of  colloid  goiter  in  both  primary  and  secondary  tumors. 
The  lobes  of  the  thyroid  were  uniformly  enlarged  and  presented  the  appear- 
ance of  simple  goiter,  while  in  the  left  lobe  were  three  large  nodules  of  ordinary 
gelatinous  adenoma,  one  of  which  had  penetrated  the  lumen  of  the  inferior 
thyroid  artery.  Extensive  metastatic  tumors  were  found  in  bronchial  nodes, 
lungs,  femur,  and  lumbar  spine.  All  of  these  tumors  gave  the  typical  alveolar 
structure  of  thyroid  tissue,  and  only  in  a  very  few  cell  groups  was  a  lumen 
with  colloid  absent.  Other  somewhat  similar  cases  are  reported  by  Runge, 
Coats,  Middledorpf,  Feurer,  Langhans,  Honsell,  Deraun,  A.  Meyer. 

Langhans  found  several  opaque  gelatinous  nodules  in  the  thyroids,  but 
no  trace  of  invasion  of  veins.  Hence  he  considers  that  the  extension  occurred 
through  the  lymphatics.  While  none  of  the  observers  admits  the  existence 
of  suspicious  actively  proliferating  areas  in  the  original  tumor,  they  usually 
describe  areas  containing  a  few  solid  cell  groups.  It  is  evident  that  the  growth 


904 


NEOPLASTIC  DISEASES 


capacity  of  the  cells  in  colloid  goiter  is  greater  than  its  clinical  course  indicates. 
Possibly  an  accidental  access  to  the  blood-  or  lymph-stream  may  release  the 
cells  from  mechanical  restraint  and  permit  them  to  exhibit  malignant  qualities 
in  more  favorable  situations.  In  Litten's  case  the  metastases  showed  both 
colloid  struma  and  carcinoma,  and  Hofmann's  metastases  were  adenocar- 
cinomatous.  In  a  case  of  Jeffries'  I  found  in  the  dural  growth  the  normal 
regularity  of  alveoli  with  colloid,  but  the  cells  were  large  and  nuclei  hyper- 
chromatic.  In  Middledorpf's  case  the  original  "adenoma"  had  perforated 


FIG.  467. — ar-Ray  photograph  of  lungs  showing  multiple  metastases  in  benign  metas- 
tasizing  thyroid  struma  (adenocarcinoma). 

a  partly  calcified  capsule  and  the  wall  of  a  vein.  The  natural  tendency  of 
the  metastatic  thyroid  cells  to  develop  into  normal  thyroid  tissue  may  pro- 
gressively alter  the  structure  of  a  secondary  growth,  so  that  an  original  car- 
cinomatous  area  may  eventually  appear  adenomatous.  This  principle,  first 
stated  by  Eberth,  is  occasionally  illustrated. 

Metastases  from  the  Normal   Thyroid. — In  a   few  instances    tumors   of 
thyroid  tissue  have  developed  under  circumstances  which  suggested  an  origin 


TUMORS  OF  THE  THYROID 


905 


from  aberrant  cells  from  the  normal  thyroid.  Riedel  removed  a  tumor  of 
the  inferior  maxilla  composed  of  normal  thyroid  tissue,  which  recurred  locally 
after  10  years.  The  thyroid  gland  is  said  to  have  remained  normal  through- 
out this  period  of  observation. 

Oderfeld  and  Steinhaus  excised  a  perforating  tumor  of  the  skull,  composed 
of  normal  thyroid  tissue.  There  was  no  enlargement  of  the  thyroid  or  of 
any  accessory  gland.  Jeffries  reported  a  parietal  subdural  tumor  composed 
of  somewhat  embryonal  thyroid  tissue,  in  a  subject  whose  thyroid  appeared 
to  be  entirely  normal. 

In  explanation  of  these  cases  it  seems  necessary  to  assume  an  origin  either 
from  aberrant  thyroid  tissue  or  from  dislodged  cells  from  the  normal  thyroid. 
Yet  in  none  of  the  cases  has  the  supposed  normal  thyroid  been  submitted 
to  microscopical  examination.  In  Becker's  case  a  supraclavicular  tumor 
probably  represented  an  aberrant  thyroid. 


FIG.  468. — Tumor  of  aberrant  thyroid  tissue  in  cerebral  dura.    So-called  benign  metas- 
tasizing  struma.     (Specimen  of  Dr.  Jeffries.) 


The  structure  of  thyroid  carcinoma  presents  an  alveolar  type  with  large 
or  small  groups  of  atypical  cells  and  nearly  constant  absence  of  colloid. 

In  some  cases  the  structure  approaches  that  of  adenocarcinoma,  but  the 
alveoli  are  closely  packed  with  hyperchromatic  cells,  and  invasive  tendencies 
are  pronounced.  Langhans  (his  Fig.  20)  classes  as  carcinoma  a  tumor  con- 
taining many  colloid  deposits  in  irregular  masses  of  atypical  cells.  Wolfler 
(his  Fig.  48)  describes  as  carcinoma  a  tumor  composed  chiefly  of  very  small 
groups,  apparently  alveoli,  of  large  atypical  cells.  Such  tumors  seem  to 
belong  among  adenocarcinomas.  In  more  typical  cases  the  cell  groups  are 
compact  without  a  trace  of  colloid,  and  little  or  no  evidence  of  formation 
of  alveoli.  Considerable  areas  of  diffuse  cell  growth  may  appear  and  here 
the  cells  may  be  small  with  very  hyperchromatic  nuclei,  or  fusiform,  resem- 
bling sarcoma. 


906  NEOPLASTIC  DISEASES 

Scirrhous  carcinoma,  first  described  by  Billroth  as  a  ring-shaped  growth 
surrounding  the  trachea,  has  been  reported  by  later  observers,  and  is  not 
infrequently  found  in  portions  of  slowly  growing  and  very  hard  tumors. 

In  the  typical  scirrhus  the  gland  may  not  be  enlarged,  but  is  extremely 
hard,  resembling  cicatricial  tissue.  The  groups  of  tumor-cells  are  small, 
scanty,  and  limited  chiefly  to  the  peripheral  portions.  The  exact  nature 
of  some  of  the  cases  described  as  scirrhus  appears  uncertain  (Ehrhardt,  Lit.). 
Other  regressive  changes  are  also  observed,  as  fatty  degeneration,  icyst 
formation,  necrosis,  and  calcification.  Glycogen  is  scanty  or  absent  in  most 
carcinomas,  but  abundant  in  parathyroid  struma.  It  is  probable  also  that 
bone  may  form  in  the  central  areas  of  old  carcinomas,  and  when  the  epithelial 
cells  are  incorporated  in  fibrous  tissue  osteosarcoma  may  be  simulated. 

Histogenesis. — The  question  of  the  histogenesis  of  thyroid  carcinoma  is 
involved  with  that  of  all  other  thyroid  growths.  Wolfler  and  Langhans 
assume  that  all  the  ordinary  epithelial  tumors  arise  not  from  the  adult 
vesicles,  but  from  cell  groups  which  remain  embryonal  through  disorders  of 
development  and  later  give  origin  to  fetal  adenoma,  gelatinous  adenoma  or 
colloid  goiter,  adenocarcinoma,  and  carcinoma.  Yet  neither  the  existence 
of  these  embryonal  cells  nor  their  participation  in  many  tumor  processes 
have  been  studied  in  sufficient  detail  to  extend  their  significance  over  such 
a  broad  field.  Only  the  fetal  adenoma  can  be  certainly  referred  to  embryonal 
cell  groups. 

On  the  other  hand,  Virchow,  Ehrhardt,  and  others  have  found  satis- 
factory evidence  that  many  adenomas,  adenocarcinomas,  and  carcinomas 
arise  from  the  adult  follicles.  Ehrhart  pictures  very  early  focal  hyperplasia 
of  follicular  cells  in  carcinoma.  I  have  seen  such  focal  areas  especially  in 
papillary  adenocarcinoma.  This  view  accords  with  the  usual  clinical  history, 
which  indicates  that  a  long  period  of  benign  overgrowth  precedes  the  malignant 
tumor. 

There  are  many  indications  that  tumors  of  the  thyroid,  as  in  many 
other  organs,  fall  into  two  groups,  embryonal  and  adult,  and  that  each 
variety  includes  forms  of  adenoma  and  carcinoma.  Some  atypical,  usually 
rapidly  growing  tumors,  described  as  sarcoma,  appear  to  find  their  true  ex- 
planation in  an  embryonal  epithelial  origin. 

Squamous-cell  epithelioma  in  the  thyroid  has  been  observed  in  a  series 
of  cases  and  pursues  the  usual  course  of  destructive  acanthoma.  It  arises 
not  from  branchial  remnants,  but  from  the  thyroglossal  duct  and  its  pyra- 
midal process  (Langhans).  Secondary  acanthoma  from  esophagus,  larynx, 
and  branchiogenic  cysts  is  frequently  observed. 

Sarcoma  of  Thyroid. — Tumors  interpreted  as  sarcoma  are  almost  as 
frequent  in  the  thyroid  as  carcinoma.  Thus  Ehrhardt  collected  150  carci- 
nomas with  99  sarcomas.  Ewald  states  that  the  proportions  are  about  3  or  4 
carcinomas  to  i  sarcoma.  In  goiterous  regions  they  are  said  to  be  very  com- 
mon. Kocher  states  that  the  thyroid  is  one  of  the  chief  seats  of  "acute" 
sarcoma. 

The  general  etiology  is  identical  with  that  of  carcinoma.  Sarcoma  occurs 
chiefly  after  40  years,  about  equally  in  both  sexes.  An  hereditary  tendency 
and  a  history  of  previous  goiter  is  very  common.  The  rapid  course  of  thyroid 
sarcoma  is  its  chief  distinguishing  feature.  Morf  found  the  shortest  duration 
4  weeks,  the  longest,  17  months. 

The  gross  anatomy  fails  to  show  any  definite  variations  from  carcinoma. 
The  tumors  are  large,  circumscribed  or  diffuse,  locally  aggressive,  invading 
lymph-nodes  and  veins,  and  producing  distant  metastases,  with  or  without 
affection  of  the  nodes. 


TUMORS  OF  THE  THYROID 


907 


The  histological  varieties  are  numerous.  Of  40  cases  analyzed  by  Morf, 
the  distribution  was:  round  cell  10,  spindle-  6,  mixed  7,  alveolar  5,  fibrous  3, 
osteoid  2,  etc.  Giant-cells  are  prominent  in  some  tumors.  Lymphosarcomas 
are  described  by  Braun  and  Ehrhardt. 

Notwithstanding  the  wide  acceptance  of  numerous  reported  cases  as 
sarcoma  of  the  thyroid,  there  is  a  strong  reason  for  believing  that  the  great 
majority  of  these  tumors  are  of  epithelial  origin.  It  is  clear  that  the  diagnosis 
of  sarcoma  has  usually  been  accepted  on  the  most  superficial  resemblance 
to  a  mesoblastic  tumor,  and  without  any  effort  to  critically  interpret  the 
structure  and  origin.  Hence  many  authors  have  recognized  the  uncertain 
standing  of  thyroid  sarcoma,  but  dismissed  the  matter  by  stating  that  there  is 
no  sharp  dividing  line  between  carcinoma  and  sarcoma.  The  close  resem- 
blance of  the  general  etiology,  clinical  course,  and  gross  anatomy  of  the  two 
conditions  fully  bears  out  this  conclusion.  There  remain  only  histological 
distinctions,  but  when  these  are  examined  in  detail  they  fail  to  establish  the 
frequent  occurrence  of  malignant  mesoblastic  tumors  of  the  thyroid. 


FIG.  469. — Spindle-cell  area  in  thyroid  carcinoma. 

Of  the  reported  cases  many  showed  an  alveolar  structure  which  is  strongly 
indicative  of  an  epithelial  origin  (Forster,  Newmann,  Braun).  Wolfler's 
alveolar  sarcomas  (his  Figs.  62,  63)  are  indistinguishable  from  small  alveolar 
or  highly  vascular  embryonal  carcinoma.  C.  Kaufmann  based  his  diagnosis 
of  a  round-cell  sarcoma  on  a  minute  histological  study,  but  his  tumor  was 
alveolar,  a  striking  resemblance  to  carcinoma  was  noted  in  some  cases,  his 
drawing  shows  a  typical  adenocarcinoma  with  the  common  infiltration  of 
stroma  by  large  polyhedral  cells,  and  the  intimate  relation  of  blood-vessels 
to  tumor-cells,  on  which  he  lays  chief  stress,  is  characteristic  of  thyroid 
carcinoma.  He  also  describes  carcinoma  and  spindle-cell  sarcoma  in 
adjoining  portions  of  the  same  tumor.  Limacher  traces  in  great  detail  the 
origin  of  a  typical  fibrocarcinoma  to  the  endothelial  cells  of  blood-vessels. 
Ehrhardt  mentions  the  great  difficulty  of  distinguishing  many  reported  cases 
of  fibrosarcoma  from  scirrhus.  Some  osteosarcomas  appear  to  represent  bone 
formation  in  old  fibrous  strumas.  Pick's  osteosarcoma  was  probably  second- 


908 


NEOPLASTIC  DISEASES 


ary  to  a  growth  in  the  maxilla,  and  Ehrhardt  concluded  that  his  case  was 
secondary  to  a  tumor  in  the  femur.  Fraenkel's  melanosarcoma  showed 
cutaneous  moles.  Braun's  lymphosarcoma  presents  none  of  the  distinguish- 
ing features  of  this  disease. 

My  own  material,  which  includes  Lartigau's  case,  illustrates  so  fully  the 
transformation  of  thyroid  epithelium  into  spindle-,  round,  and  giant-cells, 
producing  a  structure  resembling  sarcoma,  as  to  lead  to  the  conclusion  that 
the  mesoblastic  origin  of  most  of  the  sarcomas  reported  in  the  literature  is 
highly  improbable,  and  that  the  occurrence  of  true  sarcoma  in  man  still 
requires  demonstration. 

Benign  Granuloma  of  the  Thyroid.  Riedel's  Struma. — In  1896  Riedel 
described  a  form  of  chronic  inflammation  of  the  thyroid  gland  which  trans- 
formed the  organ  into  a  bulky  tumor  composed  of  dense  fibrous  and  sclerotic 
tissue.  The  entire  gland  was  involved  and  converted  into  a  mass  of  almost 
iron-hard  consistence,  and  so  generally  adherent  that  extirpation  was  difficult 
or  impossible.  Although  the  disease  was  variously  diagnosed  as  syphilis, 


FIG.  4690. — Structure  of  early  stage  of  benign  granuloma  of  thyroid  gland. 

tuberculosis,  or  cancer,  potassium  iodid  was  without  effect,  and  cases  observed 
for  years  did  not  become  cachectic,  the  neighboring  nodes  were  not  invaded, 
and  metastases  did  not  develop.  Selitschek  observed  spontaneous  recovery 
of  a  moderately  advanced  case.  Occasionally  after  a  partial  resection  the 
remainder  of  the  tumor  receded.  Riedel  and  others  made  no  mention  of  ex- 
tensive infiltration  of  the  gland  with  lymphocytes  or  lymph-follicles. 

In  1912  Hashimoto  described  3  clinically  similar  cases  in  which  the  acini 
of  the  gland  were  largely  replaced  by  very  numerous  lymph-follicles  with 
prominent  germ  centers.  In  places  these  follicles  became  diffuse.  He  con- 
cluded that  he  had  to  deal  with  a  new  disease  which  was  not  to  be  identified 
with  Riedel's  iron-hard  struma. 

I  have  studied  4  cases  which  illustrate  both  the  above  conditions,  and 
in  2  of  them  a  very  extensive  and  peculiar  sclerosis  had  overtaken  and 
largely  replaced  the  lymphoid  tissue.  It  appears,  therefore,  that  Hashimoto 
and  Riedel  have  described  the  early  and  the  late  stages  of  the  same  patho- 
logical process. 


TUMORS  OF  THE  THYROID 


909 


These  cases  occurred  in  adults  and  produced  tumors  of  considerable  size 
involving  the  whole  gland.  The  growth  was  rather  active  for  a  few  months, 
after  which  the  process  became  slower  or  stationary.  The  regional  nodes 
were  unaffected.  There  were  no  symptoms  of  hypothyroidism.  One  very 
large  tumor  produced  severe  dyspnea  from  pressure,  but  receded  rapidly 
under  radium.  The  form  of  the  gland  was  retained. 

In  the  early  stages  the  gland  is  thickly  beset  with  very  numerous  lymph- 
follicles  with  active  germ  centers,  the  reticulum  cells  of  which  become  so 
numerous  as  to  suggest  lymphosarcoma.  In  one  instance  the  condition  had 
been  diagnosed  as  carcinoma.  The  persisting  reticulum  cells  incarcerated 
between  the  hyaline  strands  of  fibrous  tissue  yield  a  picture  resembling  small 
cell  alveolar  carcinoma.  All  stages  of  atrophy  of  the  alveolar  epithelium  can 
be  traced.  Fibrosis  and  hyaline  transformation  begin  early  and  eventually, 
as  in  Riedel's  cases,  the  enlarged  gland  becomes  very  firm  and  dense.  The 
specific  features  of  Hodgkin's  granuloma  are  missing. 

Tumors  of  the  Parathyroid. — Hyperplasia  of  the  parathyroids  has  been 
found  in  a  considerable  number  of  cases  of  osteomalacia,  osteoporosis,  and 


FIG.  470. — Symmetrical  tumors  of  para- 
thyroid glands.     (After  Harbitz.) 


FlG.  471. — Adenoma  of  parathyroid  gland 
in  osteomalacia.     (After  Harbitz.) 


rickets,  and  has  been  interpreted  as  an  indication  of  hyperf unction  with 
disturbance  in  calcium  metabolism  (Harbitz,  Lit.).  In  several  cases  the 
hyperplasia  has  been  regarded  as  adenomatous. 

The  recognition  of  extrathyroid  tumors  of  parathyroid  origin  may  be 
accomplished  with  sufficient  certainty,  but  in  the  case  of  intrathyroid  growths 
it  is  difficult  to  establish  a  parathyroid  origin  unless  the  tumor  presents  very 
definite  structural  peculiarities.  There  is  thus  ground  for  the  doubt  expressed 
by  Harbitz  regarding  the  nature  of  certain  intrathyroid  tumors  referred  by 
various  authors  to  the  parathyroid. 

The  peculiar  structure  and  rich  glycogen  content  of  certain  thyroid  tumors 
was  interpreted  by  Kocher,  Jr.,  in  1899  as  evidence  of  a  parathyroid  origin. 
Very  similar  but  smaller  extrathyroid  growths  were  later  recognized  as  of 
parathyroid  origin  by  Benjamins,  Erdheim,  and  MacCallum.  The  occur- 
rence of  aberrant  parathyroid  tissue  in  the  thyroid  (Getzowa,  Erdheim) 
accounts  for  the  presence  of  these  growths  within  the  confines  of  the  organ. 

The  parathyroid  struma  produces  an  encapsulated  tumor  involving  a 
part  or  the  whole  of  one  side,  or  appearing  as  a  separate  mass  at  the  lower 


910 


pole  of  the  thyroid.  The  extrathyroid  tumors  are  small  and  adenomatous 
(Erdheim,  MacCallum)  or  large  and  malignant  (Benjamins).  Within  the 
thyroid  they  produce  firm,  nodular,  adherent,  rapidly  growing  and  malignant 
tumors,  with  pain,  dyspnea,  invasion  of  nodes,  and  metastases  (Kocher,  Sr.). 
Small  cysts  may  form  from  dilated  ducts. 

The  structure  recalls  that  of  the  parathyroid  and  presents  chiefly  compact 
columns  of  opaque  epithelium  often  arranged  in  palisade  form.  There  is 
much  variation  in  the  size  and  appearance  of  these  columns.  In  one  of  my 
cases  they  vary  from  very  thin  strands  to  large  alveoli,  bordered  by  palisade 
cells  and  filled  with  large  cuboidal  cells.  These  areas  are  very  vascular, 
especially  when  the  cell  columns  are  small,  and  the  vessels  are  very  thin- 
walled  sinuses.  Areas  of  very  large  clear  cells  with  dense  cell  borders  and 
cytoplasm  rich  in  glycogen,  recalling  the  structure  of  hypernephroma,  are  a 
second  characteristic  feature.  Occasionally  there  are  canals  lined  with 
cylindrical  epithelium,  which  Langhans  derives  from  the  embryonal  tubules 
traced  by  Kursteiner  from  the  parathyroid  to  the  thymus.  Groups  of 
strongly  acidophile  cells  may  also  be  present.  The  cell  columns  are  not  al- 
ways intact,  but  there  is  a  strong  tendency  in  rapidly  growing  tumors  toward 


FIG.  472. — Detail  of  adenoma  of  parathyroid.     (After  Erdheim.) 

a  diffuse  growth  of  small  round  or  spindle-  or  giant-cells,  producing  a  pseudo- 
sarcoma.  Such  a  structure  is  described  by  Langhans,  and  appears  in  one 
of  my  cases.  In  the  smaller  tumors  the  structure  is  more  regular  and  adeno- 
matous, and  in  MacCallum's  case  the  question  arose  whether  the  process 
was  a  simple  hypertrophy  or  a  neoplasm.  Hulst's  small  tumor  lay  in  a  calcified 
capsule.  In  several  cases  there  were  present  droplets  of  colloid,  or  definite 
alveoli  filled  with  colloid  or  mucin,  and  these  tumors  may  be  separated  with 
difficulty  from  thyroid  growths. 

Cysts  of  Thyroid  and  Parathyroid.— The  middle  lobe  of  the  thyroid  is 
developed  from  an  invagination  of  the  buccal  epithelium,  just  behind  the 
tuberculum  impar,  which  marks  the  junction  of  the  second  and  third  branchial 
clefts  and  goes  to  form  the  anterior  portion  of  the  tongue.  Behind  this  in- 
vagination later  rises  a  fold  formed  by  the  second  and  third  branchial  arches, 
which  goes  to  form  the  base  of  the  tongue.  The  thyroid  invagination  (thyro- 
glossal  duct)  passes  down  in  front  of  the  hyoid  bone  and  its  lower  portion 
gives  origin  to  the  middle  lobe  of  the  thyroid.  The  upper  end  may  remain 
patent,  opens  at  the  foramen  cecum,  and  is  lined  by  pavement  cells.  The 
middle  portion  usually  atrophies,  but  may  persist  as  a  canal  lined  by  ciliated 
epithelium.  Bochdalek  found  many  salivary  gland  acini  opening  by  lateral 
ducts  into  this  canal  (Bochdalek's  duct  or  gland).  Secretion  in  the  upper 


TUMORS  OF  THE  THYROID  911 

portion  of  this  canal  (lingual  duct)  is  readily  discharged  through  the  foramen 
cecum,  but  in  the  deeper  portions  (thyroid  duct)  secretion  is  retained  and 
gives  rise  to  median  cysts  lined  by  squamous  or  cylindrical  cells  and  often 
containing  thyroid  follicles  in  the  wall  (Konig).  Cysts  lined  by  ciliated 
epithelium,  lying  in  the  middle  line  between  the  base  of  the  epiglottis  and 
the  upper  border  of  the  hyoid  bone,  have  been  traced  to  dilatation  of  the 
ducts  of  Bochdalek's  gland  opening  into  the  lingual  duct  (Schmidt).  Some 
of  these  cysts  lie  at  or  below  the  hyoid  bone  and  are  single  or  multilocular, 
with  a  lining  of  squamous  or  ciliated  cells,  and  mucinous  contents  (Streckeisen). 
Others  may  appear  in  the  floor  of  the  mouth  as  forms  of  ranula  (Neumann). 

Accessory  thyroid  gland  tissue  may  be  found  along  the  entire  length  of 
the  thyroglossal  duct,  and  according  to  their  position  have  been  termed 
supra-,  pre-,  and  intrahyoid.  The  uppermost  glands  are  very  prone  to  hyper- 
trophy at  puberty  and  produce  tumors  presenting  at  the  foramen  cecum. 
In  2  cases  extirpation  of  these  tumors  was  followed  by  myxedema,  showing 
that  the  lingual  thyroid  was  the  only  portion  of  the  gland  which  developed 
(Seldowitsch,  Chamisso) . 

In  cases  of  thyroid  aplasia  in  cretins,  or  of  unilateral  aplasia  of  adults, 
small  multilocular  cystic  tumors  regularly  appear  in  the  region  of  the  lingual 
duct.  The  cysts  are  lined  by  squamous  or  ciliated  cells  and  remnants  of 
the  aplastic  thyroid  are  found  in  the  walls  (Erdheim,  Lit.). 

As  with  the  median  lobe,  so  the  lateral  thyroid  lobes  develop  from  invagi- 
nations  of  entodermal  epithelium.  These  divide  into  a  dorsal  portion, 
giving  origin  to  the  parathyroids  and  a  ventral  or  thyroid  portion.  Either 
of  these  ducts  may  persist  and  yield  cysts  in  thyroid  or  parathyroid,  or 
separate  ducts  from  third  and  fourth  buccal  pouches  lead  to  the  lower  and 
upper  parathyroids,  as  well  as  to  various  accessory  parathyroids,  of  which 
Erdheim  has  found  as  many  as  eight.  In  cases  of  unilateral  thyroid  aplasia 
Erdheim  finds  normal  parathyroids  and  a  cyst  with  tubular  glands  repre- 
senting the  atrophic  lateral  thyroid. 


CHAPTER  XL VI 
THE  THYMUS  AND  ITS  TUMORS 

No  group  of  tumors  has  more  successfully  resisted  attempts  at  inter- 
pretation and  classification  than  those  of  the  thymus.  The  problems  in- 
volved include  those  which  have  complicated  the  embryological  and  histo- 
logical  study  of  the  gland,  while  added  difficulties  arise  from  the  comparative 
rarity  and  considerable  diversity  of  the  tumors,  and  from  the  somewhat 
imperfect  knowledge  of  the  general  pathology  of  the  thymus. 

A  short  resume  of  the  knowledge  of  the  origin  and  structure  of  the  gland 
will  facilitate  the  interpretation  of  its  tumors  (Hammar,  Lit.). 

Anatomy. — The  thymus  is  a  paired  organ  arising  from  evaginations  of 
the  third  branchial  clefts  (Thymus  III).  Its  anlage  is  contiguous  with  that 


Tm.3 


FIG.  473. — Scheme  of  derivatives  of  branchial  clefts  in  the  human  embryo.     (After 
Sobotta.}      Tr,  thyroid;  e,  parathyroids;  Tm,  thymus;  p,  postbranchial  body. 

of  the  parathyroids,  arising  from  the  same  clefts,  a  relation  which  explains 
the  occasional  presence  of  parathyroid  alveoli  in  the  thymus,  as  well  as  the 
rare  association  of  thymus  tissue  with  parathyroid  in  the  thyroid  gland.  A 
second  portion  of  the  thymus  arises  from  the  fourth  cleft,  where  it  holds  the 
same  relation  to  the  parathyroids  developed  from  this  cleft  (Thymus  IV). 
From  these  four  sources  the  growing  entodermal  epithelium  coalesces  to 
form  a  four-lobed  fetal  organ  which,  with  the  descent  of  the  heart,  becomes 
drawn  out  in  an  elongated  double-pear  shape.  In  Hammar's  early  fetal  models 
the  stems  stretch  from  the  lateral  lobes  of  the  thyroid  down  below  the  sternal 
notch  where  the  main  mass  of  the  gland  develops,  the  stems  disappearing. 
This  mode  of  origin  only  partly  explains  the  occurrence  of  accessory  thymus 
lobes  beside  and  below  the  thyroid  (Erdheim),  and  laterally  in  the  neck. 
Sharp  describes  a  large  accessory  thymus  extending  from  the  anterior  border 
of  the  trapezius  behind  sternomastoid  and  clavicle. 

The  fully  developed  organ  consists  of  a  stroma  and  reticulum,  paren- 
chyma, and  capsule.     The  supporting  stroma  is  chiefly  found  in  the  net- 

912 


THE  THYMUS  AND  ITS  TUMORS 


913 


work  of  arterioles,  capillaries,  and  venules,  to  which  is  confined  practically 
all  of  the  connective  tissue  within  the  organ. 

The  finer  stroma  is  a  derivative  of  the  original  epithelium  of  the  gland, 
which  becomes  elongated  into  a  fine  reticulum  in  the  meshes  of  which  lie 
the  parenchyma  cells.  This  reticulum  has  nodal  thickenings  or  syncytia, 
or  may  be  stretched  into  fine  fibrils.  By  accumulation  of  its  cells  in  the 
medulla  are  formed  concentric  groups  of  flat  cells  (Hassall's  corpuscles), 
with  which  the  reticulum  is  directly  continuous,  while  on  the  periphery  in 
many  fetal  glands  the  epithelium  appears  in  groups  and  cords  in  cubical  or 
cylindrical  form.  Hassall's  corpuscles  are,  therefore,  not  remnants  of  embryo- 
nal epithelium,  but  collections  of  adult  reticulum  cells.  In  the  medulla  the 
reticulum  is  far  more  abundant  than  in  the  cortex. 

The  parenchyma  cells  have  the  appearance  of  very  small  lymphocytes, 
from  which  they  have  not  been  successfully  distinguished  by  many  studies 


VKJ     ••*  a*'.'  t       ^<*  - .> « 

FIG.  474. — Structure  of  thymus  of  human  embryo  of  70  mm.     Coarse  epithelial  retic- 
ulum, beginning  infiltration  by  lymphocytes.     (Hammar.) 

directed  to  their  morphology,  microchemical  reactions,  serological  relations, 
or  behavior  in  most  pathological  conditions. 

Their  origin  is  as  yet  undetermined.  In  favor  of  the  view  that  they  are 
epithelial  derivatives,  as  claimed  by  Beard,  Stohr,  and  others,  the  following 
facts  may  be  cited:  (i)  The  occurrence  of  transition  forms  between  the 
reticulum  cells  and  the  lymphocytes  (Prenant,  Bell).  Yet  Maximow  is  able 
to  distinguish  between  the  small  darkly  staining  epithelium  and  the  lympho- 
cytes. (2)  The  very  early  appearance  of  lymphocytes  in  the  thymus.  (3) 
The  apparent  absence  of  any  signs  of  infiltration  by  lymphocytes  from  with- 
out. (4)  The  apparent  transformation  of  small  thymus  cells  into  epithelium. 
Against  the  epithelial  origin  stand  chiefly  the  evident  identity  of  the  cells 
with  other  lymphocytes,  the  development  of  other  lymphoid  organs  by  the 
inwandering  of  lymphocytes,  and  the  behavior  of  these  cells  in  pathological 
conditions.  Most  observers,  including  Maximow,  Hammar,  and  Wiesel, 
58 


914  NEOPLASTIC  DISEASES 

consider  the  thymus  an  organ  with  peculiar  reticulum  of  epithelial  origin 
infiltrated  by  lymphocytes.  Yet  the  organ  never  assumes,  either  in  structure 
or  functions,  the  position  of  a  simple  lymphoid  organ.  In  many  conditions 
it  fails  to  participate  with  other  lymphoid  organs  in  systemic  diseases  (Hart). 

In  addition  to  the  lymphocytes  other  cells  are  often  seen  in  the  thymus. 
Shaeffer  observed  many  plasma-cells  derived  from  the  lymphocytes  in  the 
involuting  gland,  and'  with  these  may  occur  eosinophile  cells  and  mast- 
cells  (Maximow).  Watney  describes  giant  phagocytes.  Myoid  cells  with 
cross  striation  are  scanty,  but  very  constant  derivatives  of  the  epithelium. 
Wasutoschkin,  however,  considers  that  they  are  derived  from  the  muscle-cells 
in  the  capsule.  The  formation  of  red  cells  appears  to  be  limited  to  lower 
animals,  but  evidences  of  the  formation  of  leukocytes  are  frequently  observed 
in  man.  The  efforts  to  establish  the  thymus  as  a  gland  of  internal  secretion 
and  a  unit  in  the  chromamn  system  are  reviewed  by  Wiesel. 

General  Pathology. — A  horn  of  thymus  tissue  reaches  upward  to  the 
thyroid  gland  in  20  per  cent,  of  young  subjects  (Rieffel),  and  strands  of  thymus 
tissue  may  encircle  the  great  vessels  of  the  neck  and  the  vagus  nerve  at  the 
level  of  the  hyoid  bone  in  the  infant  (Harman,  Bien).  Accessory  lobes  appear 
occasionally  in  the  thyroid  and  in  connection  with  the  parathyroids. 

The  weight  of  the  thymus  at  birth  varies  greatly  from  2  to  14  gm.,  but 
averages  7.7  gm.  (Bovaird  and  Nicoll).  It  increases  hi  size  at  least  to  the 
1 5th  year,  when  the  average  weight  is  from  20  to  28  gm.  (v.  Sury,  Ronconi). 
It  then  steadily  diminishes,  but  persists  in  most  subjects  throughout  life. 
Its  proportion  to  the  body  weight  is  highest  at  birth,  0.42  per  cent.,  but  after 
25  years  the  permanent  ratio  of  0.3  per  cent,  is  reached.  Owing  to  numerous 
accidental  variations  it  is  extremely  difficult  to  establish  the  existence  of 
hypertrophy  unless  of  very  marked  degree.  Involution  takes  the  form  chiefly 
of  fat  invasion  of  the  parenchyma,  with  persistence  of  many  Hassall's  cor- 
puscles. 

Simple  hypertrophy  of  the  thymus  occurs  in  infants,  in  which  the  enlarged 
gland  exerts  at  least  in  part  a  mechanical  effect  in  fatal  thymic  asthma  by 
compression  of  the  trachea.  The  structure  of  these  glands  is  usually  normal. 
In  status  lymphaticus  the  thymus  usually  exceeds  the  normal  weight  for 
the  age  and  weight  of  the  patient,  and  at  times  the  excess  is  very  marked. 
In  Graves'  disease  thymus  hypertrophy  is  nearly  constant  and  often  marked. 
In  all  of  these  conditions  the  hypertrophy  is  due  to  lymphocytic  hyper- 
plasia,  and  does  not  reach  the  grade  of  a  neoplasm.  In  aberrant  thymus 
tissue  the  hyperplasia  has  at  times  been  very  active,  as  in  Sharp's  lymphade- 
noma  of  a  cervical  thymus.  Hyperplasias  interpreted  as  lymphadenomas 
are  described  by  Rolleston,  Edmunds  and  McKenzie,  Pepper  and  Stengel,  and 
Hektoen.  In  these  cases  the  organ  was  several  times  the  normal  size,  the 
capsule  was  intact,  the  medulla  largely  obliterated,  and  Hassall's  corpuscles 
widely  scattered.  Tarozzi  describes  as  simple  hyperplasia  a  very  large  en- 
capsulated tumor  occupying  all  the  anterior  mediastinum  in  a  boy  of  18 
years. 

Proliferation  or,  more  correctly,  increase  in  number  of  Hassall's  corpuscles 
occurs  in  Graves'  disease  (Soupault)  and  in  hemophilia  (Acland).  Exfolia- 
tion of  very  numerous  large  reticulum  cells  in  the  involuting  thymus  has 
been  described  by  Lochte  in  gangrenous  gingivitis  and  in  leukemia.  Hahn 
and  Thomas  collected  several  cases  of  thymic  tuberculosis.  It  is  a  notable 
fact  that  in  most  cases  of  leukemia  and  pseudoleukemia  the  thymus  fails  to 
participate  in  the  process.  In  a  series  of  such  cases  Schridde  found  no  thymic 
enlargement.  Yet  a  leukemic  blood-picture  has  been  observed  in  a  series 
of  large  sarcomatous  tumors  of  the  thymus  (Fabian).  In  a  case  of  Coenen's, 


THE  THYMUS  AND  ITS  TUMORS 


915 


with  leukemic  blood,  it  was  difficult  to  determine  whether  the  thymic  lesion 
was  leukemic  or  granulomatous. 

Cysts  form  in  the  thymus  from  several  sources  (Pigache,  Beclere,  Heuter, 
Lit). 

(i)  The  epithelial  canals  of  the  embryonal  thymus  may  persist  and  form 
one  or  several  small  or  large  cysts  in  or  along  the  horns  of  the  gland.  They 
are  especially  frequent  in  syphilitic  infants.  Each  lobe  of  the  organ  may 
be  converted  into  a  large  cyst  (Bednar).  Pollosson  and  Piery  describe  a 
congenital  multilocular  cyst  of  a  cervical  thymus,  extending  from  behind  the 
sternum  to  the  midcarotid  region.  It  was  lined  by  flat  pavement  cells.  In 
a  sclerosed  and  luetic  thymus  in  a  man  of  25  years  Hueter  found  general 
cystic  alterations.  The  cysts  were  lined  by  flattened  cells,  filled  with  mucoid 
and  lipoid  material,  and  into  many  of  them  grew  polypoid  masses  of  thymus 


FIG.  475. — Ciliated  epithelial  cyst  in  thymus  of  human  embryo  of  70  mm.     (Hammar.) 

tissue.  The  origin  was  attributed  to  persistent  epithelial  cell  groups. 
Westernak  recognized  a  mediastinal  cyst,  lined  by  ciliated  epithelium,  by 
means  of  thymus  tissue  in  the  wall,  and  he  attributed  its  origin  to  the  thymus 
duct.  The  demonstration  of  lymphoid  tissue  and  Hassall's  corpuscles  in 
the  wall  aided  Funke  in  the  recognition  of  a  thymus  cyst  in  the  thyroid. 

In  Graves'  disease  Soupault  describes  multiple  cysts  lined  by  columnar 
epithelium.  In  a  man  of  69  years  he  found  a  thymus  15  cm.  in  length,  hyper- 
plastic  above,  but  in  the  lower  half  diffuse  overgrowth  of  epithelial  cells, 
and  small  cysts  filled  with  mucus. 

(2)  Dermoid  cysts,  of  which  Hare  has  collected  9  cases,  may  arise  from 
portions  of  the  ventral  ectoderm  or  from  the  branchial   clefts.     Rollestori 
describes  a  compound  cyst  with  adenomatous  structures  resembling  Lieber- 
kuhn's  follicles  and  areas  of  cartilage  and  sarcoma. 

(3)  Invasion  and  distention  of  Hassall's  corpuscles  by   lymphocytes  is 


916 


K EOF LAST  1C  DISEASES 


of  common  occurrence,  and  many  small  cysts  may  form  throughout  the  gland 
by  degeneration  of  these  wandering  cells.  Chiari  showed  that  Dubois'  ab- 
scesses consist  of  distended  corpuscles  filled  with  lymphocytes.  The  lining 
of  these  corpuscle  cysts  is  of  cubical  or  flat  epithelium.  All  these  cysts  are 
regarded  by  Ribbert  as  derived  from  persistent  embryonal  tubules. 

(4)  Cystic  lymphangioma  is  described  by  Seidel  in  an  infant  of  2  years. 
The  entire  organ  was  the  seat  of  many  small  cysts  filled  with  bloody  fluid 
and  lined  by  flat  endothelial  cells. 

PRIMARY  TUMORS  OF  THE  THYMUS 

Primary  tumors  of  the  thymus  are  probably  not  as  rare  as  the  scanty 
reports  would  indicate.  Rubaschow  collected  69  cases,  but  questioned  the 
thymic  origin  of  many.  The  age  of  incidence  of  33  sarcomas  was:  before 


FIG.  476. — Anterior  view  of  a  large  thymoma.    The  tumor  covers  the  pericardium,  sur- 
rounds the  bronchi  and  great  vessels,  and  extends  slightly  to  pleura  and  lung. 

25  years,  18  cases;  from  25  to  40  years,  8  cases;  over  40  years,  7  cases.  Carci- 
nomas occur  in  later  years  and  usually  after  50.  Steudener  found  a  large 
lymphosarcoma  in  an  infant  of  one  year.  While  Virchow  believed  that  thy- 
mic hypertrophy  led  to  tumor  growth,  Bartel's  statistics  do  not  show  that 
cases  of  status  lymphaticus  are  especially  prone  to  develop  thymic  tumors. 
Eisenstadt's  case  gave  a  history  of  trauma.  The  age  of  incidence  and  the 
usual  course  of  involution  strongly  suggest  that  thymic  carcinoma  is  affected 
by  disturbances  in  the  natural  process  of  involution.  The  origin  of  the  sar- 
comas seems  closely  connected  with  that  of  lymphosarcoma  in  general,  and  not 


THE  THYMUS  AND  ITS  TUMORS  917 

a  few  of  these  cases  show  marked  resemblances  to,  or  a  practical  identity  with, 
granuloma  malignum.  Analogy  suggests  that  the  peculiar  reticulum  cells  of 
the  thymus  may  at  times  respond  to  infection  by  inflammatory  and  eventually 
neoplastic  overgrowth. 

Classification. — Thymic  tumors  fall  into  two  main  groups: 

(1)  Lymphosarcoma  or  thymoma,  composed  of  a  diffuse  growth  of  round, 
polyhedral,  and  giant-cells.    The  chief  source  of  this  tumor  is  probably  the 
reticulum  cell,  but  lymphocytes  are  often  present  in  abundance. 

(2)  Carcinoma  arising  from  the  reticulum  cells. 

To  these  may  be  added  very  rare  and  somewhat  questionable  cases  of 
tumors  attributed  to  the  stroma  and  called  (3)  Spindle-cell  or  myxosarcoma. 

Owing  to  the  uncertainty  which  still  surrounds  the  nature  of  the  thymic 
round  cells,  the  term  "thymoma"  has  been  suggested  by  Thiroloix  and 


FlG.  477. — #-Ray  photograph  of  a  thymic  tumor.    The  growth  forms  a  pyramid  capping 

the  pericardium. 


Debert,  Simmonds,  and  others,  for  tumors  of  this  origin,  while  Schridde 
employs  the  phrase  "malignant  thymus  tumors." 

The  exact  origin  of  the  so-called  lymphosarcomas  of  the  thymus  remains 
undetermined.  My  own  study  of  several  cases  has  led  to  the  conclusion 
that  the  thymic  round-cell  tumors  differ  from  round-cell  tumors  of  lymph- 
nodes,  that  the  reticulum  cell  is  here  the  chief  or  sole  source  of  the  tumor,  the 
lymphocytes  being  largely  passive,  that  many  of  these  tumors  seem  to  fall 
in  the  class  of  granuloma  malignum.  The  term  "thymoma"  may  perhaps  de- 
serve recognition  as  a  parallel  to  lymphoma. 

(i)  Lyrnpho sarcoma  or  thymoma  is  the  most  frequent  form  of  thymus 
tumor.  The  tumors  occupy  the  anterior  mediastinum  in  the  position  of  the 
thymus,  and  usually  extend  from  the  sternal  notch,  or  as  high  as  the  thyroid, 


918  NEOPLASTIC  DISEASES 

down  to  the  diaphragm.  Many  authors  have  questioned  the  diagnosis  of 
thymic  origin  based  on  the  location  of  the  tumor,  but  the  objections  seem  to 
apply  chiefly  to  clinical  diagnosis.  There  is  little  difficulty  in  distinguishing 
thymic  tumors  at  autopsy  from  tumors  of  mediastinal  lymph-nodes,  lung,  or 
sternum.  They  usually  surround  and  compress  the  trachea,  bronchi,  peri- 
cardium, and  great  vessels.  Both  by  compression  and  less  often  by  invasion 
of  vessels  and  air  passages  they  cause  death  by  asphyxia  and  venous  obstruc- 
tion, which  may  increase  gradually  or  supervene  suddenly.  The  more  rapidly 
growing  tumors  are  soft,  but  as  a  rule  they  are  found  to  be  remarkably  dense 
from  diffuse  fibrosis.  The  soft  tumors  may  be  vascular  and  hemorrhagic, 
while  the  firm  growths  exhibit  a  characteristic  lobulation  from  dense  fibrous 
septa.  Rarely  areas  of  softening  and  cyst  formation  are  observed.  In 
many  cases  the  tumors  exhibit  a  characteristic  creamy  yellow  or  lemon 
color. 


FIG.  478. — Malignant  thymoma;  extensions  to  axillae,  neck,  pharynx,  and  orbit. 

A  strict  encapsulation  within  the  mediastinum  has  been  a  notable  feature 
in  some  histologically  malignant  growths,  but  the  more  malignant  forms 
regularly  become  adherent  to  surrounding  organs,  and  invade  pleura, 
lung,  pericardium,  walls  or  lumina  of  vessels,  and  trachea.  The  bronchial 
and  cervical  nodes  are  frequently  invaded.  The  axillary  nodes  may  early 
be  enlarged  and  in  Gabcke's  case  the  invasion  of  nodes  was  very  wide-spread. 
Tumors  of  the  axillary  nodes  without  known  origin  should  call  for  the  in- 
vestigation of  the  thymus  by  the  #-ray,  especially  before  any  operation  is 
attempted  on  the  axilla.  Occasionally  there  are  metastases  in  the  organs, 
spleen,  liver,  adrenal,  pancreas,  and  kidney  (Zniniewicz).  Perforation  of  the 
chest  wall  has  occurred  in  several  cases  and  was  the  first  localizing  symptom 
in  a  case  I  have  recently  observed  (Seebohm,  Zniniewicz,  Le  Tulle).  Fracture 


THE  THYMUS  AND  ITS  TUMORS 


919 


of  the  humerus  from  bone-marrow  metastases  is  recorded  by  Zniniewicz,  and 
infiltration  of  the  orbits,  brain,  and  other  organs  by  Meigs  and  de  Schweinitz. 
The  structure  of  these  tumors  varies  greatly.  Exactly  the  same  diffi- 
culties are  encountered  in  their  histological  classification  as  one  meets  with 
tumors  of  lymph-nodes.  In  one  group  the  structure  resembles  that  of  an 
infectious  granuloma  of  the  type  of  Hodgkin's  disease.  The  tissue  presents 
lymphocytes,  plasma-cells,  and  larger  polyhedral  cells  irregularly  distributed. 
Several  cases  of  this  type  have  been  recorded,  with  emphasis  on  the  presence 
of  many  large  polyhedral  or  giant-cells  (Ertmann,  Weigert,  and  Laquer). 
These  large  cells  must  be  derived  from  the  reticulum.  When  they  become 
very  numerous  the  lymphocytes  largely  disappear  and  the  tumor  may  be 
classed  as  a  carcinoma,  as  has  commonly  been  done  by  French  writers  (Le 
Tulle).  In  another  group  the  reticulum  cells  are  said  to  be  missing  and  the 


FIG.  479. — Malignant  thymic  tumor  composed  of  large  round  polyhedral  and  columnar 

cells. 

tumor  is  composed  of  a  diffuse  growth  of  small  round  cells  (Le  Tulle,  Stock- 
art).  These  tumors  have  not  been  distinguished  from  other  lymphosarco- 
mas,  but  it  does  not  appear  that  any  definite  effort  has  been  made  to  do  so. 
The  existence  of* a  pure  lymphocytoma  of  the  thymus  apart  from  leukemia 
does  not  appear  to  have  been  established. 

The  blood-vessels  may  be  very  numerous  and  in  some  cases  cells  of 
medium  size  may  form  sheaths  about  the  vessels.  When  the  perivascular 
arrangement  becomes  very  marked  and  lymphocytes  are  scanty  the  diagno- 
sis of  endothelioma  or  perithelioma  may  be  suggested,  as  in  the  cases  of 
Hahn  and  Thomas  and  Mandelbaum  and  Celler. 

It  seems  highly  probable  that  these  cells  arise  from  the  reticulum,  pro- 
ducing an  analogue  of  perivascular  endothelioma  of  the  lymph-nodes.  In 


920 


NEOPLASTIC  DISEASES 


the  same  manner  may  be  explained  the  mixed  tumors  described  by  Gabcke 
and  Schneider,  who  found  round  and  spindle-  and  many  giant-cells  in  their 
tumors,  all  of  which  may  readily  be  derived  from  the  reticulum. 

On  close  analysis  the  round-cell  tumors  of  the  thymus  are  found  to  differ 
in  structure  from  the  round-cell  tumors  of  lymph-nodes.  The  lymphocytes 
are  scanty.  The  chief  cell  showing  mitosis  is  often  polyhedral,  with  acido- 
phile  cytoplasm,  vesicular  nucleus,  and  well-developed  nucleoli.  They  often 
cling  to  the  walls  of  numerous  small  capillaries  where  they  assume  a  cubical 
or  even  cylindrical  form.  They  may  produce  abortive  Hassall's  corpuscles. 
The  giant-cells  are  of  two  main  types:  (i)  pale  staining  reticulum  cells  with 
irregular  outlines,  distended  with  vacuoles  and  red  cell  detritus,  and  (2) 


FlG.  480. — Portion  of  thymoma  perforating  sternum.    Note  the  many  peculiar  giant-cells. 


myeloid  giant-cells  with  opaque  acidophile  cytoplasm  and  many  vesicular 
nuclei.  These  giant-cells  differ  from  the  smaller  giant-cells  of  lymphatic 
Hodgkin's  disease.  The  marked  fibrosis  suggests  the  desmoplastic  property 
of  carcinoma.  In  a  report  of  3  cases  I  have  described  these  and  other  struc- 
tural features  in  detail. 

(2)  Thymic  Carcinoma. — In  many  cases  the  main  tumor-cell  appears  in 
the  form  of  pavement,  cubical,  or  rarely  cylindrical  epithelium  and  the  growth 
must  be  classed  as  carcinoma. 

The  gross  anatomy  of  thymic  carcinoma  is  identical  with  that  of  the  hard 
thymomas  of  round-cell  type.  Although  metastases  may  occur,  it  is  notable 
that  the  invasion  of  surrounding  organs  is  less  active  than  is  usual  with  a 
distinctly  carcinomatous  tumor.  An  aberrant  thymic  carcinoma,  containing 


THE  THYMUS  AND  ITS  TUMORS 


921 


lymphoid  tissue  and  numerous  bodies  resembling  Hassall's  corpuscles,  was 
observed  in  the  thyroid  by  Achard  and  Paisseau. 

The  structure  in  typical  cases  presents  coherent  sheets,  cords,  and  columns 
of  large  flat  or  polyhedral  cells  lying  in  dense  connective  tissue.  Hornifica- 
tion  is  absent,  but  concentric  layers  of  flat  cells  may  form  structures  resem- 
bling Hassall's  corpuscles  (Thiroloix,  Debret,  Paviot-Gerest).  In  other  cases 
the  pavement  characters  are  less  evident  and  the  cells  are  chiefly  cubical 
and  form  alveoli.  Le  Tulle  and  Ambrosini  found  accumulation  of  mucus 
in  the  spaces  of  an  alveolar  carcinoma.  In  many  cases  both  round  cells  and 
epithelium  participate  in  the  tumor  process,  and  the  authors  speak  of  the 
growth  as  carcinosarcoma  or  adenosarcoma.  Thus  in  Rubaschow's  case 


FIG.  481. — Thymoma.     Duration  3  years.     Structure  resembling  Hassall's  corpuscles. 


the  main  mass  was  composed  of  round  cells,  in  which  lay  many  foci  of  flat 
epithelium  forming  pearls  or  surrounding  blood-vessels.  Giant-cells  of  a 
variety  of  forms  are  frequently  present. 

(3)  Thymic  Sarcoma.— Although  it  has  been  commonly  assumed  that 
various  spindle-cell  or  alveolar  or  perivascular  tumors  arise  from  the  connec- 
tive-tissue stroma  of  the  thymus,  this  origin  has  never  been  fully  traced  and 
there  are  strong  grounds  for  concluding  that  the  so-called  spindle-cell  sarco- 
mas and  endotheliomas  are  varieties  of  thymoma.  Congenital  myxoma,  10 
X  8  cm.  hi  dimensions,  weighing  182  gm.,  containing  lymphocytes  and  Has- 
salPs  corpuscles  in  the  tumor  tissue,  was  observed  by  Caso  in  an  infant  of 
2^  months,  and  a  similar  case  is  described  by  Winogradoff. 


922 


NEOPLASTIC  DISEASES 


Interpretation  of  Thymomas. — The  foregoing  review  of  the  structure  of 
thymus  tumors  reveals  extreme  confusion  in  the  nomenclature  employed  by 
different  authors,  great  difficulty  in  establishing  sharply  denned  varieties 
and  the  existence  of  transitional  forms  connecting  the  two  types.  The  great 
polymorphism  of  the  cells  noted  by  Ambrosini  has  been  emphasized  by  later 
writers  as  the  chief  characteristic  of  thymic  neoplasms  and  has  led  to  the 
use  of  the  term  "thymoma." 

It  is  significant  that  the  carcinomas  have  been  recorded  almost  entirely 
by  French  observers,  while  practically  all  the  German  reports  are  of  sarcoma. 
Yet  Le  Tulle  and  Ambrosini  describe  as  carcinoma  tumors  which  have  many 
of  the  features  which  Ertmann  and  Zniniewicz  have  designated  as  sarcoma. 
It  is  also  clear,  as  in  Dansac's,  Mauser's,  and  Rubaschow's  cases,  that  many 
tumors  present  an  overgrowth  of  both  reticulum  and  parenchyma  cells.  A 


FlG.  482. — Thymoma  of  granulomatous  type.     Proliferation  of  large  reticulum  cells, 

scanty  lymphocytes. 

full  survey  of  the  structural  variations  reveals  at  one  extreme  a  mixed  process 
involving  lymphocytes  and  reticulum  cells,  with  giant,  plasma,  and  eosino- 
phile  cells,  producing  a  structure  nearly  identical  with  Hodgkin's  granuloma. 
At  the  other  extreme  are  nearly  pure  tumors  of  rounded  or  polyhedral 
reticulum  cells,  i.  e.,  lymphosarcoma  and  carcinoma.  Exactly  similar  rela- 
tions exist  between  tumors  of  lymph-nodes,  including  Hodgkin's  granuloma 
and  the  "sarcomas"  arising  from  it,  pseudoleukemia,  and  pure  endothelioma. 
Hence  the  conclusion  is  reached  that  the  great  majority  of  thymus  tumors 
and  especially  the  mixed  growths,  represent  infectious  granulomas  or  particu- 
lar forms  of  cell  overgrowth  arising  on  the  basis  of  an  infectious  granuloma. 
Detailed  evidence  supporting  this  conclusion  is  presented  in  the  writer's 
study  of  endothelioma  of  lymph-nodes.  This  etiological  point  of  view  offers  a 


THE  THYMUS  AND  ITS  TUMORS  923 

simple  explanation  of  the  great  variety  of  structural  forms  which  thymus 
tumors  present. 

In  a  series  of  cases  of  Hodgkin's  granuloma  the  granulomatous  process 
has  shown  malignant  properties  both  in  local  aggressiveness  and  in  the  pro- 
duction of  metastases.  Such  cases  are  recorded  by  Yamasaki,  Chiari,  J.  E. 
Welch,  Symmers,  Karsner,  and  Beitzke.  In  most  of  these  cases  it  is  stated 
that  the  main  tumor  was  mediastinal  and  occupied  the  region  of  the  thymus, 
while  the  structure  presented  a  diffuse  growth  of  cells  larger  than  lympho- 
cytes and  many  giant-cells  of  myeloid  type.  In  the  report  of  Symmer's 
case,  studied  in  this  laboratory,  a  thymic  origin  was  suggested.  I  have  re- 
examined  various  portions  of  this  tumor  and  find  in  it  all  the  features  of 
thymoma,  including  HassalPs  corpuscles,  polyhedral  reticulum  cells,  and 
myeloid  giant-cells.  In  the  light  of  this  and  other  cases  it  seems  highly  prob- 
able that  the  mediastinal  Hodgkin's  disease  of  the  above  writers  is  a  thy- 
mic tumor  which  should  be  separated  from  other  forms  of  Hodgkin's  disease 
and  owes  its  malignancy  to  its  origin  from  the  peculiar  reticulum  cells  of  the 
thymus. 

Clinical  Course. — Many  thymus  tumors  are  highly  malignant  and  prove 
rapidly  fatal  from  asphyxia,  but  the  actual  duration  is  difficult  to  determine. 
Ambrosini's  5  cases  were  all  fatal  in  from  2  to  9  months.  The  very  rapidly 
growing  tumors  are  usually  very  cellular  and  vascular.  In  i  of  Zniniewicz's 
cases,  lasting  10  weeks,  there  were  general  metastases,  while  in  Ambrosini's 
case  of  2  months'  duration  the  extensions  were  local.  Ertmann's  tumor 
of  2  months'  course  was  vascular,  contained  .very  large  polyhedral  cells, 
areas  of  perivascular  growth  and  collections  of  colloid,  but  metastases  were 
limited  to  the  pleura.  The  tumor  described  by  Hahn  and  Thomas  reached 
dimensions  of  26  X  18  X  9  cm.  in  i  year. 

Constitutional  symptoms  suggesting  a  sympathetic  disturbance  of  the 
chromaffin  system  are  not  observed,  but  Gabcke  records  for  his  case  that  the 
adrenals  were  very  large  and  the  skin  pigmented. 

In  a  notable  group  of  cases  thymic  tumor  has  been  associated  with 
myasthenia  gravis  (Oppenheim,  Weigert  and  Laquer,  Buzzard).  Of  45 
cases  of  myasthenia  gravis,  Mandelbaum  and  Celler  found  thymus  lesions 
recorded  in  n.  The  thymic  tumor  has  usually  shown  the  structure  of  lympho- 
sarcoma  mingled  with  epithelioid  cells.  In  Hun's  case  the  epithelioid  cells 
were  abundant,  but  showed  no  tendency  to  form  Hassall's  corpuscles,  while 
plasma-cells,  eosinophile  cells,  and  focal  hemorrhages  are  often  present. 
Mandelbaum  and  Celler  found  a  tumor  composed  of  small  concentric  groups 
of  polyhedral  cells,  while  the  numerous  vessels  were  sheathed  with  lympho- 
cytes and  surrounded  by  tumor-cells.  The  tumors  are  usually  of  moderate 
size,  and  in  several  cases  the  lesion  was  regarded  as  simple  hyperplasia  (Link, 
Burr,  Buzzard). 

Throughout  the  skeletal  muscles  and  often  in  the  organs  are  found  foci 
of  lymphocytes  with  varying  numbers  of  polynuclear  leukocytes,  and  eosino- 
phile, plasma,  or  epithelioid  cells.  Weigert  and  Laquer  regarded  these  lesions 
as  metastatic  foci,  while  others  consider  them  as  of  local  inflammatory  origin. 
Their  occurrence  favors  the  view  that  many  thymic  tumors  are  manifesta- 
tions of  an  infectious  granuloma. 


CHAPTER  XLVII 
TUMORS  OF  THE  HYPOPHYSIS 

Because  of  the  remarkable  clinical  phenomena  with  which  they  are 
associated,  uncertainty  regarding  the  origin  and  nature  of  the  processes 
concerned,  and  the  peculiar  problems  involved  in  their  diagnosis  and  treat- 
ment, tumors  of  the  hypophysis  form  one  of  the  most  interesting  of  all  groups 
of  neoplasms. 

The  history  of  our  knowledge  of  pituitary  enlargements  begins  with 
isolated  anatomical  reports  dating  from  1700  (Bonnetus)  and  1705  (Vieus- 
sens)  and  continuing  until  1886,  during  which  period  tumors  discovered  at 
autopsy  were  known  to  have  caused  chiefly  cerebral  pressure  symptoms.  In 
1886  Marie  initiated  a  second  period  of  more  minute  clinical  study,  by  pointing 
out  the  essential  connection  between  pituitary  tumors  and  acromegaly, 
while,  later,  gigantism  was  included  among  the  clinical  phenomena  by 
Cunningham,  Tamburini,  Brissaud  and  Meige,  and  Launois  and  Roy. 

Although  the  association  of  obesity  with  hypophyseal  tumors  was  noted 
as  early  as  1840  by  Mohr,  and  hypoplasia  of  the  genital  organs  as  well 
as  obesity  were  described  by  Pechkranz,  the  considerable  frequency  of  this 
association  was  first  emphasized  by  Froelich,  1901,  and  by  Bartels  and  Gush- 
ing, 1906.  The  modern  period  of  elaboration  of  the  clinical  features  may  be 
said  to  date  from  these  observations  which  have  led  directly  to  more  accurate 
diagnostic  methods  especially  by  the  x-ray  and  to  the  development  of  physical 
and  surgical  treatment.  Gushing  especially  has  demonstrated  that  the  natural 
history  of  primary  hypophyseal  disease  passes  through  an  initial  period  of 
overactivity  of  the  gland  with  acromegaly,  into  a  later  status  of  underactivity 
with  adiposogenital  dystrophy. 

The  use  of  the  x-ray  introduced  by  Beclere  (1902)  greatly  facilitated 
the  diagnosis  and  clinical  study  of  the  tumors,  and  this  agent  was  successfully 
employed  in  treatment  by  Gramegna  and  Beclere  in  1909.  Hypophysectomy 
was  first  performed  by  Horsley,  Schloffer,  and  v.  Eiselsberg  in  1907,  and 
successful  results  were  soon  reported  by  Hochenegg,  Hirsch,  Gushing,  Lecene, 
and  others.  Minute  histological  studies  were  contributed  by  Benda  (1900  to 
1904),  Erdheim  (1904  to  1910),  Lowenstein,  1907,  Gushing,  Lewis,  and  many 
others,  and  considerable  success  has  followed  the  attempt  to  attach  the  various 
syndromes  to  different  types  and  locations  of  the  tumors.  The  discovery  of 
accessory  pharyngeal  pituitary  tissue  by  Haberfeld  served  to  elucidate 
some  problems,  while  complicating  others.  The  obscurity  surrounding  the 
interrelations  of  the  ductless  glands  includes  the  functions  of  the  hypophysis 
and  its  influence  on  glycosuria,  polyuria,  and  many  other  disturbances  of 
internal  secretions,  and  most  of  these  questions  still  await  final  answer.  This 
phase  of  the  subject  is  at  present  being  rather  actively  pursued. 

General  Etiology. — Tumors  conveniently  regarded  as  hypophyseal  are 
relatively  uncommon  and  many  of  the  recorded  cases  must  be  interpreted 
as  simple  hyperplasia.  Nevertheless  the  series  of  cases  now  available  for 
statistical  study  is  numerous.  Collarit  in  1905  collected  52  cases  without 
acromegaly  or  glycosuria.  Creuzfeld,  1908,  in  60  autopsies  on  cases  of 
acromegaly,  reported  47  hypophyseal  tumors  and  collected  55  tumors  with- 
out acromegaly.  Eleven  tumors  were  associated  with  gigantism.  Frankl- 
Hochwart,  1909,  collected  85  cases  of  various  types  of  tumors.  Strada,  1911, 

924 


V 


TUMORS  OF  THE  HYPOPHYSIS  925 

collected  33  cases  of  tumor  without  acromegaly,  but  with  obesity  and  genital 
hypoplasia. 

Among  3620  autopsies  at  Prague  4  hypophyseal  tumors  were  found 
by  Klebs,  while  Boyce  and  Beadles  collected  6  tumors  in  3000  autopsies. 

Owing  to  the  uncertainties  of  histological  diagnosis  the  relative  frequency 
of  the  different  types  of  tumors  cannot  be  accurately  estimated.  Epithelial 
neoplasms  of  the  anterior  lobe,  with  much  excess  of  eosinophile  or  chromo- 
phobe  cells  and  associated  with  acromegaly,  are  the  most  common.  Of  47 
such  cases  Creuzfeld  found  15  described  as  sarcoma,  to  which  he  added  one 
glioma  of  the  posterior  lobe.  On  the  other  hand,  this  author  collected  55 
cases  without  acromegaly,  of  which  15  were  designated  as  sarcoma,  18  as 
glandular,  19  as  squamous-cell  growths,  one  teratoma,  and  one  lipoma  of 
the  posterior  lobe.  Frankl-Hochwart's  series  contained  12  carcinomas  (7 
squamous);  22  glandular  (13  adenomas);  27  sarcomas;  15  cysts,  3  gliomas,  and 
2  teratomas.  Of  Strada's  31  cases  with  obesity  and  genital  hypoplasia  2 
were  described  as  simple  struma,  5  as  adenoma,  5  as  carcinoma,  10  as  acan- 
thoma  of  infundibulum,  and  9  as  sarcoma.  It  is  probable  that  all  the  sarco- 
mas were  really  epithelial  tumors.  Gushing  reports  about  29  hypophyseal 
tumors  examined  microscopically  with  analyses  of  symptoms  and  refers  to 
148  cases  of  hypophyseal  disease  observed  clinically. 

An  hereditary  element  appears  distinctly  in  certain  cases  of  gigantism 
which  has  affected  several  members  of  the  same  family  (Gushing,  Case  31, 
de  Neuville).  Cerebral  trauma  occurred  in  6  of  Cushing's  cases  of  hypo- 
pituitarism,  in  5  of  which  there  was  an  interpeduncular  tumor.  The  marked 
functional  hyperplasia  of  pregnancy  appears  to  have  led  to  progressive  changes 
with  acromegaly  and  secondary  hypopituitarism.  Lowenstein  and  Erdheim 
found  several  definite  adenomas  in  the  glands  following  pregnancy.  Ascenzi 
observed  acromegaly  develop  after  ten  rather  rapidly  succeeding  gestations, 
the  hypophysis  containing  a  large  cystadenoma.  Occasionally  acromegaly 
has  followed  attacks  of  pulmonary  tuberculosis,  typhoid  fever,  or  pneumonia 
(Massedaglia,  Gushing). 

Acromegaly  has  been  referred  to  severe  fright  by  Ingermann  and  Poin- 
decker  and  has  followed  ovariotomy  in  reports  of  Strumpell  and  Goldstein. 

Anatomy  of  the  Hypophysis. — The  normal  anatomy  of  the  hypophysis  is  complex  and 
several  embryological  and  histological  features  are  of  prime  importance  in  tracing  the 
origin  of  tumors  of  this  organ.  The  weight  of  the  hypophysis  from  the  third  to  seventh 
decade  averages  61.2  gm.,  and  its  size  21.5  X  14.4  X  5.5  mm.  Variations  in  weight 
from  30  to  75  gm.  are  probably  normal  (Erdheim). 

The  organ  consists  of  (1)  an  anterior  glandular  lobe  which  is  developed  by  an  upward 
evagination  of  oral  ectoderm,  (2)  a  posterior  nervous  portion  which  is  an  elongated  por- 
tion of  nervous  tissue  derived  from  the  tuber  cinereum  at  the  floor  of  the  third  ventricle, 
and  (3)  a  stalk  or  pedicle  which  passes  through  the  arachnoid  and  connects  the  organ 
with  the  tuber  cinereum. 

(1)  The  anterior  lobe  or  pituitary  gland  proper,  is  partly  subdivided  into  two  lateral 
portions  by  constriction  of  the  encircling  posterior  lobe.  A  long  lingual  process  of  this 
lobe  encircles  the  stalk  as  a  glove  over  a  finger,  covering  the  anterior  surface  below  and 
completely  surrounding  it  above  and  almost  to  the  optic  chiasm.  A  cross-section  of  the 
stalk  therefore  presents  a  central  cavity,  the  prolongation  of  the  third  ventricle  (in- 
fundibulum), surrounded  by  a  zone  of  nervous  tissue  which  is  sheathed  in  turn  by  the 
lingual  process  of  the  anterior  lobe.  This  lingual  process  is  often  designated  as  pars 
intermedia.  The  lingual  process  often  contains  small  cysts,  and  Erdheim  showed  that 
it  very  frequently  contains  groups  of  squamous  epithelium,  remains  of  the  oral  ecto- 
derm, which  give  rise  to  tumors.  The  presence  of  such  epithelial  debris  had  previously 
been  described  by  Luschka,  Saxer,  and  Launois,  who  also  suggested  its  probable  rela- 
tion to  tumors  of  the  brain. 

The  anterior  lobe  is  separated  from  the  posterior  by  a  connective-tissue  septum  which 
usually  contains  a  multilocular  cleft,  the  remains  of  Rathke's  ectodermal  pouch.  About 
this  cleft  Erdheim  describes  the  remains  of  salivary  gland  alveoli. 


926 


NEOPLASTIC  DISEASES 


(2)  The  posterior  lobe  (pars  nervosa)  is  a  club-shaped  mass  of  glia-tissue  which  de- 
scends from  the  stalk  and  partly  surrounds  and  constricts  the  anterior  lobe.  It  is  largely 
surrounded  by  a  thin  sheathing  of  neutrophile  epithelium  merging  with  a  similar  sheath- 
ing of  the  stalk,  and  continuous  with  the  epithelium  of  the  anterior  lobe  from  which  it 
is  derived.  The  glia-cells  contain  variable  amounts  of  insoluble  pigment  which  is  probably 
derived  from  the  wandering  cells  of  the  anterior  lobe  or  pars  intermedia  (Kohn,  Vogel)  . 


FIG.  483. — Median  sagittal  section  through  pituitary  of  monkey;  semidiagrammatic. 
(Herring.}  a,  Optic  chiasma,  b,  third  ventricle;  c,  g,  pars  intermedia;  d,  epithelium  of 
pars  intermedia  extending  round  neck  of  pars  nervosa;  e,  pars  glandularis  seu  epithelialis; 
/,  intraglandular  cleft,  lying  between  pars  glandularis  (e)  and  pars  intermedia  (g) ;  ht 
pars  nervosa. 


FIG.  484. — Salivary  gland  alveoli  in  the  neighborhood  of  Rathke's  cyst  between 
anterior  and  posterior  lobes  of  hypophysis.  They  give  rise  to  cysts  of  the  hypophysis. 
(After  Erdheim.) 

The  pars  intermedia  is  all  that  sheath  of  epithelium  which  surrounds  the  posterior  lobe 
and  stalk,  including  the  lingual  process.  Its  peculiar  relations  to  the  inclosed  nervous 
tissue  render  it  of  much  physiological  interest.  Its  epithelial  cells  exhibit  evidences  of 
secretion,  in  the  form  of  many  colloid  globules  which  collect  in  round  masses  between  the 
cells  and  have  been  traced  apparently  passing  through  the  pars  nervosa  into  the  infun- 
dibulum  and  thence  to  the  third  ventricle  and  cerebrospinal  fluid  (Herring,  Gushing, 
Goetsch). 


TUMORS  OF  THE  HYPOPHYSIS 


927 


(3)  The  stalk  or  pedicle  connects  the  organ  with  the  tuber  cinereum,  passing  through 
the  dural  septum  and  arachnoid.  It  contains  a  central  cavity,  infundibulum,  which  is 
the  downward  prolongation  of  the  third  ventricle,  surrounded  by  a  mass  of  nerve  tissue 
which  enlarges  below  to  form  the  pars  nervosa,  while  externally  it  is  sheathed  by  the 
lingual  process  of  the  anterior  lobe. 

The  whole  organ  is  enclosed  in  a  dural  capsule  which  has  an  upper  diaphragm  stretch- 
ing from  the  four  clinoid  processes  and  is  perforated  by  the  pedicle.  Pressure  of  an  en- 
larging gland  is  therefore  slightly  limited  above  and  laterally,  while  below  there  is  bony 
resistance. 

The  blood-supply  of  the  posterior  lobe  is  derived  from  one  of  three  slender  vessels 
entering  below  from  the  internal  carotid,  while  the  vessels  of  the  anterior  lobe  pass 
down  the  stalk.  Sympathetic  nerve-fibers  also  pass  down  the  stalk  (Dandy). 

Accessory  Pituitary  Glandules.— Rathke's  pouch,  which  is  the  remnant  of  the  oral 
ectodermal  evagination,  does  not  always  undergo  complete  involution,  but  regularly  in 
some  lower  animals,  and  occasionally  in  man,  it  persists  and  gives  rise  to  accessory  gland- 


FIG.  485. — Topography  of  dog's  hypophysis.    AL,  Anterior  lobe.    Note  hyaline  material 
in  epithelial  investment  of  pars  nervosa.     (After  Gushing.) 

ules.  These  were  first  observed  by  Erdheim  in  the  pharyngeal  mucosa  and  later  by  Arai 
and  Civalleri.  Haberfeld  in  51  human  subjects  of  various  ages  regularly  found  a  thin 
glandular  strand,  3  to  9  mm.  in  length,  5  to  S|  mm.  in  breadth,  in  the  pharyngeal  sub- 
mucosa  just  behind  the  alae  of  the  vomer,  and  extending  inward  to  the  base  of  the  skull. 
These  glandules  are  composed  chiefly  of  chromophobe  cells,  but  acidophile  cells  are  com- 
monly present  and  flat  epithelium  may  be  observed  at  the  lower  pole.  Dandy  and 
Goetsch  found  similar  glandules  in  a  central  pit  in  the  sellar  floor  of  dogs.  Erdheim  has 
described  an  intra-osseous  tumor  of  acidophile  cells,  with  acromegaly,  which  probably 
arose  from  such  an  accessory  glandule,  and  he  derives  certain  squamous-cell  tumors 
from  this  same  source.  Distinct  heterotopia  of  the  entire  pituitary  body  below  the  sella 
has  been  reported  (Haberfeld,  Lit.). 

Histology. — The  structure  of  the  pituitary  body  is  subject  to  wide  variations  which 
are  of  much  significance  in  the  interpretation  of  functional  changes  and  neoplasms  of 
this  organ. 

The  normal  gland  contains  two  main  classes  of  cells,  chromophile  and  chromophobe 


928 


N  EOF  LAST  1C  DISEASES 


(Flesch).  A  third  cell  type  is  chromophobic  or  neutrophile.  The  chromophile  cells  are 
either  (a)  acidophile  or  (0)  basophile,  by  virtue  of  the  microchemical  reactions  of  their 
abundant  granules  (Schoneman).  The  acidophile  cells  are  usually  more  numerous  along 
the  central  sinuses,  while  the  basophiles  occupy  the  periphery  and  anterior  portion  of  the 
lobe.  It  is  not  yet  clear  whether  the  two  types  are  distinct  or  represent  different  func- 
tional phases  of  the  same  cell  order.  Benda  and  others  accept  the  former  view,  while 
Erdheim  supports  the  la.tter.  The  acidophile  granules  after  fixation  in  Miiller-formol 
stain  deeply  with  eosin,  black  with  Heidenhain's  hematoxylon,  deep  red  by  Mallory's 
stain,  and  usually  decolorize  in  Gram's  stain.  These  cells  are  normally  the  most  abun- 
dant of  the  three  types.  The  basophilic  cells  are  less  numerous,  but  larger  than  the 
acidophiles,  and  the  large  granules  stain  deep  blue  by  Mallpry  or  Gram,  violet  with 
hematoxylon,  and  are  decolorized  by  complete  differentiation  in  iron  hematoxylon. 
The  nuclei  are  large  and  pale. 

The  chromophobe  cells  are  the  least  numerous  of  the  cell  types,  and  the  smallest. 
The  cytoplasm  is  scanty  and  the  nuclei  are  relatively  compact.  They  often  appear  in 
groups  resembling  acini,  and  surrounded  by  chromophile  cells. 

In  the  pars  intermedia  the  cells  lie  in  small  groups  surrounded  by  connective  tissue. 
Often  they  form  alveoli  of  cubical  or  cylindrical  cells  surrounding  colloid  globules,  and 


Cc 


FIG.  486. — Normal  hypophysis  of  a  subject  of  37  years.  Stain,  hematoxylon  and 
eosin.  E,  Eosinophile  cells,  large  and  small;  B,  basophile  cells,  large  and  granular;  Cc, 
chief  cells,  small  with  little  cytoplasm.  (After  Erdheim  and  Stumme.} 

they  have  a  close  relation  to  the  blood-vessels.  The  cytoplasm  is  clear,  chromophobic, 
and  lacking  in  specific  granules  (Lewis).  Numerous  special  methods  for  the  demon- 
stration of  cell  granules  have  been  recommended,  but  none  -appears  to  have  an  essential 
advantage  over  fixation  in  Miiller-formol  and  staining  by  hematoxylon  and  eosin.  For 
demonstration  of  basophilic  granules  Erdheim  prefers  long  staining  in  kresofuchsin,  pre- 
ceded by  lithium  carmine  as  a  nuclear  stain.  Many  prefer  Zenker  fixation 

Functional  changes  in  the  pituitary  gland  are  frequent  and  so  pronounced 
as  often  to  simulate  neoplasms.  The  range  of  alterations  associated  with 
disturbed  function  is  even  greater  than  occurs  in  the  thyroid  gland,  and  it  is 
probable  that  true  tumors  develop  on  the  bases  of  functional  hyperplasia. 
Probably  the  most  marked  series  of  changes  occurs  in  gestation,  in  which 
extensive  and  specific  hyperplasia  has  been  described  by  Comte,  Launois  and 
Mulon,  Erdheim,  and  others.  According  to  Erdheim,  hyperplasia  begins  early 
in  the  first  gestation,  reaches  its  height  at  term,  persists  several  weeks  or 
months  after  parturition,  and  is  more  pronounced  in  succeeding  pregnancies. 


TUMORS  OF  THE  HYPOPHYSIS 


929 


The  size  of  the  normal  hypophysis  averages  61.2  gm.  in  adults,  but  reaches  an 
average  size  of  84.7  gm.  in  primiparse,  and  106  gm.  in  multipart.  The  hyper- 
plasia  affects  only  the  chief  or  chromophobe  cells  which  greatly  increase 
in  size  and  number,  becoming  more  abundant  than  the  chromophiles.  The 
cytoplasm  contains  many  fine  granules  staining  slightly  with  Heidenhain's 
hematoxylon.  These  cells  multiply  by  mitosis,  form  large  solid  groups, 
and  displace  the  chromophile  elements.  In  10  per  cent,  of  the  cases  the 
specific  cells  of  pregnancy  form  single  or  multiple  focal  adenomas  i  to  4  mm. 
in  diameter,  free  from  fat  globules,  but  without  marked  variation  from  the 
normal  type  and  without  encapsulation.  They  probably  regress  after  the 
puerperium  and  are  not  true  tumors.  Transitions  to  atypical  adenoma  of 
malignant  appearance  may  be  observed,  in  which  the  cords  are  narrow  or  very 
broad  or -present  a  peritheliomatous  arrangement,  but  the  clinical  course  of 
such  adenomas  cannot  be  predicted  from  their  structure.  In  4  cases  of  gesta- 
tion-hypertrophy Erdheim  saw  adenomas  of  chromophile  cells.  Pressure 


FlG.  487. — Structure  of  hypertrophied  hypophysis  of  a  recent  multipara.  The  cords 
are  composed  chiefly  of  the  hyperplastic  cells  of  gestation,  among  which  are  many  large 
basophile  cells.  The  eosinophiles  are  black.  Stained  by  Heidenhain's  hematoxylon. 

(After  Erdheim  and  Stumme.) 

symptoms,  as  hemianopsia,  may  apparently  result  from  the  hyperplasia  of 
gestation  (Reuss). 

Varying  grades  of  pituitary  hyperplasia  have  been  observed  in  infectious 
diseases.  Experimental  studies  of  the  effects  of  extirpation  or  ingestion 
of  the  substance  of  other  glands  of  internal  secretion  have  supported  the  view 
that  there  is  a  close  interdependence  of  all  these  glands,  but  the  exact  types 
of  pituitary  hyperplasia  produced  by  these  methods  still  remain  to  be  accu- 
rately defined. 

Gross  Anatomy  of  Hypophyseal  Tumors.- — The  several  portions  of  the 
hypophysis  each  give  origin  to  tumors  which  may  be  classified  accordingly  as: 

(1)  Tumors  of  the  pituitary  body; 

(2)  Tumors  of  the  hypophyseal  duct  and  its  derivatives; 

(3)  Tumors  of  the  pars  intermedia; 

(4)  Tumors  of  the  pars  nervosa. 

59 


930 


NEOPLASTIC  DISEASES 


i.  Tumors  of  the  pituitary  proper  include: 

(a)  Diffuse  hyperplasia  and  focal  adenoma; 

(£>)  Adenocarcinoma; 

(c)  Malignant  atypical  carcinoma  (sarcoma). 

(a)  Diffuse  hyperplasia  arising  from  functional  overgrowth  occurs  in 
most  advanced  form  after  multiple  pregnancies  when  the  gland  may  reach 
a  weight  of  165  gm.  (Erdheim).  The  growth  distends  the  dural  diaphragm, 
spreads  laterally,  may  produce  hernia  of  the  capsule  and  in  cases  with  some 
anatomical  predisposition  may  press  upon  the  optic  chiasm  with  hemianopsia. 
Considerable  widening  of  the  sella  may  exist  with  all  the  simple  hyperplasias. 
On  section  the  overgrowth  may  be  diffuse,  or  in  about  10  per  cent,  of  the  cases 
focal  adenomas  may  appear  as  opaque  spots  3  to  7  mm.  in  diameter. 

The  natural  course  of  these  hyperplasias  is  slow  regression,  but  some 
probably  pass  into  malignant  and  progressive  adenocarcinoma.  The  struc- 
ture presents  compact  groups  or  narrow  or  wide  cords  of  chromophobic  cells 
derived  from  the  chief  cells  of  the  gland. 


FIG.  488. — -Hypophyseal  adenoma  of  gestation.     (After  Erdheim.) 

In  many  cases  of  acromegaly  the  glandular  lesion  takes  the  form  of  a 
diffuse  hyperplasia  often  with  adenomas.  In  56  cases  of  acromegaly  Creuz- 
feld  found  12  glands  with  simple  hyperplasia,  8  designated  as  struma,  12  as 
adenoma,  15  as  sarcoma,  and  5  without  demonstrated  hypophyseal  lesions. 
There  is  thus  a  wide  variety  in  the  extent  of  the  glandular  lesion  associated 
with  acromegaly,  and  it  appears  that  this  disease  may  result  from  very  mod- 
erate hyperplasia  or  from  very  small  adenomas.  As  a  rule  the  changes  in 
acromegaly  pass  far  beyond  those  observed  in  gestation,  and  yet  in  many 
instances  the  hyperplasia  is  succeeded  by  regression  and  the  signs  of  over- 
activity  are  followed  by  glandular  insufficiency. 

Many  of  the  glandular  lesions  in  acromegaly  are  therefore  not  true  tumors, 
but  self -limiting  functional  hyperplasias.  The  structure  of  these  enlarged 
glands  often  presents  an  overgrowth  of  eosinophile  cells  which  are  increased 
in  size  and  number,  form  compact  masses  or  adenomatoid  accumulations 
and  displace  the  other  cell  types.  The  arrangement  of  the  cells  is  orderly 


TUMORS  OF  THE  HYPOPHYSIS 


931 


and  mitoses  are  rare.    While  the  gland  usually  remains  solid  and  firm,  small 
cysts  filled  with  colloid  may  develop  and  hemorrhages  may  occur. 

The  areas  of  eosinophile  cells  accord  with  the  view  that  the  overactivity 
of  the  gland  resides  in  these  cells.  Yet  many  of  the  moderately  enlarged 
glands  of  acromegaly  contain  not  acidophile  but  chromophobic  cells  (Gush- 
ing). Eosinophile  adenomas  are  observed  also  in  gestation. 


FIG.  489. — Miliary  basophile  adenoma  of  hypophysis.     (After  Erdheim.) 

Roussy  and  Clunet  describe  a  form  of  pathological  hyperplasia  occurring  in 
alcoholism,  nephritis,  Parkinson's  disease,  and  arteriosclerosis,  and  signifying 
a  reaction  to  the  failure  of  thyroid  function.  Hyperplasia  of, the  basophilic 
cells  with  the  production  of  small  adenomas  is  described  by  Erdheim,  who 
found  such  a  nodule  i^  mm.  in  diameter  in  the  anterior  lobe.  In  a  case  of 
acromegaly  he  found  both  eosinophile  and  basophile  adenomas  of  small  size. 


FIG.  490. — Detail  of  miliary  basophile  adenoma  of  hypophysis. 

(After  Erdheim.) 


Stain,  kresofuchsin. 


Nothdurft  describes  a  small  basophilic  adenoma  in  the  posterior  lobe.  In 
none  of  these  cases  does  it  appear  that  the  adenoma  was  responsible  for  any 
local  symptoms.  In  the  giant  acromegalic  subject  of  Huchard  and  Launois 
the  tumor  appeared  to  be  composed  chiefly  of  basophilic  cells.  A  malignant 
tumor  of  such  cells  has  not  yet  been  demonstrated,  although  Nagaeli  assumed 


932  NEOPLASTIC  DISEASES 

that  a  large  peritheliomatous  growth  composed  of  non-granular  cells  had 
such  an  origin.  Pick  describes  an  extensively  calcined  tumor  in  a  case  of 
adiposogenital  dystrophy  which  he  designated  as  basophile  adenoma  or 
adenocarcinoma. 

(6)  Adenocarcinoma. — True  adenoma  of  the  pituitary  may  be  difficult 
to  recognize  by  its  size  and  structure,  but  it  is  probable  that  true  neoplasms 
of  this  gland  are  always  atypical  in  structure  and  malignant.  In  a  consider- 
able group  of  cases  the  gland  exceeds  in  size  the  limits  of  simple  hyperplasia, 
the  structure  is  distinctly  atypical,  the  capsule  is  ruptured,  extension  beyond 
the  limits  of  the  sella  is  observed,  pressure  symptoms  are  marked,  and  the 
process  must  be  classed  as  malignant  adenoma  or  adenocarcinoma. 

The  size  of  these  tumors  varies  greatly,  but  they  regularly  distend  or 
rupture  the  dural  diaphragm,  they  widen  and  absorb  the  sella  so  that  the 
x-ray  shows  extensive  excavation,  the  clinoid  processes  are  often  destroyed 
and  the  basilar  portion  of  the  sphenoid  may  be  extensively  eroded.  Growing 
beyond  the  sella  the  tumor  compresses  the  optic  chiasm,  extends  along  the 


FIG.  491. — Cross-section  through  a  large  hypophyseal  adenoma. 

frontal  lobes,  and  penetrates  the  third  and  even  the  lateral  ventricles.  With 
reference  to  their  bony  relation  the  growths  may  be  described  as  intrasellar, 
with  uniform  widening  of  the  bony  wall,  or  as  extrasellar  when  the  clinoid 
processes  are  absorbed,  and  as  voluminous  when  tumors  absorb  much  of  the 
bone  and  extend  into  the  brain.  Usually  the  tumors  long  remain  solid,  but 
cysts  form  from  colloid  secretion,  hemorrhage,  and  necrosis.  In  one  group 
the  tumor  tends  to  become  cystic  from  the  first  and  many  areas  filled  with 
soft  colloid  material  are  traversed  by  thin  strands  of  epithelium,  or  well- 
marked  papillary  outgrowths  develop.  These  tumors  are  difficult  to  dis- 
tinguish from  papillary  epithelioma  of  the  ventricles,  but  their  location 
emanating  from  the  sella  is  usually  decisive.  While  the  majority  of  growths 
long  remain  encapsulated  and  preserve  the  general  form  of  the  organ,  exten- 
sion into  the  brain  is  often  accompanied  by  diffuse  invasion  of  this  tissue. 

In  advanced  cases  the  tumor  has  perforated  the  cavernous  sinus,  invaded 
frontal  and  temporal  lobes,  compressed  many  of  the  cranial  nerves,  and  ex- 
tended to  the  peduncles,  medulla,  and  even  to  the  cerebellum.  Pechkranz's 
tumor  penetrated  the  orbit,  and  Kruger's  large  round-cell  "sarcoma" 


TUMORS  OF  THE  HYPOPHYSIS 


933 


eroded  the  atlas  at  the  base  of  the  skull.  In  several  cases  the  growth  has 
communicated  with  the  superior  nares  and  produced  a  watery  or  bloody 
discharge  (S.  Ingermann,  O'Malley,  Sommer).  Access  to  the  ventricles 
may  be  accompanied  by  hydrocephalus. 

Metastases  occasionally  occur.  With  comparatively  typical  glandular 
tumors  Smoler  found  a  cerebellar  metastasis;  Stolpe  reports  a  large  secondary 
growth  in  the  occipital  lobe;  Bruns  saw  a  nodule  in  the  tongue;  Cagnetto 
describes  subpial  nodules  along  the  spinal  cord  from  a  colloid  adenocarcinoma 
in  a  remarkable  case  of  acromegaly. 

The  structure  of  the  pituitary  adenocarcinomas  varies  extensively.  Some 
resemble  the  adenomatoid  hyperplasia  with  solid  cords  or  compact  groups 
of  atypical  polygonal  epithelium.  These  tumors  are  of  moderate  malignancy, 


FlG.  492. — Hypophyseal  adenoma,  with  large  imperfectly  walled  blood  sinuses. 

and  while  most  of  the  cells  are  distinctly  chromophobic,  traces  of  the  chromo- 
phile  differentiation  may  at  times  be  detected.  Chiefly  acidophile  cells 
occurred  in  the  cases  of  Benda,  Tamburini,  Zak,  Alquier,  Presbeanu, 
Marinesco,  Cagnetto,  and  Erdheim  (1903  to  1904,  1909,  1910).  Gushing 
describes  most  of  his  cases  as  chromophobe  struma,  as  do  Carbone,  Lecene, 
Strada,  Krumbhaar,  and  others.  In  general  the  latter  group  is  more  dis- 
tinctly neoplastic. 

Other  tumors  are  more  atypical,  composed  strictly  of  chromophobic 
cells,  arranged  in  cords  or  groups,  or  often  forming  distinct  acini  in  which 
colloid  secretion  may  accumulate.  Excess  of  colloid  or  fluid  may  yield  soft 
cystic  .growths  in  which  a  papillary  structure  may  appear.  A  perivascular 
arrangement  of  cubical  or  cylindrical  cells  is  common  (Moskalew),  and  the 


934 


NEOPLASTIC  DISEASES 


numerous  blood-vessels  with  their  epithelial  sheaths  may  simulate  a  papillary 
adenoma  or  angiosarcoma.  Many  cellular  growths  fail  to  show  any  sub- 
division of  the  cells  into  groups  or  acini  and  the  structure  is  diffuse.  In  differ- 
ent portions  of  the  same  tumor  the  structure  may  vary  widely.  Thus  Launois 
and  Roy  and  Strada  describe  an  alveolar  structure  in  intrasellar  portions, 
and  a  diffuse  growth  in  extrasellar  areas  of  their  tumors.  Meyer  describes 
new  growth  of  nerve-cells  in  the  pars  nervosa  of  a  case  of  acromegaly  and 
diabetes  with  hypophyseal  tumor. 

(c)  Malignant  atypical  carcinoma  has  usually  been  reported  as  sarcoma, 
angiosarcoma,  myxosarcoma,  perithelioma  or  endothelioma,  and  a  consider- 
able proportion  of  pituitary  tumors  falls  in  this  class.  Of  243  tumors  col- 
lected by  Marie,  Creuzfeld,  Frankl-Hochwart,  and  Strada,  64,  or  26  per  cent., 
were  entered  as  sarcoma.  Since  the  demonstration  by  Benda  of  specific 
epithelial  cell  granules  in  the  cells  of  supposed  sarcomas  and  the  recognition 


r«r»l>»«i>>li.«  »*.  •  »v-i.  rr.»  *:•'  •»»»»»»^i>»i%T  >r*»-*^ 

FIG.  493. — Section  of  large  hypophyseal  adenocarcinoma. 

that  epithelial  growths  of  the  pituitary  very  readily  assume  various  atypical 
structures,  the  diagnosis  of  sarcoma  has  practically  disappeared  from  the 
literature.  With  very  rare  possible  exceptions  all  these  tumors  must  be 
classed  by  atypical  carcinomas.  Only  in  their  more  atypical  structure  do 
they  differ  from  malignant  adenocarcinoma. 

Angiosarcomas  are  described  by  Pechkranz,  Jakubowsky,  Kon,  and  others,  and  peri- 
thelioma by  Kon,  but  the  descriptions  strongly  recall  the  structure  of  vascular  pituitary 
adenocarcinomas.  Roth,  Beck,  and  others  described  spindle-  and  round-cell  sarcomas, 
but  the  data  are  inadequate  to  exclude  an  epithelial  origin.  In  many  cases  the  epithelium 
of  the  gland  merged  with  the  sarcoma,  so  that  the  author  was  in  doubt  as  to  the  nature 
of  the  growth,  and  employed  the  term  "adenosarcoma"  (Hippel,  O'Malley).  The  presence 
of  colloid  in  round-cell  tumors  sometimes  warns  against  the  diagnosis  of  sarcoma  (v. 
Bonin).  "Sarcomatous  struma"  was  the  term  applied  by  Hansemann  to  a  tumor  of  the 
pituitary  composed  of  large  ovoid  cells.  Benda,  whose  minute  studies  threw  many 
sarcomas  into  the  epithelial  class,  accepts  the  occurrence  of  true  sarcoma  of  the  hy- 
pophysis and  Ingerman's  case  in  particular.  This  was  an  actively  growing,  circumscribed, 
soft,  gelatinous  tumor  7  X  65  X  3  cm.,  producing  pressure  symptoms  and  obesity  in  a 


TUMORS  OF  THE  HYPOPHYSIS  935 

woman  of  35  years.  It  was  composed  of  closely  packed  cells  slightly  larger  than  lymph- 
ocytes, while  some  cells  were  polygonal  or  spindle.  Intercellular  substance  was  lacking. 
The  structure  resembled  pvervascular  splenic  pulp  and  a  perithelial  arrangement  was 
prominent.  This  description  varies  little  from  that  of  many  atypical  gland-cell  tumors. 
Caussade  and  Laubry  describe  a  nodular  growth,  3^  X  3  cm.,  involving  the  anterior 
lobe.  There  were  many  spindle-cells  arranged  in  whorls,  groups  of  polygonal  cells,  and 
some  acidophile  cells.  This  tumor  resembled  certain  duraj  endotheliomas,  but  its  exact 
nature  appears  uncertain.  Wolf  designates  as  sarcoma  cylindromatodes  a  structure  with 
hyaline  changes  in  the  vessels. 

Agostini  in  a  prolonged  case  of  dyspituitarism  with  mental  symptoms  described  a 
spindle-cell  melanotic  fibrosarcoma  with  ossification  of  the  capsule. 

Degenerative  changes  occur  in  the  advanced  simple  hyperplasias  and 
frequently  in  the  true  tumors.     Colloid  secretion  may  be  very  abundant, 


FIG.  494. — Hypophyseal  adenoma.     (After  Martins.) 

diffused  through  the  stroma,  and  lead  to  myxomatoid  softening.  From  this 
source  as  well  as  from  central  necrosis  and  hemorrhage  large  tumors  may  be 
converted  into  cysts  with  mucus  or  chocolate  colored  fluid.  Calcification 
appears  in  granules  in  and  between  cells,  in  the  blood-vessels,  and  diffusely 
(Pick).  In  Konjetzny's  cases  the  entire  tumor  was  calcine. 

2.  Tumors  of  the  Hypophyseal  Duct  and  its  Derivatives. — Owing  chiefly 
to  the  studies  of  Erdheim,  a  well-defined  group  of  hypophyseal  tumors  has 
been  traced  to  the  remnants  of  the  hypophyseal  duct.  These  growths  are 
usually  of  squamous  epithelial  type,  but  many  present  the  features  of  basal- 
cell  carcinoma,  and  it  is  probable  that  certain  mixed  tumors,  or  teratoids  of 
the  salivary  gland  type,  arise  from  epithelium  of  the  duct  or  from  salivary 
gland  acini  carried  along  with  the  oral  evagination.  The  distribution  of  these 
epithelial  derivatives  has  been  discussed  with  the  anatomy  of  the  hypophysis. 


936  NEOPLASTIC  DISEASES 

The  hypophysea'l  duct  tumors  arise  from  any  point  along  the  course  of 
this  embryonal  structure,  from  the  squamous  epithelial  nests  in  the  lingual 
lobe  from  the  chiasm  downward,  from  Rathke's  cyst  between  the  anteri6r  and 
posterior  lobes,  beneath  the  hypophysis  in  the  floor  of  the  sella  or  the  sphe- 
noidal  spaces,  and  in  the  wall  of  the  pharynx  at  the  entrance  of  the  duct. 

The  gross  form  of  these  tumors  presents  a  number  of  variations. 

(a)  Simple  cysts  develop  from  distentions  of  Rathke's  pouch.  They 
arise  between  the  anterior  and  posterior  lobes,  compress  both  portions,  and 
contain  serous  or  gelatinous  or  chocolate-colored  material.  According  to 
Erdheim  they  are  relatively  common  in  infants.  In  adults  they  may  reach 
a  considerable  size,  chiefly  by  distention  with  fluid  derived  from  the  salivary 
acini  in  their  walls.  Occasionally  they  may  rupture  or  the  walls  become  so 
richly  infiltrated  with  lymphocytes  as  to  resemble  a  lymph-node.  It  is  prob- 
able that  some  of  the  cysts  lined  by  ciliated  epithelium  are  derived  from  this 
source  (Weichselbaum). 

Cysts  are  believed  to  arise  from  separated  portions  of  the  infundibular 
extension  of  the  ventricular  cavity  into  the  nervous  portion  of  the  stalk. 


FIG.  495. — Relations  of  a  cystic  papillary  epidermoid  carcinoma  of  hypophyseal  duct. 

(After  Strada.) 

They  develop  above  the  hypophysis,  are  lined  by  ependymal,  rarely  ciliated, 
epithelium,  and  contain  serous  fluid.  From  them  may  possibly  develop  some 
of  the  papillary  tumors  of  ependymal  epithelium  (Saxer,  Hart,  Langer). 

Cystic  tumors  also  develop  from  distention  of  dermoids  and  other  tumors 
derived  from  the  hypophyseal  duct,  as  well  as  from  liquefaction  of  pituitary 
adenomas.  Some  cystic  tumors  of  Boyce  and  Beadles  appear  to  be  of  this 
type.  In  one  of  these  the  wall  was  partly  ossified  and  the  contents  inspissated. 

(b)  Epidermoid  carcinoma  is  the  most  frequent  type  of  tumor  derived 
from  the  hypophyseal  duct.  It  arises  from  the  remnants  of  oral  epithelium 
found  by  Erdheim  in  the  lingual  process  along  the  pedicle,  or  from  similar 
remnants  lying  between  the  lobes  (Launois).  That  the  ependymal  cells  of 
the  infundibulum  may  give  rise  to  squamous  epidermoid  carcinoma  remains 
unproved  and  appears  improbable,  although  many  papillary  tumors  of 
cylindrical  covered  by  flat  cells  have  been  referred  to  the  ependyma  or  cho- 
roid  plexus  (Fahr,  Selke,  Saxer,  Boudet,  Clunet).  It  appears  impossible 
to  determine  where  many  recorded  cases  really  belong,  and  quite  likely  that 
too  many  have  been  referred  to  misplaced  remnants  of  the  hypophyseal  duct. 
The  simple  squamous-cell  tumors  of  the  duct  are  to  be  separated  from  more 


TUMORS  OF  THE  HYPOPHYSIS 


937 


complex  dermoids  and  teratoid  growths,  and  probably  from  cholesteatomas, 
which  Bostroem  and  Erdheim  trace  to  imaginations  of  cranial  epidermis 
carried  into  the  brain  vesicles  in  the  closure  of  the  neural  canal.  This  latter 
group  of  tumors  contains  true  skin  and  appendages,  hair  and  sebaceous 
follicles,  the  tumors  are  scattered  widely  over  the  base  of  the  brain,  and  Erd- 
heim pointed  out  that  they  rarely  lie  in  the  median  line.  The  occurrence  of 
chorda-like  tissue  in  Kon's  case  also  indicates  an  origin  apart  from  the  duct. 
Yet  it  is  not  easy  to  sharply  distinguish  all  tumors  of  these  classes.  The 
absence  of  keratohyalin  granules  emphasized  by  Erdheim  is  not  invariable, 
for  both  granules  and  keratin  have  been  demonstrated  in  duct  tumors  by 


FIG.  496. — Epidermoid  carcinoma  of  hypophyseal  duct.     Adamantinoma. 

Allgayer,  Bartels,  and  Strada.  Intercellular  spines  occur  in  both  groups. 
In  some  of  the  duct  tumors  extensive  scaling  occurs,  recalling  cholesteatoma, 
and  metaplastic  changes  in  the  stroma  may  yield  bone  and  cartilage  (Breg- 
mann  and  Steinhaus).  The  presence  of  hair  and  much  sebaceous  material 
points  clearly  to  a  dermal  origin. 

The  distinction  between  epithelial  tumors  of  the  hypophyseal  duct  and 
papilloma  of  the  choroid  plexus  is  also  difficult  and  must  be  based  chiefly  on 
the  location  and  attachments  of  the  tumor.  The  structure  in  both  groups 
may  be  very  similar.  Most  tumors  of  the  choroid  plexus  lie  well  within  the 
ventricles  and  only  when  they  involve  the  third  ventricle  do  they  suggest  a 


938  NEOPLASTIC  DISEASES 

hypophyseal  origin-.  For  the  demonstration  of  a  hypophyseal  origin  one 
may  demand  a  close  relation  to  the  pituitary  gland,  destruction  of  the  stalk 
alone  or  both  stalk  and  gland,  and  an  intact  choroid  plexus.  Many  of  these 
tumors  are  separated  by  a  membrane  from  the  cavity  of  the  ventricle.  The 
structure  of  the  hypophyseal  growths  is  more  solid,  or  cystic  with  inverted 
papillae,  and  the  squamous  characters  are  prominent.  Tumors  of  the  plexus 
are  very  vascular,  even  angiomatous,  the  papillae  are  everted,  mucoid  degenera- 
tion of  the  stroma  is  common,  and  the  cells  are  usually  small  and  delicate, 
while  squamous  changes  are  less  prominent  or  absent. 

Epidermoid  carcinoma  as  a  rule  develops  from  the  hypophyseal  stalk, 
lies  above  the  hypophysis,  widens  the  chiasm  and  circle  of  Willis,  protrudes 
toward  the  ventricle,  and  compresses  the  hypophysis  below.  Arising  within 
the  gland  the  tumor  may  destroy  the  organ.  The  growth  is  solid,  spongy,  or 
cystic.  Erdheim  describes  a  unilocular  cyst  6  cm.  in  diameter,  lined  by 
squamous  epithelium.  From  the  wall  many  low  warty  projections  may  form, 
and  it  is  probable  that  the  epithelial  lining  may  be  lost,  giving  rise  to  cysts 
of  uncertain  origin  containing  chocolate  fluid,  such  as  are  described  by  Benda. 
Saxer's  markedly  papillary  tumor  was  composed  of  very  vascular  connective 
tissue  covered  by  squamous  cells.  Other  tumors  are  comparatively  solid 
or  contain  only  few  and  small  cysts.  While  commonly  well  encapsulated 
there  may  be  invasion  of  surrounding  soft  tissues  and  bone.  The  main  struc- 
tural type  is  that  of  adenoid  cystic  epithelioma.  In  acellular  connective- 
tissue  stroma  lie  anastomosing  masses  of  epithelium  the  outer  layers  of  which 
are  cylindrical,  while  the  inner  layers  become  flattened  and  vacuolated.  There 
is  often  a  distinct  tendency  to  reproduce  the  reticulated  structure  of  ada- 
mantinoma,  and  many  small  cysts  form  in  the  liquefied  central  areas,  as  well 
as  in  the  edematous  stroma.  Or  squamous  metaplasia  is  pronounced,  pearls 
and  intercellular  bridges  form,  and  keratohyalin  granules  appear.  In  some 
cases  squamous  cells  are  wanting  and  the  tumor  is  composed  of  many  closely 
packed  papillae  lined  chiefly  by  cylindrical  cells  (Lewis).  Either  in  the  epi- 
thelial masses  or  in  the  walls  of  vessels  calcific  concretions  may  form. 

The  stroma  may  present  a  variety  of  features.  The  cellular  connective 
tissue  may  be  infiltrated  with  blood  and  contain  cysts  with  chocolate  fluid. 
Portions  of  the  nervous  tissue  of  the  posterior  lobe  or  the  gland  tissue  of  the 
anterior  lobe  may  be  scattered  through  the  tumor.  By  metaplasia  areas  of  car- 
tilage or  bone  may  form  as  in  the  salivary  gland  tumors.  Walker  described 
his  tumor  as  osteoma.  Benda's  teratoma  in  a  dwarf  contained  epider- 
moid  cysts  with  cholesterin  and  bony  plates  in  the  wall.  All  the  so-called 
teratomas  (teratoids)  of  the  hypophysis  may  safely  be  included  in  this  group. 
While  there  is  thus  a  wide  variety  of  structure  attributable  to  this  origin  and 
illustrated  in  many  reported  cases,  the  great  majority  of  these  tumors  are 
comparatively  simple  and  resemble  adamantinomas. 

Duffy,  in  a  careful  analysis,  recognizes  three  groups  of  hypophyseal  duct 
tumors:  (a)  Intracystic  papillomas,  which  are  relatively  benign;  (b)  solid 
or  cystic  basal  cell  carcinomas  of  the  type  of  adamantinoma,  which  may  in- 
filtrate locally,  but  do  not  metastasize;  (c)  squamous  carcinoma  which  may 
yield  metastases  to  the  cervical  nodes,  as  in  Fahr's  case.  In  the  second  group 
calcific  deposits  are  common  and  yield  a  characteristic  #-ray  picture. 

3.  Tumors  of  the  Pars  Intermedia. — In  3  cases  the  relations  of  a  hypo- 
physeal tumor  have  strongly  suggested  an  origin  from  the  pars  intermedia. 

Boyce  and  Beadles  describe  a  firm  tumor  as  large  as  a  pea  attached  to 
the  pedicle  of  the  hypophysis  above  the  sella.  It  was  composed  of  large 
polygonal  cells  with  single  or  multiple  nuclei,  lying  in  slightly  acinar  arrange- 
ment in  a  vascular  stroma.  Erdheim  mentions  a  similar  growth  composed 


TUMORS  OF  THE  HYPOPHYSIS  939 

of  large  polygonal  cells  with  densely  staining  cytoplasm.  Gushing  studied 
a  large  adenomatous  tumor  which  compressed  the  anterior  lobe  in  such  a 
way  as  to  indicate  an  origin  from  the  pars  intermedia  alone.  The  structure 
resembled  that  of  the  thyroid  gland. 

4.  Glioma  of  the  posterior  lobe  is  briefly  reported  by  Bury.  A  soft  cellu- 
lar growth  with  colloid  deposit  and  composed  of  small  round  and  spindle- 
cells  merging  with  the  normal  tissue  of  the  posterior  lobe  was  regarded  by 
Roxburg  and  Collis  as  a  glioma  or  sarcoma. 

Two  small  lipomas  were  found  replacing  the  posterior  lobe  by  Weichsel- 
baum.  They  might  arise  from  fat  tissue  occasionally  seen  about  Rathke's 
cyst.  W.  Hutchinson  describes  a  fibrosed  gland  in  a  dwarf. 

Miscellaneous  Tumors  of  the  Hypophysis. — Cholesteatomas  and  true  der- 
moids  containing  hair  and  sebaceous  material  occasionally  appear  in  or  near 
the  sella  turcica,  but  they  seldom  originate  within  the  hypophysis.  Bostroem 
has  shown  that  they  take  origin  from  ectodermal  rests  carried  in  with  the 
closure  of  the  brain  vesicles.  Erdheim  has  collected  a  series  of  15  tumors  of 
this  group  in  various  locations,  none  of  them  strictly  hypophyseal.  Complex 
teratomas  are  described  by  Beck,  Hecht,  Gushing,  and  others.  They  are 
probably  autochthonous  teratoids  developed  by  metaplasia  from  hypophyseal 
duct  remnants.  Margulis  records  an  adult  tridermal  teratoma  in  the  rab- 
bit's hypophysis.  Fetal  implantations  apparently  attached  to  the  hypophy- 
sis were  recorded  by  Wegelin  and  Rippmann. 

Symptomatology. — The  combined  clinical,  anatomical,  and  experimental 
studies  of  tumors  of  the  hypophysis  have  not  only  thrown  much  light  on  the 
nature  and  behavior  of  these  growths,  but  rather  unexpectedly  have  opened 
up  fields  of  research  which  have  a  broad  relation  to  many  problems  in  the 
physiology  and  pathology  of  the  glands  of  internal  secretion.  The  outline 
of  a  brief  presentation  of  this  complex  subject,  which  is  an  essential  part  of 
the  study  of  hypophyseal  tumors,  includes,  first,  a  clinical  classification  of  the 
tumors,  and  second,  a  discussion  of  the  pathogenesis  of  symptoms. 

In  general,  hypophyseal  tumors  are  associated  with  two  main  groups  of 
symptoms.  Some  produce  almost  exclusively  cerebral  pressure  symptoms, 
and  thereby  greatly  lose  in  interest.  Others  not  only  yield  pressure  symp- 
toms, but  are  accompanied  by  peculiar  forms  of  general  dystrophy  usually 
involving  other  glands  of  internal  secretion  and  thus  adding  greatly  to  their 
interest  as  well  as  their  clinical  complexity.  Rarely  the  tumors  are  found 
at  autopsy,  having  run  a  latent  course.  These  groups  may  be  termed  (i) 
cephalic,  (2)  dystrophic. 

(i)  Cephalic  Type. — The  usual  symptoms  of  headache,  vertigo,  and 
vomiting  are  typical  signs  of  onset  which  are  common  to  many  cerebral 
tumors.  Rising  beyond  the  sella,  ocular  symptoms  first  appear  and  take  a 
variety  of  forms  which  may  permit  very  accurate  localization  of  the  point 
of  pressure.  Dimness  of  vision  often  appears  very  early  on  one  or  both  sides, 
and  results  in  blindness  of  one  eye  in  33  per  cent,  of  the  cases  and  of  both 
eyes  in  16  per  cent.  In  Henneberg's  case  ocular  disturbance  appeared  13 
years  before  death.  Bitemporal  hemianopsia,  with  loss  of  pupillary  reac- 
tion to  light,  is  a  characteristic  symptom  resulting  from  pressure  on  the  chiasm 
with  atrophy  of  the  nasal  half  of  the  retina.  Later,  homonymous  hemianop- 
sia occurs  from  pressure  on  the  whole  optic  tract.  The  directness  of  the 
pressure  on  the  optic  tract  renders  stasis  of  the  retinal  papilla  relatively  rare 
(15  per  cent.).  Bilateral  non-pulsating  exophthalmos  occurs  in  10  per  cent, 
of  acromegalics  and  without  acromegaly  (Scalincie). 

Oculomotor  paralysis  occurred  in  10  of  174  cases  of  acromegaly  (Hertel) 
and  in  29  per  cent,  of  tumors  without  acromegaly  (Lapersonne,  Cantonnet). 


940  NEOPLASTIC  DISEASES 

Any  of  the  cranial  nerves  may  be  affected.  When  the  tumor  reaches  the 
peduncle  hemiplegia  or  more  extensive  paralyses  result.  Diffuse  cerebral 
symptoms  characterize  many  cases  and  are  exclusively  present  in  some. 
Narcolepsy,  brief  or  prolonged,  occurs  in  25  per  cent,  of  the  cases  without 
acromegaly  (Fr.  Hochwart),  but  is  not  observed  in  acromegaly  itself 
(L'Hermitte).  In  775  cases  of  cerebral  tumors  with  psychoses,  mania, 
hypochondria,  hallucinations,  or  dementia,  Schuster  found  61  tumors  of  the 
hypophysis,  12  of  which  were  associated  with  acromegaly.  Glycosuria  and 
diabetes,  at  times  very  severe,  is  comparatively  frequent  in  acromegaly. 
Launois  and  Roy  collected  16  cases.  Without  acromegaly  glycosuria  is 
rare,  but  simple  polyuria  is  more  frequent. 

Radiographic  examination  is  constantly  indicated  in  hypophyseal  tumors, 
but  the  interpretation  of  enlargements  of  the  sellar  outlines  is  surrounded  by 
many  uncertainties.  Individual  variations  in  the  size  of  the  sella,  physiolog- 
ical swelling  of  the  hypophysis,  widening  of  the  sella  by  increased  intracranial 
pressure  from  other  cerebral  tumors,  and  tuberculous  or  syphilitic  lesions 
of  the  bones  are  possible  sources  of  diagnostic  error.  Actual  erosion  of  bone 
beginning  with  the  posterior  clinoid  processes  is  far  more  reliable  evidence 
than  simple  enlargement  of  the  sella. 

(2)  Dystrophic  Type. — Three  forms  of  general  dystrophy  occur  with 
hypophyseal  tumors;  giantism  or  dwarfism,  acromegaly,  and  obesity  with 
genital  hypoplasia. 

Giantism  is  the  result  of  precocious  activity  of  the  hypophysis  in  infancy, 
while  dwarfism  follows  loss  of  pituitary  function  in  early  life  (Brissaud,  Meige, 
Launnois,  Roy).  Acromegaly  results  from  overactivity  of  the  hypophysis 
in  the  adolescent  or  adult.  The  adiposogenital  syndrome  is  the  expression 
of  functional  underactivity  of  the  gland,  chiefly  of  the  posterior  lobe.  There 
are  giant  acromegalics  in  whom  the  overactivity  established  in  infancy 
persists  after  the  limit  of  height  has  been  reached  and  many  cases  of  giantism 
reveal  traces  of  the  adiposogenital  dystrophy  when  the  glandular  function 
is  exhausted.  The  passage  of  acromegaly  into  the  adiposogenital  dystrophy 
is  easily  conceivable,  and  this  tendency  has  been  emphasized  especially  by 
Gushing  in  cases  showing  symptoms  of  both  classes.  While  the  relation  of 
these  dystrophies  to  the  functional  state  of  the  gland  appears  with  sufficient 
clearness  to  constitute  a  general  principle,  yet  numerous  apparent  violations 
of  the  principles  are  observed,  and  other  complicating  factors  are  found  in 
associated  disturbances  of  other  glands  of  internal  secretion  and  in  combina- 
tions of  individual  features  of  the  various  dystrophies.  Hence  it  has  become 
increasingly  evident  that  each  case  of  dystrophy  connected  with  hypophyseal 
disease  is  best  analyzed  as  a  form  of  polyglandular  disturbance.  The  neces- 
sity and  the  difficulties  of  this  method  are  well  illustrated  in  Cushing's  studies. 

(a)  Giantism. — Pure  cases  of  giantism  fully  studied  from  the  polyglandu- 
lar standpoint  are  rare.  In  Cushing's  case  (32),  age  37,  the  body  measured 
251.5  cm.  in  length,  the  brain  weighed  1884  gm.,  spleen  1000  gm.,  thymus 
atrophic,  thyroid  not  enlarged,  adrenals  extremely  small,  testes  atrophic, 
pancreas  fibrosed.  There  were  marked  signs  of  pituitary  insufficiency  with 
impotence,  hypotrichosis,  and  obesity.  The  sella  measured  2.2  X  2.7  cm. 
and  was  occupied  by  a  large  cystic  tumor  in  the  walls  of  which  were  irregular 
alveoli  of  chromophobe  cells.  This  case  represents  a  preadolescent  hyper- 
pituitarism  with  terminal  insufficiency. 

In  Bassoe's  case  (Winkler)  there  were  leontiasis  of  the  skull  and  a  large 
osteosarcoma  compressing  hypophysis  and  brain.  The  enlarged  hypophysis 
contained  focal  eosinophilic  adenomas,  areas  of  small,  round,  densely  staining 
cells,  alveoli  filled  with  colloid,  hyaline  vessels,  hemorrhages  and  pigmenta- 


941 


tion.  There  was  a  large  colloid  goiter,  thymus  and  testes  were  atrophic, 
adrenals  and  pancreas  normal. 

Giantism  with  acromegaly  is  a  relatively  numerous  class.  Sternberg 
states  that  40  per  cent,  of  all  giants  are  acromegalic,  but  the  literature  con- 
tains few  fully  reported  cases.  The  increase  in  height  begins  in  early  life  and 
ceases  after  a  period  of  years,  but  the  acromegalic  changes  continue,  and 
evidences  of  dyspituitarism  are  often  added. 

In  Dana's  acromegalic  giant  there  was  extensive  enlargement  of  the 
pituitary  which  led  to  central  hemorrhage  and  softening,  probably  a  pure 
adenoma  (cf.  Hutchinson). 

In  the  case  of  Lady  Aama  Hutchinson  found  the  hypophysis  as  large 
as  a  pigeon's  egg,  but  no  microscopical  study  could  be  made. 


FIG.  497. 


FIG.  498. 


FIG.  497. — Preadolescent  hyperpituitarism  with  giant  overgrowth.  Enlarged  sella, 
containing  a  cystic  struma  pituitaria.  No  neighborhood  symptoms.  Terminal  gland- 
ular insufficiency  (hypopituitarism).  Note  extreme  length  of  arms  and  thighs  in  rela- 
tion to  usual  18-inch  chair.  (Gushing,  "The  Pituitary  Body  and  Its  Disorders."} 

FIG.  498. — Pituitary  dystrophy,  Lorain  type.  Pituitary  tumor,  small  adult  body,  re- 
tarded sexual  development,  no  adiposity.  (After  Stewart.} 


(V)  Infantilism. — Various  types  of  imperfect  development  of  the  skeleton 
and  especially  of  the  genital  organs  are  associated  with  hypophyseal  disease. 
In  general,  pituitary  infantilism  results  from  pre-adolescent  hypopituitarism, 
but  the  influence  of  disorders  of  the  thyroid,  thymus,  and  adrenal  are  often 
added.  Considering  the  very  numerous  clinical  forms  and  complex  etiology 
of  the  conditions  designated  as  infantilism  it  is  evident  that  pituitary  lesions 
have  a  very  restricted  importance  in  this  field  (cf.  Strauch).  Dwarfism 
in  pronounced  form  was  associated  with  a  diffuse  fibroma  or  fibrosis  of  the 
pituitary  in  Hutchinson's  case. 

A  combination  of  gigantism  with  infantilism  is  described  by  Lemos. 


942 


NEOPLASTIC  DISEASES 


There  is  excessive,  growth  of  long  bones  and  some  facial  hypertrophy,  but 
the  general  bodily  conformation  is  infantile  and  there  is  genital  hypoplasia. 
The  mentality  is  defective.  It  is  referred  to  a  congenital  hypertrophy  of  the 
pituitary  which  manifests  itself  early  in  life. 

Lorain  described  a  form  of  infantilism  characterized  by  a  general  smallness 
and  delicacy  of  body  with  correspondingly  small  genitals,  but  without  obesity. 
Growth  is  arrested,  but  adult  proportions  of  the  body  are  maintained.  While 
Gushing,  Levi,  Leman,  and  others  have  demonstrated 
by  radiographs  enlargement  of  the  sella  in  such  cases, 
microscopical  studies  of  the  glands  I  have  been  unable 
to  find. 

Infantilism  reversif  of  Gandy,  or  tardif  of  Brissaud 
and  Bauer,  is  marked  by  traces  of  myxedema,  atrophy 
of  genitals,  and  loss  of  hair.  In  such  cases  Gandy 
found  atrophy  of  thyroid  and  hypophysis,  while  Sainton 
and  Rathery  observed  atrophy  of  thyroid,  genital 
organs,  and  adrenal,  but  the  hypophysis  was  repre- 
sented by  a  large  cystic  carcinoma  containing  altered 
blood.  They  review  several  cases  of  myxedema  with  tu- 
mors, chiefly  chromophile  hyperplasia  of  the  hypoph- 
ysis, and  interpret  the  condition  as  a  compensatory 
effect  from  thyroid  hypoplasia.  Claude  and  Gougerot 
in  a  similar  case  of  polyglandular  disturbance  report 
atrophy  of  thyroid,  adrenals,  and  testis  with  a  diminu- 
tive hypophysis,  sclerosed  but  otherwise  normal. 

Ateliosis  is  a  term  used  by  Gilford  to  indicate  a 
form  of  infantilism  in  which  active  growth  ceases  and 
an  infantile  or  adolescent  body  type  persists.  It  is 
probably  a  polyglandular  syndrome  in  which  the 
hypophysis  is  functionally  deficient. 

(c)  Acromegaly. — The  dictum  of  Marie  that  acro- 
megaly is  essentially  the  result  of  pituitary  disease 
has  been  strongly  supported  by  the  observations  and 
debates  of  recent  years.  Coincidentally  it  has  been 
shown  that  acromegaly  is  associated  chiefly  with 
hyperpituitarism,  that  numerous  sub  varieties  of  this 
disease  are  referable  to  complications,  chiefly  those 
resulting  from  gradual  functional  failure  of  the  gland 
and  involvement  of  other  glands  of  internal  secretion. 
The  further  claim  advanced  by  B.  Fischer  and  others, 
that  hyperplasia  or  a  tumor  of  the  pituitary  is  in- 
variably present,  may  not  be  admissible,  but  is  not 
far  from  demonstration.  Petren  reviews  the  consid- 
erable list  of  reported  cases  of  acromegaly  without 
hypophyseal  lesion  and  accepts  6  as  fully  attested 
by  microscopical  examination  (Dallemagne,  Mitchell,  LeCount,  Huchard, 
Launois,  Lewis,  Widal,  Roy,  Froin,  and  Petren). 

B.  Fischer,  however,  rejects  all  such  cases,  and  affirms  that  there  is  no 
recorded  instance  of  acromegaly  in  which  the  absence  of  specific  changes  in 
the  pituitary  has  been  proved.  This  position  may  be  too  radical,  but  it  is 
obvious  that  changes  once  present  may  disappear.  Thus  Huchard's  and 
one  of  Cushing's  cases  showed  a  small  sclerosed  pituitary  in  an  enlarged 
sella.  The  primary  pituitary  origin  of  acromegaly  is'  strongly  indicated  by 
the  fact  that  the  great  majority  of  cases  show  pronounced  hyperplasia  or 


FIG.  499. — A  typical 
case  of  infantilism  of 
type  Lorain,  with  an 
enlarged  2  cm.  sella. 
Patient  aged  20  years, 
6  months;  height  4  ft., 
5  in.  (133  cm.).  (Ettore 
Levi.} 


TUMORS  OF  THE  HYPOPHYSIS  943 

tumors  of  this  organ.  The  hypophysis,  however,  is  not  the  only  organ  in- 
volved in  acromegaly.  The  disease  is  of  complex  etiology  and  pathogenesis 
and  several  clinical  varieties  depend  upon  associated  lesions. 

Many  cases  of  pituitary  enlargement  fail  to  give  acromegaly  even  when, 
as  in  Cagnetto's  and  Zak's  cases,  the  eosinophile  cells  are  greatly  in  excess. 
The  disease  is  observed  with  pineal  tumors,  and  the  thyroid  and  sex  glands 
are  commonly  involved.  Hypophyseal  disease  is  therefore  an  essential,  but 
not  a  sufficient  cause  of  acromegaly  (Parisot).  Acromegalic  changes  are 
also  observed  with  hydrocephalus  from  cerebellar  cyst  (Cushing),  in  neuro- 
fibromatosis  (Nichols  and  Favre),  and  in  syringomyelia  (Petren). 

An  hereditary  element  is  observed,  especially  in  negroes.  Infantile 
acromegaly  has  been  observed  in  a  series  of  20  cases  collected  by  Hutinel, 
and  Babonneix  and  Paisseau.  Matassari  has  shown  that  this  condition  may 
be  prevented  by  precocious  ossification  of  epiphyseal  cartilages  (Claude, 
Franchini,  Giglio).  There  may  be,  however,  very  marked  overgrowth  of 
skull,  face,  hands,  and  feet.  Many  cases  show  acromegalic  overgrowth  with 
adiposogenital  dystrophy. 

Acromegalic  conditions  of  moderate  degree  combined  with  myxedema  and 
associated  with  hypophyseal  tumors  are  of  not  infrequent  occurrence 
(Grahaud,  Lit.).  In  such  a  case  Calderara  found  an  atrophic  thyroid,  while 
the  pituitary  was  doubled  in  size  by  a  chromophobe  struma.  Boyce  and 
Beadles  in  a  myxedematous  obese  subject  found  the  hypophysis  much  en- 
larged, while  in  a  similar  case  Dalton  reports  an  atypical  "sarcoma"  destroy- 
ing pituitary  and  posterior  lobe.  Other  reports  worthy  of  mention  include  a 
"sarcoma"  (Pechkranz),  endothelioma  compressing  the  hypophysis  (Stewart), 
carcinoma  extending  into  the  face  (Zollner),  and  a  cystic  tumor  as  large  as 
an  orange  (Sainton,  Rathery). 

Colloid  goiters  are  frequently  observed  in  acromegaly,  but  hyperthy- 
roidism  rarely.  Exophthalmos  may  result  from  the  pituitary  tumor.  Thy- 
roid hyperplasia  occurred  after  partial  hypophysectomy  in  2  of  Hochenegg's 
cases  (Exner). 

Acromegalics,  especially  in  the  late  stages  of  dyspituitarism,  may  give 
evidence  of  adrenal  insufficiency  in  the  form  of  pigmentation  of  the  skin, 
extreme  asthenia,  low  blood-pressure,  and  hypoglycemia.  While  the  adrenals 
are  usually  reported  as  normal,  yet  in  a  giant  acromegalic  with  cystic  pitui- 
tary struma  (32)  Cushing  found  atrophic  adrenals.  Hyperactivity  of  the 
adrenal  is  sometimes  indicated  in  acromegaly,  and  Renon  and  De  Lille  ob- 
served adrenal  hypertrophy  after  injections  of  hypophyseal  extracts.  In 
rare  cases  of  acromegaly  there  is  marked  hypertrophy  of  the  adrenals. 
Schultze  and  Fischer  report  cases  in  which  hyperplasia  of  the  Z.  fasciculata 
reached  an  almost  adenomatous  grade. 

Glycosuria  and  diabetes  are  often  associated  with  acromegaly.  The 
pancreas  is  usually  reported  as  normal,  but  Hansemann  found  interstitial 
pancreatitis  and  a  colloid  goiter,  and  pancreatic  lesions  are  reported  by 
Dallemagne  and  Pineles.  In  one  case  with  malignant  hypophyseal  adenoma 
I  found  interstitial  pancreatitis  and  giant-cell  formation  in  hypertrophied 
island's.  Although  polyuria  is  induced  by  injections  of  extracts  of  the  pars 
nervosa  its  occurrence  with  hypophyseal  tumors  is  probably  to  be  classed 
with  the  polyuria  of  other  brain  tumors. 

Grahaud  has  collected  u  cases  of  young  acromegalics  with  marked  or 
extreme  obesity.  Such  a  condition  is  referred  by  Fischer  to  a  tumor  of  the 
anterior  compressing  the  posterior  lobe.  It  may  also  be  explained  as  a  com- 
bination of  acromegaly  with  primary  testicular  hypoplasia.  Analysis  of  the 
case  reports  shows  that  both  these  explanations  may  apply.  Fischer's  case 


944  NEOPLASTIC  DISEASES 

was  a  perivascular  round-cell  tumor  with  an  epithelial  colloid  cyst  compress- 
ing the  remainder  of  the  pituitary  and  pars  nervosa. 

Nearly  all  cases  of  acromegaly  are  accompanied  by  genital  dystrophy, 
a  fact  which  accords  with  the  view  that  a  slight  long-continued  pressure  on 
the  pars  nervosa  affects  the  genital  glands  (L.  Pick,  Fischer). 

In  the  adult  evidence  of  hypophyseal  failure  appears  in  the  tendency 
of  most  acromegalics  to  lay  on  fat.  This  feature  is  pronounced  in  Dercum's 
disease,  adiposis  dolorosa,  marked  by  local  or  general  adiposity, .  pains  and 
tenderness,  asthenia,  and  psychoses.  Hypophyseal  lesions  observed  in  this 
condition  include:  pituitary  glioma  (Burr);  adenocarcinoma  (McCarthy); 
alveolar  carcinoma  (Guillain,  Alquier);  processes  suggesting  carcinoma, 
2  cases  (Price);  epithelial  tumor  (Launois,  Clunet);  aneurysm  compressing 
hypophysis  (Lyon).  Dammann,  however,  reports  a  normal  hypophysis 
and  emphasizes  the  frequency  of  various  phases  of  chronic  thyroid  disturb- 
ance in  this  disease. 

Status  lymphaticus  with  persistent  thymus  and  lymphoid  hyperplasia 
is  occasionally  observed  in  acromegaly,  but  belongs  more  clearly  with  adiposo- 
genital  dystrophy.  In  2  such  cases  Gushing  reports  a  chromophobe  ade- 
noma and  a  cerebellar  cyst.  Epileptic  seizures  are  also  common  in  this 
group  of  cases.  Amenorrhea  has  long  been  recognized  as  an  early  symptom 
in  many  acromegalics,  and  most  male  subjects  of  the  disease  are  sexually 
deficient  (Marie,  Gushing).  The  ovaries  are  usually  cystic  or  atrophic,  and 
in  the  testes  the  interstitial  cells  are  deficient  or  absent  (Gushing).  In  a 
peculiar  syndrome  of  precocious  sexual  development,  hypertrichosis,  obesity, 
asthenia,  and  blindness  Gushing  observed  some  hyperplasia  of  the  inter- 
stitial cells. 

Finally,  in  a  group  of  cases,  many  organs  and  tissues  are  affected  by 
developmental  anomalies  and  acquired  disorders,  revealing  a  disturbance 
of  growth  and  function  which  is  nearly  universal.  Thus  in  Harbitz's  case 
there  was  a  large  chromophobic  adenoma  with  apparent  destruction  of 
pars  nervosa,  associated  with  acromegaly,  hemiatrophia  facialis,  overgrowth 
of  lung,  trachea,  liver,  spleen,  kidney,  heart,  larynx,  thyroid,  pancreas,  and 
adrenals.  In  Amsler's  case  an  adenoma,  chiefly  eosinophile,  was  associated 
with  enlargement  of  tongue,  spleen,  liver,  kidneys,  thyroid  and  heart,  and 
atrophy  of  testis. 

(d)  Dystrophia  adiposogenitalis  is  the  most  characteristic  form  of  hypo- 
physeal dyscrasia.  Its  numerous  subvarieties  suggest  the  implication  of  other 
glands  of  internal  secretion.  Both  clinical  and  experimental  studies  indicate 
that  the  glandular  insufficiency  affects  chiefly  the  posterior  lobe.  The 
secretion  of  this  lobe  raises  blood-pressure  and  exerts  a  peculiar  influence 
on  the  metabolism  of  fats  and  carbohydrates.  The  subjects  exhibit  hypo- 
glycemia  and  high  sugar  tolerance,  300  to  400  gm.  of  glucose  by  mouth 
failing  to  produce  glycosuria.  Apparently  carbohydrates  are  converted 
into  fats  and  deposited  in  the  depot  regions,  subcutaneous  and  subserous 
tissues,  and  the  liver.  The  associated  genital  hypoplasia  doubtless  favors 
fat  deposit  by  some  other  mechanism.  While  other  glands  may  be  second- 
arily concerned  the  predominance  of  the  hypophysis  is  indicated  by  the 
remarkable  improvement  observed  after  operation.  V.  Eiselsberg,  Gushing, 
and  others  have  reported  improvement  in  pressure  symptoms,  restoration 
of  sexual  function,  growth  of  hair,  etc.,  after  extirpation  of  various  tumors. 
Moreover,  Gushing  has  shown  that  partial  extirpation  of  the  anterior  lobe 
leads  to  obesity  and  genital  hypoplasia.  In  subsequent  experiments,  how- 
ever, he  attributed  this  result  to  injury  to  the  pars  nervosa. 

The  cases  differ  chiefly  in  the  feature  of  overgrowth  and  in  the  condition 


TUMORS  OF  THE  HYPOPHYSIS 


945 


of  the  genitals.  In  the  type  described  by  Froelich  a  hypophyseal  tumor  is 
associated  with  diminished  growth,  genital  hypoplasia,  and  adiposity.  In 
childhood  the  condition  produces  many  of  the  characteristic  excessively  fat 
children  with  genital  hypoplasia  (Neurath).  The  fully  developed  condition 
presents  many  or  all  of  the  following  features:  fat  deposits  in  the  skin  of 
hips,  abdomen,  and  genitals;  atrophy  and  loss  of  function  of  the  genital  organs, 
amenorrhea,  anaphrodisia,  hypotrichosis;  limitation  of  skeletal  growth  and 
traces  of  infantilism,  malformation  of  genitals,  cryptorchismus,  hypospadias, 
absence  of  one  testicle,  transformation  of 
sexual  characters,  hypertrophy  of  breasts, 
and  widening  of  pelvis  in  males.  In  many 
details  these  cases  may  present  the  features 
of  status  lymphaticus,  but  the  hypoplasia  of 
the  aorta  and  hyperplasia  of  the  lymphatic 
structures  are  usually  not  noted. 

Genital  hyperplasia  and  skeletal  over- 
growth with  obesity  are  observed  without 
hypophyseal  tumor  in  cases  of  hydrocephalus 
(Marburg).  Or  hydrocephalus  without  hypo- 
physeal tumor  may  yield  skeletal  overgrowth, 
obesity,  and  genital  hypoplasia  (Gushing, 
Case  24). 

In  adolescence  the  male  develops  feminine 
outlines,  genital  hypoplasia,  hypotrichosis, 
and  adiposity,  and  when  lymphoid  hyperplasia 
and  persistent  thymus  are  added,  the  con- 
dition merges  with  status  lymphaticus  (Gush- 
ing, 5,  8,  10),  Mixter  and  Quackenboss,  Strada, 
Souques,  and  Chauvet. 

In  general,  the  tumors  associated  with 
adiposogenital  dystrophy  are  characterized 
by  a  wide  diversity  of  origin  and  structure, 
by  a  frequent  failure  to  involve  the  pituitary, 
by  a  tendency  to  grow  into  the  third  ventricle 
and  to  destroy  the  infundibulum,  and  by 
their  comparative  inaccessibility  to  surgical 
attack.  Of  34  cases  collected  by  Strada, 
Ottenberg,  and  Pick,  6  left  the  hypophysis 
normal,  8  were  derived  from  the  hypo- 
physeal duct,  23  represented  nearly  all  the  histological  varieties  of  pituitary 
neoplasms,  and  some  arose  from  the  choroid  plexus  or  ependyma,  or  from  the 
pial  endothelium.  Pick  emphasizes  the  bipartite  character  of  many  tumors, 
which  present  a  small  intrasellar  and  a  larger  extrasellar  or  intraventricular 
portion  connected  by  a  pedicle. 

Relation  Between  the  Type  of  Tumor  and  the  Symptom  Complex. — Through- 
out the  above  clinical  types  of  hypophyseal  disturbance  a  certain  relation  may 
be  traced  between  the  type  and  location  of  the  tumor  and  the  symptoms. 
Skeletal  and  tissue  overgrowth  and  the  various  form  of  acromegaly  and  giant- 
ism, at  least  during  their  active  stages,  are  associated  with  hyperplasia  of  the 
eosinophile  cells  of  the  pituitary.  Although  the  gland  may  be  considerably 
enlarged  by  this  process,  it  is  doubtful  if  any  of  the  eosinophile  hyperplasias 
can  be  regarded  as  true  neoplasms.  Even  in  actively  progressive  and  early 
acromegaly  it  cannot  be  claimed  that  eosinophile  cells  are  exclusively  con- 
cerned, since  acromegaly  develops  from  the  hyperplasia  of  gestation  which 
60 


FIG.  500. — Hypopituitarism. 
Adiposogenital  dystrophy,  type 
Frohlich.  No  sign  of  tumor. 
(After  Batten.) 


946 


NEOPLASTIC  DISEASES 


affects  the  specific  cells  of  Erdheim.  Moreover,  the  great  majority  of  glands 
examined  microscopically  from  advanced  cases  of  acromegaly  show  not 
eosinophile  overgrowth,  but  adenomas  of  chromophobic  or  quite  atypical 
small  or  large  round  cells.  Such  cases  usually  show  evidences  of  dyspitu- 
itarism.  Hence  the  pituitary  lesion  beginning  with  hyperplasia  of  specific 
functionating  cells,  if  it  assumes  the  character  of  a  neoplasm,  does  so  at  the 
expense  of  form  and  function  of  the  secreting  cells.  It  is  clear  that  the  same 

type  of  atypical  adenoma  may  occur  in  both 
acromegaly  and  in  adiposogenital  dystrophy 
(Wurmbrand) . 

The  natural  course  of  these  hyperplasias 
varies  considerably.  Some  appear  to  be  long 
maintained  as  simple  functional  hyperplasia 
and  are  found  in  this  condition  at  operation 
or  autopsy.  Others  reaching  a  large  size  tend 
to  suffer  central  softening  and  terminate  in 
cysts  with  gelatinous  or  blood-stained  con- 
tents. Gradual  atrophy  with  calcification, 
which  may  be  complete  (Pick,  Konjetzny), 
may  supervene.  In  many  cases  the  functional 
hyperplasia  passes  rapidly  or  slowly  into  a 
neoplastic  process  and  distinctly  malignant 
features  may  appear.  In  these  relations  the 
hypophysis  presents  a  close  parallel  with  the 
thyroid.  Yet  it  is  frequently  noted  that  ma- 
lignant histological  structures  are  associated 
with  slow  clinical  course,  and  in  several  in- 
stances the  symptoms  have  regressed  after 
partial  removal  of  the  tumors  (Pick).  Nearly 
all  the  extreme  forms  of  pituitary  overgrowth 
are  associated  with  functional  insufficiency, 
while  the  period  of  functional  excess  is  early 
and  transient.  In  this  stage  there  appears  to 
be  little  relation  between  the  various  histo- 
logical peculiarities  of  the  tumor  and  the 
clinical  symptoms.  The  former  represent 
local  phases  of  tumor  growth,  while  the  latter 
reveal  an  increasing  participation  of  other 
glands  of  internal  secretion,  and  the  complicating  pressure  symptoms. 

While  cases  of  pure  acromegaly  are  comparatively  rare,  signs  of  glandular 
insufficiency  overtake  most  cases  of  acromegaly,  and  various  forms  of  primary 
hypophyseal  atrophy  are  relatively  common.  The  lists  of  pronounced  adi- 
posogenital dystrophy  contain  a  large  proportion  of  atypical  overgrowths 
and  true  tumors  (Strada,  Ottenberg).  Extrapituitary  tumors  and  those 
derived  from  the  hypophyseal  duct  almost  invariably  lead  to  primary  dys- 
trophy without  acromegaly.  Wurmbrand  and  others  have  noted  a  prompt 
response  of  the  thyroid  and  genital  organs  after  operations  on  hypophyseal 
adenoma. 


FIG.  501. — -Adiposogenital  dys- 
trophy, from  bullet  wound  of 
hypophysis.  (Madelung.) 


Three  theories  have  been  advanced  in  explanation  of  the  adiposogenital  dystrophy: 
(a)  deficiency  of  the  internal  secretion  of  the  hypophysis  (Frohlich),  (&)  pressure  from 
any  source  on  a  supposed  cerebral  center  (Erdheim),  and  (c)  a  lesion  of  the  posterior 
lobe  or  the  infundibulum.  In  most  cases  the  anatomical  condition  is  consistent  with 
any  one  of  the  three  theories.  In  considering  the  evidence  bearing  on  these  theories  it 
is  necessary  to  distinguish  between  the  secondary  adiposogenital  dystrophy  which  fol- 


TUMORS  OF  THE  HYPOPHYSIS  947 

lows  acromegaly  and  the  primary  form  which  develops  without  a  preliminary  period  of 
hyperpituitarism. 

(1)  The  chief  evidence  in  favor  of  the  theory  of  pituitary  deficiency  is  the  fact  that 
dystrophy  overtakes  most  acromegalics  in  later  stages  and  is  associated  with  destructive 
tumors  of  the  hypophysis  and  in  general  with  chromophobic  strumas.     This  condition 
has  also  arisen  from  a  bullet  wound  of  the  pituitary  (Madelung),  and  from  solitary 
tubercle  of  the  anterior  lobe  (Gushing).     An  old  hemorrhage  destroying  two-thirds  of 
the  pituitary  was  the  sole  lesion  found  in  a  case  of  Maranon's.     On  the  other  hand, 
there  have  been  many  destructive  lesions  of  the  pituitary,  including  tumors,  tubercle, 
and  gummas,  which  have  failed  to  produce  dystrophy  (L.  Pick,  Lit.).     Atrophy  of  the 
pituitary  leads  to  dwarfism  rather  than  to  adiposogenital  dystrophy.     Many  considera- 
tions favoring  the  theory  of  pituitary  insufficiency  are  collected  by  Marburg,  Melchoir, 
and  Strada. 

(2)  While  a  certain  grade  of  cerebral  adiposity  has  appeared  with  miscellaneous  brain 
tumors  and  hydrocephalus,  yet  the  existence  of  such  a  center  as  Erdheim  assumes  is 
quite  hypothetical,  and  in  many  cases  of  dystrophy  the  element  of  cerebral  pressure 
has  been  absent. 

(3)  Many  observations  favor  the  importance  of  disturbed  function  of  the  pars  nervosa 
in  adiposogenital  dystrophy.     In  many  cases  there  is  a  tumor  of  the  hypophyseal  duct 
which  compresses  the  infundibulum  and  the  pars  nervosa  while  leaving  the  pituitary 
intact.     It  appears  to  be  the  location  rather  than  the  type  of  tumor  which  determines 
the  dystrophy.    Tumors  involving  the  third  ventricle  frequently  give  rise  to  dystrophy, 
apparently  by  occluding  the  infundibulum   (Erdheim,  Selke,   Bartels,  Zak).     Fischer 
describes  a  tumor  of  the  third  ventricle  which  he  details  as  meeting  these  conditions 
exactly.     Extensive  lesions  of  the  anterior  lobe  without  involvement  of  the  posterior, 
as  by  tubercle  or  gummas  (Pick),  have  repeatedly  failed  to  yield  the  characteristic 
dystrophy  (Stroebe,  Schmidt).    There  is  a  theoretical  difficulty  in  assuming  that  hyper- 
function  with  acromegaly  can  coexist  in  the  same  gland  with  hypofunction.     Finally, 
Gushing  has  shown  that  experimental  lesions  of  the  pars  nervosa  alone  lead  to  adi- 
posogenital dystrophy,  and  in  not  a  few  cases  marked  improvement  has  followed  opera- 
tive removal  of  cystic  tumors  compressing  chiefly  the  posterior  lobe  and  infundibulum. 
The  weight  of  evidence  is  thus  distinctly  in  favor  of  the  mechanical  theory  of  pressure 
on  the  pars  nervosa.     L.  Pick,  also,  after  a  critical  review  of  much  of  the  literature,  is 
inclined  to  favor  the  mechanical  theory. 


CHAPTER  XLVIII 
THE  PINEAL  GLAND  AND  ITS  TUMORS 

Histology. — The  pineal  gland  at  full  development  measures  10  to  12  X  5  to  8  mm., 
but  suffers  gradual  atrophy  beginning  at  the  seventh  year.  Its  normal  weight  in  chil- 
dren is  20  to  25  centigrams.  It  is  surrounded  by  a  thin  capsule  of  connective  tissue 
which  closely  invests  the  gland,  joins  with  many  septa  supporting  groups  of  parenchy- 
mal  cells,  and  is  connected  with  a  loose  vascular  tunic  derived  from  the  choroid  plexus. 
The  stroma  steadily  increases  in  amount  with  age,  fine  acellular  strands  appear  sub- 
dividing the  cell  groups  and  fusing  with  them,  while  hyaline  or  calcific  granules  appear 
in  increasing  numbers.  Blood-vessels  are  scanty. 

The  parenchyma  is  composed  of  groups  of  polyhedral  cells  irregular  from  mutual 
pressure.  The  cells  are  finely  granular  and  often  contain  small  vacuoles.  The  nuclei 
are  somewhat  peculiar  in  their  reticular  network,  small  nucleoli,  and  large  size,  in 
comparison  with  the  cytoplasm.  They  stain  more  deeply  in  young  subjects.  At  this 
age  both  nuclei  and  cytoplasm  may  contain  hyaline  globules  which  Dimitrowa  regards 
as  secretion.  The  lipoid  mitochondria  demonstrated  by  Ruggeri  are  much  more  definite 
indications  of  a  secretory  function.  Krabbe  in  100  human  glands  always  found  baso- 
philic  granules  in  and  about  the  nucleus  which  he  regarded  as  secretory.  The  cells  are 
distinctly  epithelioid  in  infancy  and  form  well-defined  groups  without  lumina,  but  in 
adults  they  are  less  regular  and  the  groups  are  less  compact.  By  Weigert's  or  Heiden- 
hain's  stains  glia  fibrils  may  be  demonstrated  arising  from  the  cells,  passing  between 
cells,  and  surrounding  cell  groups.  Compact  areas  of  glia  fibers  may  appear  in  the 
adult.  Marburg  demonstrated  medullated  fibers.  This  structure  suggests  that  the 
gland  is  composed  essentially  of  modified  glia-cells  which  first  resemble  neuro-epi- 
thelium  with  secretory  functions  and  later  assume  the  form  of  glia-cells. 

About  the  vessels  may  sometimes  be  seen  small  cells  with  compact  nuclei  and  acido- 
phile  cytoplasm  (Galasescu,  Urechia).  According  to  Marburg  the  gland  always  contains 
ependymal  cells  derived  from  the  ependymal  recess  in  which  it  lies. 

Striated  muscle-fibers,  common  in  the  beef,  have  occasionally  appeared  in  the  stroma 
of  the  human  gland.  Pappenheimer  regards  them  as  analogues  of  the  myoid  cells  of  the 
thymus  and  as  derivatives  of  epithelium.  , 

General  Pathology. — Hypertrophy  of  the  epiphysis  is  recorded  by  Virchow  in  an 
infant  and  in  an  aged  woman  with  dural  psammoma;  by  Heurot  in  myxedema;  and  by 
Marburg  in  a  case  of  general  cerebral  hypertrophy.  In  a  polyglandular  syndrome  with 
hypophyseal  adenoma  Bartlett  describes  hyperplasia  of  the  pineal  gland.  Atrophy  of 
the  gland  of  quite  unusual  degree  has  been  observed  by  Laignel  and  Lavastine. 

Calcific  deposits  are  constantly  present  after  the  seventh  year.  While  usually  limited 
to  coarse  granules  the  process  reached  an  extreme  degree  in  the  case  of  Drelincourt  in 
which  the  gland  was  a  stony  mass  as  large  as  a  pigeon  egg.  Schnepf  in  an  idiot  found 
the  gland  replaced  by  two  small  concretions.  Extensive  hematomas  are  described  by 
Ziegler  and  Simon. 

Cysts  are  frequently  observed  at  all  ages.  Many  small  cysts  without  definite  lining 
may  form  during  involution  by  softening  of  the  increasing  areas  of  gliosis.  Ependymal 
cysts  lined  by  cubical  or  high  epithelium  arise  from  distention  of  alveoli  of  included  epen- 
dymal cells  (Marburg).  Either  variety  may  be  found  without  symptoms  and  some 
have  produced  hydrocephalus  and  fatal  tumor  syndromes  (Bouchut,  Joukowsky, 
Nieden,  Neumann,  Campbell,  et  al.). 

TUMORS  OF  THE  PINEAL  GLAND 

Of  the  very  rare  tumors  those  of  the  pineal  gland  are  of  much  interest 
because  of  the  peculiarities  of  their  structure  and  origin  and  because  of  the 
remarkable  disturbance  of  growth  with  which  they  are  often  associated 
(Seigneur,  Lit.). 

Occurrence. — Sixty  cases  were  collected  by  Bailey  and  Jelliffe  in  IQII, 
while  Seigneur,  1912,  found  reports  of  65.  To  these  may  be  added  the  cases 
of  Wood,  Goldzieher,  and  Rorschach.  Other  reports,  as  those  of  Pellizzi, 
are  of  clinical  diagnoses. 

948 


THE  PINEAL  GLAND  AND  ITS  TUMORS  949 

Classification. — Pineal  tumors  form  three  well-defined  groups: 

(1)  Cysts. 

(2)  Teratomas. 

(3)  Ependymal  gliomas. 

Cysts  of  various  types  constituted  12  of  the  65  tumors  collected  by 
Seigneur.  Most  of  them  were  simple  cysts  without  tumor  growth,  but  their 
general  and  local  symptoms  did  not  appear  to  be  influenced  by  that  fact. 

The  simple  cysts  vary  in  size  from  that  of  a  pea  (Garrod)  to  a  tumor 
containing  20  c.c.  of  fluid  (Joukowsky).  They  project  into  or  fill  the  third 
ventricle  and  compress  the  corpora  quadrigemina  or  the  optic  tracts.  By 
pressure  on  the  veins  of  Galen  and  occlusion  of  the  ventricle  they  almost 
invariably  lead  to  hydrocephalus.  They  have  occurred  in  the  newborn  and 
at  the  age  of  59  years  (Joukowsky,  Friedreich).  They  produce  the  usual 
symptoms  of  pineal  tumors,  but  simple  cysts  have  not  as  yet  been  observed 
with  genital  overgrowth. 

The  simple  hydrops  cysticus  produces  multiple  small  cysts  filled  with  clear 
fluid  and  lined  by  flattened,  cubical,  or  cylindrical  epithelium.  Very  simi- 
lar multiple  cysts  from  softened  areas  of  gliosis  fail  to  show  a  definite  cell 
lining.  In  5  cases  the  cyst  formed  in  a  true  neoplasm,  usually  of  the  type 
of  gliosarcoma  (Ogle,  Verger,  Neumann).  The  wall  in  Falkson's  tumor  con- 
tained cartilage,  and  in  Friedrich's  tumor  the  solid  tissue  was  psammomatous. 

Teratoma. — The  pineal  teratoma  is  exclusively  observed  in  young  males 
from  4  to  1 6  years  of  age,  and  is  regularly  associated  with  precocious  sexual 
development,  hirsuties,  and  sometimes  with  adiposity  and  general  overgrowth. 
About  12  cases  have  been  recorded,  but  the  distinctly  teratomatous  nature 
of  some  of  them  is  doubtful.  Thus  Oestreich  and  Slawyk  describe  as  cystic 
psammosarcoma  a  cystic  growth  as  large  as  an  apple,  which  Askana2y  re- 
garded as  a  teratoma  on  account  of  the  presence  of  islets  of  tissue  resembling 
cartilage. 

The  complex  teratomas  are  of  moderate  size,  solid  or  cystic,  circumscribed, 
and  produce  the  usual  local  changes  from  pressure.  They  may  be  largely 
dermoidal,  containing  hair,  sebaceous  material,  epidermoid  cysts,  and  carti- 
lage (Bailey  and  Jelliffe).  Weigert's  tumor  was  a  complex  growth  contain- 
ing cysts  lined  by  squamous  or  cylindrical  cells,  hair,  sebaceous  glands, 
sebum,  calcific  grains,  cartilage,  fat  tissue,  and  non-medullated  nerve-fibers. 
Gutzeit's  tumor  presented  skin,  sebaceous  glands,  fat,  and  smooth  muscle. 

A  layer  of  normal  or  adenomatous  pineal  tissue  may  be  found  alongside 
of  the  tumor  (Hochwart,  Gutzeit).  Less  complex  growths  classed  as  tera- 
tomas have  yielded  the  structure  of  adenochondrosarcoma  with  smooth 
muscle  (Coats).  Somewhat  uncertain  data  are  available  in  the  cases  of 
Gauderer,  Ogle,  and  P.  Neumann. 

In  a  hemorrhagic  growth  Askanazy  found  the  typical  structure  of  cho- 
rioma  with  well-defined  syncytium  and  glycogen-holding  Langhans'  cells. 

The  significance  of  the  teratomas  has  been  variously  interpreted.  The 
development  of  the  tumor  anteriorly  from  the  gland  and  the  presence  of 
nerve-fibers  seemed  to  Marburg  to  support  the  theory  that  the  tumor  repre- 
sents an  abortive  third  eye.  Ogle  ventured  to  liken  the  high  epithelial  lining 
of  a  cyst  to  the  retina  of  a  third  eye.  Askanazy  applies  the  theory  of  origin 
from  a  totipotent  sex  cell  and  traces  in  the  condition  a  form  of  pseudoges- 
tation.  It  may  be  noted  that  the  breasts  were  enlarged  in  Oestreich's 
case.  This  change  as  well  as  the  genital  overgrowth  he  would  refer  to  the 
presence  of  fetal  tissue  in  the  body.  Yet  the  same  genital  precocity  occurs 
in  simple  tumors  of  the  epiphysis. 

Were  it  not  for  the  presence  of  hair,  skin,  and  sebaceous  glands  it  would 


950 


NEOPLASTIC  DISEASES 


be  possible  to  regard  all  these  simple  tumors  as  autochthonous  teratoids. 
A  partial  choriomatdus  structure  is  produced  in  testicular  tumors  by  altera- 
tions in  the  cylindrical  cell  lining  of  blood  spaces.  While  the  structure 
of  Askanazy's  tumor  closely  approaches  that  of  chorioma,  Goldzieher's  very 
similar  tumor  was  traced  to  the  cells  lining  numerous  blood  spaces.  The 
presence  of  cartilage  may  be  satisfactorily  explained  by  metaplasia.  Smooth 
and  striated  muscle  is  an  occasional  element  of  the  normal  epiphysis. 
Ependymal  epithelium  may  become  high  and  cylindrical  or  flat,  and  squa- 
mous  and  sharp  transitions  from  one  to  the  other  type  are  observed  in  the 
so-called  teratomas  (Weigert).  Thus  all  the  elements  except  dermal  struc- 
tures may  be  derived  from  the  pineal  gland  itself.  The  dermal  structures,  as 
hair  and  sebaceous  glands,  if  they  have  been  correctly  interpreted,  seem  to 
require  an  ectodermal  tissue,  which  may  possibly  reach  the  pineal  gland  by  the 
same  developmental  disturbance  that  yields  dermal  cholesteatomas  at  the 


FIG.  502. — Chorioma  of  pineal  gland.     (After  Askanazy.) 

cerebral  base.  The  pure  pineal  lipoma  of  Hirtz  indicates  that  misplaced 
tissue  may  rest  in  this  gland  as  well  as  in  the  hypophysis. 

The  few  recorded  cases,  especially  those  of  Falkson  and  Hochwart  and 
Coats,  seem  already  to  furnish  many  transitions  from  autochthonous  mixed 
tumors,  as  adenochondrosarcoma,  to  teratomas,  so  that  the  pineal  teratomas 
are  not  so  sharply  separated  from  teratoids  as  to  warrant  their  final  accept- 
ance as  genuine  tridermal  neoplasms. 

Ependymal  Glioma. — The  majority  of  pineal  tumors  present  a  structure 
best  interpreted  as  formal  variations  of  the  modified  ependymal  cells  from 
which  the  human  epiphysis  is  immediately  derived. 

They  occur  at  later  ages  than  the  other  tumors,  raising  the  average  age 
of  incidence  of  all  pineal  growths  to  20  years  for  males  and,  for  the  14  cases 
in  females,  to  21  years.  The  usual  duration  is  from  i  to  18  months  (Falkson, 
Oestreich).  A  hard  tumor  of  Blane's,  not  examined  microscopically,  and 
Hertz's  lipoma,  progressed  for  3  and  4  years.  Hempel's  patient  died  3  years 
after  trauma.  As  a  rule  they  grow  more  rapidly  and  reach  a  larger  size  than 


THE  PINEAL  GLAND  AND  ITS  TUMORS  951 

other  pineal  tumors,  although  many  are  soon  fatal.  Turner's  mixed  tumor 
reached  the  size  of  a  kidney  and  Hempel's  solid  carcinoma  was  as  large  as  a 
hen's  egg.  The  larger  growths  may  distend  the  third,  lateral,  and  fourth 
ventricles,  with  hydrocephalus,  which  in  children  may  widen  the  cranial 
sutures.  Finkelburg's  sarcoma  involved  the  corpora  quadrigemina,  hypoph- 
ysis, floor  of  third  ventricle,  chiasm,  and  posterior  commissure.  Howell's 
first  case  was  quite  as  extensive.  Forster's  carcinoma  with  general  metastases 
is  out  of  line  with  all  later  reports.  The  exact  origin  of  some  other  large 
tumors  of  this  region  must  also  be  accepted  with  reserve. 

The  structure  of  the  mixed  pineal  tumors  is  extremely  varied  and 
these  growths  have  been  reported  under  many  terms  which  served  to  desig- 
nate the  amin  structural  type.  Thus  there  appear  3  pure  gliomas,  4  glio- 
sarcomas,  4  angiosarcomas,  4  psammosarcomas,  2  chondrosarcomas,  and 
4  round-cell  or  spindle-cell  sarcomas,  while  one  tumor  was  called  adenoma, 
and  3  carcinoma  (Seigneur).  There  is  no  good  reason  to  doubt  that  all  these 
types  represent  variations  in  the  growth  tendencies  of  the  fully  differentiated 
cells  of  the  gland. 

An  adenomatous  structure  is  approached  by  tumors  which  reproduce 
the  features  of  the  normal  gland  and  in  which  many  well-defined  groups  of 
polyhedral  cells  appear  in  a  scanty  fibrous  stroma.  The  polyhedral  cells 
are,  however,  fused  with  the  stroma  and  lumina  are  absent  or  ill-defined,  so 
that  the  resemblance  to  a  glandular  adenoma  is  seldom  pronounced. 

Ependymal  neuroglioma  is  the  term  employed  by  Pappenheimer  to  desig- 
nate a  cellular  mixed  tumor,  and  may  well  be  extended  to  cover  the  entire 
group,  to  the  exclusion  of  such  terms  as  adenoma,  carcinoma,  and  sarcoma. 
The  cells  are  usually  abundant  and  are  arranged  in  groups  surrounded  by 
stroma,  or  they  grow  diffusely  between  fibrous  strands,  or  sheath  numerous 
blood-vessels.  They  are  polyhedral,  with  clear  cytoplasm  and  sharp  borders 
resembling  ependymal  epithelium,  and  such  cells  may  inclose  fine  lumina. 
Wide  lumina  lined  by  high  cylindrical  cells  appear  in  teratomas  and  also  in 
mixed  tumors  without  other  teratomatous  characters.  Many  cells  are 
rounded,  loosely  distributed,  and  exhibit  many  fibrils.  Lymphocytes  may 
be  mingled  with  the  tumor-cells.  Diffusely  growing  tumors  of  this  type  re- 
semble round-cell  sarcoma,  but  are  properly  interpreted  as  gliomas  or  gliosar- 
comas.  Excessive  development  of  blood-vessels  may  produce  the  appearance 
of  perithelioma  or  angiosarcoma.  In  these  very  vascular  tumors  syncytial 
masses  may  form,  probably  from  ependymal  epithelium.  In  Wood's  tumor 
flattened  or  spindle-cells  surrounded  many  small  blood-vessels.  Heidenhain's 
or  Mallory's  stains  may  demonstrate  neuroglia  fibrils  running  from  and  be- 
tween the  cells.  Best's  stain  demonstrates  glycogen  in  cell  vacuoles. 

In  the  stroma  calcific  deposits  are  very  common  and  chondromatous 
metaplasia  may  yield  the  masses  of  cartilage  occasionally  observed.  Marburg 
traced  the  origin  of  the  tumor-cells  from  the  pineal  parenchyma,  finding  an 
external  zone  of  gland  tissue,  an  intermediate  layer  of  proliferating  cells  of 
ependymal  type,  and  a  central  area  chiefly  gliomatous.  In  Howell's  cases  the 
central  area  was  composed  of  diffuse  large  round  cells  without  intercellular 
substance,  while  the  periphery  yielded  alveoli  somewhat  larger  than  those  of 
the  normal  gland. 

Symptomatology. — The  chief  interest  in  pineal  tumors  lies  in  their  symp- 
tomatology, the  study  of  which  is  susceptible  of  the  same  elaboration  as 
has  been  given  to  hypophyseal  growths. 

The  clinical  features  present  two  phases:  (i)  Pressure  symptoms,  gen- 
eral and  specific,  and  (2)  disturbances  in  the  physiology  of  growth. 

(i)  Pressure  symptoms  common  to  this  and  other  brain  tumors,  head- 


952  NEOPLASTIC  DISEASES 

ache,  vomiting,  paresthesias,  and  vertigo,  mark  the  onset  of  most  cases.  The 
usual  absence  of  brachycardia  is  referred  by  M.  Neumann  to  early  closure 
of  the  aqueduct  of  Sylvius  which  spares  the  vagus  in  the  fourth  ventricle 
from  pressure.  More  specific  of  the  location  of  the  tumors  are  the  staggering 
gait,  cerebellar  ataxia  from  pressure  on  the  vermis,  and  peculiar  ocular  dis- 
turbances, including  nystagmus,  ophthalmoplegia,  and  loss  of  pupillary  reac- 
tions. Seigneur  found  paralysis  of  the  common  oculomotor  nerve  in  18  cases, 
of  the  pathetic  in  7,  and  of  the  externus  in  9.  The  oculomotor  is  affected 
by  destruction  of  its  nucleus  and  the  pathetic  and  externus  by  pressure  on 
the  trunks.  Auditory  disturbance  may  be  referred  to  pressure  on  the  audi- 
tory nerve  or  corpora  quadrigemina.  Unilateral  facial  palsy  may  occur. 
Failure  of  mentality  is  marked  by  dulness,  delirium,  or  prolonged  somnolence 
in  which  hydrocephalus  probably  plays  a  part.  Epileptic  convulsions  fre- 
quently occur.  Polyphagia,  polyuria,  and  glycosuria  have  been  observed. 

(2)  The  disturbance  of  growth  affects  chiefly  the  genitals,  but  is  often 
associated  with  adiposity  and  occasionally  with  general  and  symmetrical 
overgrowth.  Hypertrophy  of  the  penis  and  testes,  growth  of  pubic  hair,  and 
precocious  sexual  instinct  have  been  observed  with  most  tumors  classed  as 
teratomas,  as  well  as  with  simple,  benign,  and  malignant  tumors.  In  the  testes 
there  is  marked  development  of  the  interstitial  cells  (Goldzieher).  In 
Oestreich's  case  the  enlarged  breasts  in  a  boy  of  4  secreted  colostrum  and 
the  testes  were  much  enlarged.  In  the  case  of  Raymond  and  Claude  the 
genital  organs  were  small,  but  there  was  a  growth  of  fine  hair  on  the  lip  and 
cheeks.  Hirsuties  has  been  much  more  frequent  than  hypertrophy  of  the 
genitals.  Hochwart  mentions  a  deepening  of  the  voice.  In  Schmidt's  case 
conception  occurred  at  15  years  and  menstruation  ceased  at  22  years.  Gen- 
eral overgrowth  of  the  body  is  described  by  Oestreich,  Raymond,  Hochwart, 
and  Bailey  and  Jelliffe.  Daly's  patient,  aged  23,  with  a  large  carcinoma, 
had  polyphagia  and  gained  30  kilos  in  6  months. 

Adiposis  has  been  observed  in  all  varieties  of  tumors  and  is  apparently 
not  to  be  distinguished  clinically  from  hypophyseal  obesity.  Marburg 
stated  expressly  that  the  hypophysis  was  normal  in  his  case  and  yet  the  usual 
obesity  was  present. 

The  pathogenesis  of  the  metabolic  symptoms  remains  obscure.  The 
combination  of  genital  overgrowth  with  obesity  is  contrasted  with  the  genital 
hypoplasia  and  adiposity  of  hypophyseal  tumors.  It  may  be  assumed  that 
the  pineal  tumor  excites  genital  overgrowth  by  a  sympathetic  influence  on  the 
interstitial  cells  of  the  testis,  which  in  some  cases  have  been  found  hyperplastic. 
The  obesity  may  then  be  attributed  to  pressure  on  the  hypophysis,  pars 
nervosa,  or  distention  of  the  infundibulum.  This  interpretation  rests  on  the 
theories  of  hyperpinealism  and  hypophyseal  insufficiency.  It  is  not  entirely 
consistent  with  Raymond's  case  of  large  glioma,  hydrocephalus,  obesity,  and 
testicular  atrophy.  Yet  most  observations  indicate  that  pineal  overgrowth 
stimulates  growth  of  the  testes. 

Adrenal  tumors  are  often  associated  with  overgrowth,  obesity,  and 
genital  precocity.  With  hypophyseal  tumors  the  adrenals  were  found  normal 
by  Marburg  and  Goldzieher,  but  were  hyperplastic  in  Raymond's  case.  In 
each  of  these  cases  there  was  genital  overgrowth.  A  direct  influence  of  the 
adrenal  may  therefore  be  eliminated. 

Signs  of  status  lymphaticus  with  persistence  of  thymus  were  noted  by 
M.  Neuman  and  Marburg. 

Experimental  studies  are  already  not  without  suggestive  results  (Dana, 
Berkeley,  Lit.).  Exner  and  Boese  destroyed  the  pineal  in  95  rabbits  without 
observing  any  change  in  22  surviving  animals.  Foa,  however,  observed 


THE  PINEAL  GLAND  AND  ITS  TUMORS  953 

increase  of  weight  and  genital  overgrowth  in  3  roosters  deprived  of  the  pineal 
gland  in  the  fifth  week  of  life.  Biach  and  Hulles  produced  marked  atrophy 
of  the  pineal  gland  by  castrating  kittens.  Berkeley  produced  acceleration 
of  growth  in  young  animals  by  injections  of  pineal  nucleoproteid,  and  he 
with  Cornell  and  Goddard  observed  considerable  mental  improvement  hi 
backward  children  fed  on  gland  substance.  McCord  also  observed  consider- 
able acceleration  of  growth  and  sexual  precocity  in  chicks  and  guinea-pigs 
fed  on  the  substance  of  calves'  pineal. 

The  foregoing  clinical,  pathological,  and  experimental  data  seem  to  point 
rather  strongly  to  the  conclusion  that  normal  activity  of  the  pineal  gland 
facilitates  normal  growth  in  general  and  sexual  development  in  particular. 
Acceleration  of  these  functions  occurring  in  the  course  of  pineal  tumors  may 
therefore  be  interpreted  as  hyperpinealism.  In  the  absence  of  further  data 
the  obesity  and  hypertrichosis  may  be  regarded  as  a  part  of  the  general  and 
sexual  overgrowth,  but  the  hypophyseal  failure  must  be  considered  as  a  pos- 
sible factor  in  the  adiposity.  The  existence  of  hypopinealism  is  less  clearly 
established.  There  is  evidently  a  close  relationship  between  pineal  and 
testicular  functions  which  is  probably  not  of  an  antagonistic  nature,  but  the 
observations  are  as  yet  inadequate  to  define  the  exact  position  of  the  pineal 
with  reference  to  other  glands  of  internal  secretion. 


CHAPTER  XLIX 
TERATOLOGY 

Only  a  very  limited  portion  of  the  extensive  subject  of  teratology  is  of 
interest  to  the  oncologist,  and  that  portion  is  probably  of  least  importance  to 
teratology.  Hence  in  the  great  scope  of  Ballantyne's  "Antenatal  Pathology" 
one  finds  an  impressive  catalogue  of  the  multitudinous  types  of  human  de- 
formities and  monsters,  but  little  regarding  human  teratomas.  Marchand  in 
Eulenberg's  Realencyclopedia  (1911)  presents  an  orderly  and  very  exhaustive 
list  of  forms  and  ably  discusses  the  subject  of  causal  genesis  of  double  mon- 
sters, without  entering  exactly  into  the  details  of  many  other  questions. 
Schwalbe's  elaborate  treatise  presents  the  sum  total  of  knowledge  up  to  igo6, 
the  scope  of  which  necessarily  renders  specific  details  somewhat  inaccessible. 
He  emphasizes  the  existence  of  an  unbroken  series  from  identical  twins, 
through  double  monsters,  teratomas,  and  mixed  tumors  down  to  some  simple 
tumors.  In  tracing  the  origin  of  these  structures  he  introduces  the 
term  "teratogenic  termination  period"  to  indicate  the  latest  period  of  embry- 
onal development  at  which  a  given  structure  could  have  originated.  A  recent 
compilation  is  that  of  Hubner. 

It  must  be  admitted,  I  think,  that  while  teratological  studies  have  nar- 
rowed down  the  range  of  possibilities  in  the  origin  of  identical  twins  and  have 
defined  the  probable  origin  of  most  double  monsters,  yet  the  divergent  views 
regarding  the  nature  of  fetal  inclusions  and  adult  teratomas  are  almost  as 
numerous  as  ever. 

Experimental  teratology,  as  presented  by  Fischl,  illuminates  the  principles 
of  embryogenesis,  but  points  out  how  teratomas  may  develop  rather  than 
demonstrating  how  they  actually  arise. 

Under  these  conditions  it  seems  most  serviceable  for  the  present  purpose 
to  indicate  the  present  position  of  the  various  forms  of  abnormal  growths 
which  belong  to  oncology,  their  general  relation  to  one  another  in  a  series  of 
diminishing  complexity,  and  to  briefly  review  the  factors  probably  present 
in  their  origin.  For  the  more  complete  discussion  of  all  these  subjects  the 
reader  should  refer  to  the  above-mentioned  works. 

There  are,  however,  two  important  tendencies  discernible  in  recent 
embryological  research  which  seem  to'  be  insufficiently  considered  in  most 
text-books  on  teratology.  These  are  the  growing  recognition  of  frequent 
impurities  in  specific  germ  layers  and  the  increasing  scope  now  being  given 
to  the  process  of  budding  in  embryogenesis. 

It  must  be  admitted  that  the  doctrine  of  the  rigid  specificity  of  the  germ 
layers  has  suffered  some  limitation  in  recent  years.  The  possibility  that 
in  the  formation  of  these  layers  the  separation  may  be  incomplete  and  that 
portions  of  one  layer  may  be  carried  over  into  another  has  been  entertained 
with  increasing  freedom.  The  further  possibility  that  the  formative  capaci- 
ties of  anatomically  pure  germ  layers  may  not  always  be  restrained  within 
the  rigid  limits  formerly  set  must  also  be  considered.  Especially  in  the 
field  of  teratogenesis  these  infractions  of  the  set  laws  of  growth  become  of 
first  importance,  for  the  practical  inviolability  of  these  laws  has  always  been 

954 


TERATOLOGY 


assumed  as  a  necessary  basis  in  the  construction  of  theories  of  origin  of  tera- 
tomas.  To  what  extent  recent  studies  in  this  direction  will  remodel  the 
conceptions  of  teratomas  remains  for  the  future  to  determine. 

Secondly,  the  importance  of  budding  of  originally  simple  embryonal 
tissues  as  a  source  of  complex  teratomas  has  probably  been  underestimated 
by  many  observers  who  have  been  inclined  to  attribute  all  such  complex 
growths  to  originally  complex  sources,  as  isolated  blastomeres,  totipotent 
sex  cells,  or  embryonic  inclusions.  This  principle,  long  since  recognized 
and  amplified  by  R.  Williams,  applies  especially  to  the  parasitic  implanta- 
tions and  complex  mixed  tumors,  although  it  may  be  of  less  importance  than 
that  author  seems  to  imply  in  the  origin  of  the  irritation  group  of  malignant 
tumors.  In  many  respects  this  conception  appears  in  the  references  to  the 
"genius  loci"  and  the  development  of  secondary  growth  centers,  which  appear 
in  many  discussions  of  the  origin  of  teratomas. 

Oncology  is  usually  assumed  to  deal  with  the  following  list  of  develop- 
mental anomalies  and  their  sequelae: 

(1)  Asymmetrical  double  monsters,  parasitic  fetuses,  or  fetal  inclusions. 

(2)  Teratomas. 

(3)  Complex  dermoids  or  teratoid  tumors. 

(4)  Mixed  tumors. 

(5)  Simple  dermoids  and  epidermoids. 

DOUBLE  MONSTERS 

Double  monsters  are  (i)  symmetrical  or  (2)  asymmetrical, 
(i)  Symmetrical  double  monsters  consist  of  two  equal  or  nearly  equal 
fetuses  which  are  joined  together  at  the  cephalic  ends  (cephalopagi) ;  or  at 


FIG.  503. — Case  of  ischiopagnus  duplicatus,  born  at  Hanau,  Germany,  Mar.  u,  1643. 

(After  Wilder .)' 

the  thorax  (thoracopagi) ;  or  at  the  pelvis  (ischiopagi).  Such  conditions 
may  result  from  the  partial  fusion  of  two  originally  separate  embryos  derived 
from  one  ovum,  or  from  the  incomplete  splitting  of  one  original  embryo. 
Which  of  these  two  events  actually  occurs  cannot  at  present  be  determined. 
According  to  Marchand,  all  symmetrical  double  monsters  have  a  single 
chorion,  as  do  monochorial  twins,  and  nearly  all  have  a  single  placenta. 


956 


NEOPLASTIC  DISEASES 


In  the  causation  of  symmetrical  double  monsters  there  are  several  possi- 
bilities. In  the  'case  of  the  asymmetrical  double  monster  the  parasitic 
fetus  is  rudimentary,  and  this  fact  is  the  chief  basis  of  the  view  that  it  origi- 
nates from  a  structure  of  much  reduced  embryonic  value.  Marchand  holds 
that  the  parasitic  fetus  is  derived  either  from  a  polar  body  or  from  an  early 
isolated  blastomere.  In  the  first  instance  the  isolated  structure  is  derived 
from  an  unfertilized,  in  the  latter  from  a  fertilized,  ovum.  Yet  the  possibil- 
ity of  fertilization  of  polar  bodies  even  in  the  human  subject  may  perhaps  be 
entertained,  since  in  the  flat  worms  this  event  is  of  regular  occurrence  and  has 
a  definite  function  in  the  early  embryo.  The  sacral  parasites  and  epignathi, 
from  their  structure,  position,  and  mode  of  attachment,  may  be  regarded  as 
developing  within  the  amnion,  while  the  abdominal  parasites  may  arise 

on  the  belly  stalk  outside  the  amnion  and 
become  included  during  the  closure  of  the 
abdominal  wall.  A  development  from  two 
separate  embryos  is  inconsistent  with  the 
position  of  the  parasite,  which  would 
have  to  lie  free  on  the  yolk  sac  of  the 
autosite  without  connection  with  the  cho- 
rion,  as  held  by  Ahlfeld  and  Taruffi.  Yet 
umbilical  cords  and  even  rudimentary 
placentae  have  been  observed  with  epig- 
nathi (Rathke)  and  abdominal  inclusions. 
Bonnet  has  accepted  and  elaborated  this 
view  of  the  origin  of  parasitic  inclusions 
and  many  teratomas. 

Schwalbe  concludes  that  epignathi  and 
other  teratomas  arise  from  isolated  blasto- 
meres,  but  regards  the  development  of 
polar  bodies  as  improbable.  Fischel  argues 
at  length  against  the  origin  from  polar 
bodies,  and  reasons  that  all  fetal  inclusions 
arise  (i)  from  a  second  fertilized  ovum 
attached  to  the  first,  or  (2)  from  isolation 
and  dislocation  of  portions  of  the  germ 
layers.  This  point  of  view  renders  most 
intelligible  the  apparently  unbroken  series 
of  complex  to  simpler  structures  occurring 
at  the  caudal  and  cephalic  extremities, 
but,  as  Marchand  says,  it  probably  over- 
estimates the  potencies  of  fragments  of 
differentiated  germ  layers.  The  ovum 
may  be  abnormal  and  contain  multiple 
germ  disks,  which  have  often  been  observed 
in  human  ovaries,  or  there  may  be  an  ab- 
normal distribution  of  germ  material.  The 
entrance  of  more  than  one  spermatozoon 


FIG.  504.— a  and  b,  Case  of  im- 
perfect ischiopagnus  duplicatus, 
showing  on  one  side  a  double  bi- 
lateral limb,  composed  of  halves 
belonging  to  each  component,  born 
in  Cadiz,  May  30,  1818;  c,  Mon- 
strum  Anglicum,  born  in  Salisbury, 
Eng.,  Oct.  26,  1664.  (Licetus.} 
(After  Wilder.') 


into  an  ovum  occurs  in  reptiles,  but  in  man  it  probably  entails  an  abnormality 
of  the  ovum  which  tends  to  result  in  its  death.  Yet  this  outcome  cannot 
be  assumed  as  certain.  The  occurrence  of  double  headed  and  other  abnormal 
spermatozoa  has  been  emphasized  especially  by  Bromann  and  by  Hofer  and 
considered  as  a  possible  source  of  double  monsters.  The  formation  of  the 
double  germinal  areas  necessary  for  the  origin  of  double  monsters  must  occur 
after  the  union  of  male  and  female  pronuclei,  since  twinning  is  hereditary. 


FYT 


TERATOLOGY 


957 


Experimental  studies  have  demonstrated  some  of  the  conditions  which 
may  exist  in  the  origin  of  double  monsters.  Roux  produced  one-sided 
embryos  some  of  which  were  able  to  develop  almost  perfect  embryos  of  re- 
duced size.  This  process  he  called  "post-generation."  The  bilateral  char- 


FIG.  505. — Lateral  view  of  two  cephalothoracopagi  (Janus  monsters),  showing  dif- 
ferent degrees  of  separation.  The  face  which  is  toward  the  observer  is  duplicated  by 
another  on  the  opposite  side.  Each  face  is  contributed  by  the  two  components.  (After 
Wilder.) 

acter  of  the  human  embryo  may  favor  complete  splitting,  but  there  is  no  evi- 
dence that  double  monsters  result  from  such  factors.  Mechanically,  invert- 
ing the  ova  to  180  degrees  (Schultze,  Wetzel)  and  the  distorting  effects  of 


FIG.  506. — Position,  form,  and  grouping  of  primordial  germ  cells  in  33  somite  chick 
embryos:  pr.o.,  Germ  cells;  sp.m.,  splanchnic  plate  of  mesoderm;  c.a.,  ccelomic  angle; 
ent,  entoderm.  (After  Swift.) 

distilled  water  (J.  Loeb)  have  produced  double  embryos,  but  this  method  is 
probably  not  followed  in  nature.  Two  primitive  streaks  and  embryonal  areas 
have  often  been  observed  in  ova,  and  double  monsters  of  this  origin  have 
been  traced  in  the  chicken  egg  by  Dareste.  Marchand  concludes  that  all 


958  NEOPLASTIC  DISEASES 

cases  of  symmetrical  double  monsters  arise  from  two  originally  separate 
embryonal  areas  which  imperfectly  fuse  by  ectoderm  or  entoderm  and  meso- 
derm,  and  that  this  process  occurs  during  gastrulation.  In  symmetrical 
monsters  either  member  of  the  pair  may  be  considerably  dwarfed  through 
defects  of  the  ovum  or  disturbances  in  placenta,  cord,  or  amnion. 

The  importance  of  aberrant  sex  cells  as  sources  of  fetal  implantations 
has  been  emphasized  by  the  observations  of  Nussbaum,  Allen,  and  Swift, 
who  have  found  groups  of  such  cells  marooned  in  considerable  numbers  all 
along  the  embryonal  entoderm  from  which  they  are  derived.  In  some  cases 
only  a  portion  of  these  cells  reach  their  normal  haven  in  the  sex  glands.  That 
the  teratomas  of  the  sex  glands  are  derived  from  primitive  sex  cells  is  now 
generally  accepted,  and  it  is  highly  probable  that  many  extragenital  tera- 
tomas have  the  same  origin.  Since  most  observers  agree  with  Schwalbe 
and  Marchand  that  no  essential  morphological  distinctions  separate  the 
genital  and  extragenital  teratomas  and  the  fetal  implantations,  it  seems 
not  impossible  that  the  entire  group  may  be  referred  to  a  single  origin.  At 
present  the  collateral  evidence  hardly  justifies  the  extension  of  this  theory 
to  the  epignathi  and  sacral  parasites,  but  the  sex-cell  theory  has  one  great 
advantage  in  that  aberrant  sex  cells  have  been  observed  in  numbers  and 
their  common  occurrence  in  man  is  established,  whereas  isolated  blasto- 
meres  and  developing  polar  bodies  in  the  human  subject  are  hypothetical 
structures. 

It  thus  appears  that  while  the  possible  modes  of  morphogenesis  of  fetal 
inclusions  have  been  fully  covered,  the  real  source  or  sources  of  these 
structures  remain  undetermined.  It  can  only  be  stated  that  they  arise  from 
nearly  or  quite  totipotent  material.  The  field  of  divided  single  or  fused 
double  embryonal  areas  appears  to  be  exhausted  in  the  fused  twins,  thora- 
copagi,  etc.  The  weight  of  opinion  seems  to  favor  the  view  that  the  fetal 
implantation  arises  from  material  of  much  less  growth  energy  than  is 
possessed  by  any  form  of  double  embryo  and  must  be  referred  to  isolated 
blastomeres,  to  marooned  sex  cells,  possibly  in  some  instances  to  polar  bodies, 
and  very  probably  in  many  instances  to  the  process  of  budding. 

Of  the  causal  genesis  of  double  monsters  and  fetal  implantations  nothing 
is  definitely  known.  Clinical  observations  have  given  no  hint  of  the  under- 
lying conditions.  Signs  of  syphilis  are  rarely  present,  and  no  case  of  repeated 
births  of  double  monsters  has  been  recorded.  The  extensive  field  of  experi- 
mental teratology  has,  in  the  opinion  of  Schwalbe,  added  nothing  to  our 
knowledge  of  causal  genesis.  Hubner's  review  consists  of  a  repetition  of  the 
data  regarding  multinucleated  ova,  multiple  germ  disks  and  embryonal  areas, 
abnormal  or  supernumerary  spermatozoa,  excessive  germ  material,  and  other 
conditions  which  form  the  basis  of  the  discussions  of  formal  genesis. 

THE  PARASITIC  FETUS 

This  form  of  parasitic  growth  appears  chiefly  in  the  sacral  region,  or 
protruding  from  the  pharynx  (epignathi),  or  in  the  thoracic  or  abdominal 
cavities.  Its  structure  presents  the  organs  of  a  fetus,  but  always  in  imper- 
fectly developed  or  rudimentary  form,  and  often  in  disorderly  arrangement. 
An  umbilical  cord  is  often  present  and  fetal  membranes  and  even  a  placenta 
or  its  homologous  structure  may  be  found.  Schwalbe  and  Nakayama  are 
unable  to  separate  sharply  between  such  complete  fetuses  and  much  less 
complex  growths  occurring  in  the  same  situations. 

The  origin  of  the  fetal  implantation  may  in  certain  cases  be  attributed 
to  a  second  embryo  which  in  some  way  becomes  attached  to  the  tissues  of 


TERATOLOGY  959 


its  host,  the  autosite.  This  mode  of  origin  is,  however,  probably  the  rarest 
of  events,  for  the  evidence  of  comparative  embryology  points  to  the  process 
of  budding  as  the  most  probable  source  of  parasitic  implantations,  especially 
when  the  parasites  are  multiple  and  their  development  markedly  im- 
perfect. 

Therefore  in  the  origin  of  the  parasitic  fetus  a  wholly  different  process 
is  probably  concerned  from  that  which  give  rise  to  true  twin  fetuses.  True 
twins  may  result  from  the  fertilization  of  two  separate  ova  derived  from  one 
Graafian  follicle,  or  from  simultaneous  ovulation  from  both  ovaries  as  shown 
by  the  presence  of  bilateral  corpora  lutea,  or  by  rupture  of  more  than  one 
follicle  in  the  same  ovary,  an  event  which  is  common  in  lower  animals.  In 
these  cases  the  sex  and  form  of  the  twins  may  differ  and  there  are  two  sepa- 
rate placentas  and  fetal  membranes. 

Identical  twins  develop  from  one  ovum  and  are  of  the  same  sex  and  char- 
acteristics, but  the  conformation  of  the  placenta  and  membranes  varies. 
Several  theories  of  the  origin  of  identical  twins  are  maintained,  including 
multinucleated  ova,  formation  of  two  germinal  vesicles,  or  complete  separa- 
tion in  equal  parts  of  an  originally  single  fertilized  ovum,  fusion  of  two  embryos, 
post-generation,  separation  of  the  two  initial  blastomeres.  Of  these  Wilder 
favors  the  last. 

TERATOMAS 

The  term  "teratoma"  has  a  restricted  application  to*  a  group"  of  tumors 
composed  of  recognizable  tissues  and  complex  organs  derived  from  more  than 
one  germ  layer.  While  in  the  parasitic  fetus  the  organs  are  arranged  in 
normal  or  nearly  normal  relations,  producing  a  rudimentary  fetus,  in  the 
teratoma  there  is  a  notable  lack  of  orderly  arrangement,  producing  merely  a 
veritable  potpourri  of  fetal  tissues.  The  less  complex  tumors  of  this  class 
may  be  designated  as  teratoids.  The  term  "embryoma"  is  applied  by 
Wilms  and  others  to  various  members  of  this  group.  It  is  best  limited  to 
teratomas  closely  resembling  embryos.  The  tissues  of  teratomas  may  be  of 
adult  or  embryonal  type,  and  on  this  ground  some  authors  refer  to  the  former 
as  co-etaneous,  the  latter  as  embryonal.  Since  both  types  of  tissue  occur  in 
the  same  teratoma  the  analysis  furnishes  no  indications  of  the  origin  of  the 
growths,  and  it  must  be  assumed  that  secondary  factors  determine  the  rate 
of  differentiation  of  the  cells  of  origin. 

While  the  parasitic  fetus  does  not  give  rise  to  secondary  blastomatous 
processes,  the  teratoma  frequently  originates  true  tumors,  benign  from  the 
adult  elements,  malignant  from  the  embryonal  structures. 

An  important  principle  of  the  growth  of  teratomas  is  the  tendency  of  one 
element,  either  adult  or  embryonal,  to  overgrow  and  suppress  the  others. 
The  obverse  of  this  principle,  viz.,  the  progressive  degeneration  of  germ  layers, 
is  probably  of  equal  importance.  Thus  bidermal  teratomas  are  frequently 
observed,  but  such  cases  seem  to  diminish  with  the  increased  persistence  of  the 
search  for  a  third  germ  layer.  Saxer  observed  a  single  tooth  as  the  sole 
element  of  an  ovarian  teratoma,  and  all  chondromas  of  the  testis  are  of 
teratoid  nature  (Ribbert).  The  studies  of  Wilms  on  ovarian  dermoids,  by 
showing  the  uniform  tridermal  nature  of  these  tumors,  furnished  the  basis 
of  this  principle,  which  has  been  elaborated  by  L.  Pick  and  many  others. 
The  application  of  the  rule  is  open  to  error  when  the  various  germ-layer 
derivatives  are  not  rigidly  scrutinized.  Borst  and  others  warn  against  the 
unscrupulous  identification  of  embryonal  derivatives  in  teratomas.  Yet 
the  tridermal  nature  of  certain  groups  of  teratomas  is  well  established 
and  the  warning  may  apply  chiefly  against  fantastic  interpretations  of 


960 


NEOPLASTIC  DISEASES 


organ  rudiments.  m  Another  source  of  error  lies  in  the  possibility  that  meta- 
plasia or  abnormal  self-differentiation  may  occasionally  break  down  the 
barriers  formerly  erected  between  the  germ  layers.  It  is  assumed  that  the 
separation  of  germ-layers  of  the  normal  embryo  holds  also  for  the  teratoma, 
but  if  the  abnormal  environment  of  the  teratoma  may  serve  to  disturb  the 
normal  laws  of  differentiation  the  views  of  the  origin  of  teratomas  may  have 
to  be  altered.  The  "genius  loci"  has  already  been  invoked  to  support  the 
local  origin  of  certain  apparently  heterochthonous  sacral  teratomas.  The 
overgrowth  of  one  element  in  an  embryonal  teratoma  produces  a  malignant 
tumor  of  nearly  uniform  type,  since  it  has  been  shown  that  many  malignant 
tumors  of  the  sex  glands  originate  in  this  way.  The  same  principle  probably 
applies  to  many  embryonal  tumors  of  other  regions,  but  to  what  extent  re- 
mains for  future  observations  to  determine. 


FIG.  507. — Ependymal  structures  surrounded  by  brain  tissue  in  a  small  teratoma  of 

ovary. 

In  discussing  the  morphogenesis  of  teratomas  it  must  be  admitted  that 
no  sharp  dividing  line  can  be  drawn  between  these  disorderly  embryomas 
and  fetal  implantations,  on  the  one  hand,  and  the  complex  teratoids  and  mixed 
tumors  on  the  other.  Yet  this  fact  does  not  lessen  the  probability  that  spe- 
cial conditions  determine  the  growth  of  the  large  group  of  typical  teratomas 
and  that  a  particular  material,  not  connected  with  fetal  implantations  or 
simple  mixed  tumors,  gives  origin  to  teratomas.  The  clinical  evidence  in 
the  field  lies  in  favor  of  this  view,  but  is  somewhat  neglected.  The  age  inci- 
dence, location,  and  course  of  many  typical  teratomas  strongly  suggest  a 
peculiar  formal  and  causal  genesis. 

The  chief  source  of  teratomas  is  probably  the  aberrant  sex  cell.  This 
origin  alone  adequately  accounts  for  the  predilection  of  teratomas  for  the  sex 


TERATOLOGY  961 

glands.  The  observation  of  numerous  sex  cells  displaced  along  the  entire 
length  of  the  embryonal  entoderm  offers  abundant  source  for  most  abdominal 
and  thoracic  teratomas.  Some  reported  abdominal  and  thoracic  teratomas 
may  possibly  represent  metastatic  growths  from  minute  teratomas  of  ovary  or 
testis.  I  have  recorded  a  mediastinal  teratoma  secondary  to  a  small  testicu- 
lar  growth  which  escaped  several  examinations  during  life. 

For  the  pharyngeal  and  sacral  teratomas  no  single  mode  of  origin  can  be 
adduced.  The  most  highly  developed  of  the  sacral  tumors  are  fetal  implan- 
tations. Another  larger  group,  of  which  Nakayama  traces  many  transitions 
from  comparatively  simple  up  to  very  complex  growths,  are  true  teratomas. 
Others  probably  represent  forms  of  partial  reduplication  or  are  of  strictly 
local  origin.  Exactly  similar  variations  are  observed  in  the  structure  and 
complexity  of  the  epignathi  (cf.  Arnold).  The  complex  developmental  proc- 
cesses  and  the  definite  growth  centers  located  at  the  cephalic  and  caudal 
extremities  offer  unusual  opportunities  for  the  appearance  of  complex  teratoid 
structures  derived  by  budding  from  purely  local  sources.  An  extreme 
variety  of  structural  defects  in  neighboring  tissues  is  observed  with  this  class 
of  growths,  including  cranial  fissures,  spina  bifida,  rhachischisis,  etc.,  and  the 
discovery  of  such  defects  is  of  much  value  in  establishing  the  nature  of  the 
growth. 

For  the  majority  of  extragenital  teratomas  an  origin  from  isolated  blasto- 
meres  is  maintained  by  Marchand  and  accepted  in  some  form  by  many 
authors.  The  occurrence  of  these  growths  in  median  positions  and  in  much 
the  same  localities  with  fetal  implantations,  the  difficulty  of  separating  them 
morphologically  from  the  parasitic  fetus,  and  their  obvious  origin  from  totipo- 
tent  or  nearly  totipotent  material,  strongly  suggest  an  origin  very  similar 
to  that  of  the  asymmetrical  double  monster.  The  isolation  of  an  early 
blastomere  would  theoretically  account  for  such  structures,  but  this  theory 
has  little  if  any  advantage  over  the  origin  from  sex  cells.  The  process  of 
budding,  however,  presents  strong  claims  for  consideration  in  this  field. 

Thus,  three  main  groups  may  be  recognized  of  tumors  containing  adult 
or  embryonal  organs  in  disorderly  arrangement:  (i)  Teratomas  derived  from 
aberrant  sex  cells  and  found  chiefly  in  the  sex  glands.  (2)  Extragenital  tera- 
tomas, many  of  which  approach  the  development  of  the  parasitic  fetus  and 
which  may  be  derived  from  isolated  nearly  totipotent  blastomeres,  or  from 
early  budding  of  the  blastoderm.  (3)  Teratomas  (or  teratoids)  derived  from 
multipotent  material  of  distinct  regional  stamp  and  reproducing  the  organs 
of  these  regions.  These  tumors  are  usually  associated  with  a  defect  in  the 
formation  of  the  parts  from  which  they  spring. 

Regarding  the  causal  genesis  of  teratomas  there  are  few  data.  The  isola- 
tion of  blastomeres  is  not  known  to  occur — much  less  the  causes  of  such  isola- 
tion. For  the  teratomas  of  sex  glands  there  is  much  clinical  evidence  that 
trauma  figures  in  many  cases  and  excites  the  parthenogenetic  development 
of  the  aberrant  sex  cell.  Harvey  has  tabulated  many  methods  for  the  artificial 
production  of  parthenogenesis,  some  of  which,  including  trauma,  are  suc- 
cessful in  frogs.  Teratoma  testis  arises  at  the  junction  of  rete  and  spermatic 
tubules,  and  at  this  junction  Kirkbride  has  shown  that  there  may  be  very 
marked  disorder  in  the  structure  of  the  fetal  testis  favoring  the  displace- 
ment of  cells.  Teratoma  testis  is  also  relatively  frequent  in  the  rudimentary 
undescended  testis. 

COMPLEX  DERMOIDS 

The  great  majority  of  complex  dermoids  are  imperfectly  developed  tera- 
tomas and  in  the  sex  glands  it  is  very  probable  that  all  dermoids  are  of  this 
61 


962  NEOPLASTIC  DISEASES 

nature.  Since  the  bulk  of  the  early  embryo  is  composed  of  ectoderm,  the 
overgrowth  of  this  germ  layer  in  the  development  of  teratomas  is  a  natural 
result  and  favors  the  theory  of  origin  from  sex  cells.  The  comparatively 
frequent  chorioma  testis  is  the  embryonal  equivalent  of  the  testicular  der- 
moid.  Chevassu's  series  contains  intermediate  stages  between  the  embryonal 
and  the  adult  ectodermal  tumor. 

A  local  origin  by  budding  off  of  multipotent  material  appears  to  be  respon- 
sible for  certain  complex  dermoids  of  the  cephalic  and  caudal  extremities. 
They  are  usually  associated  with  defects  in  neighboring  structures.  Medias- 
tinal  and  retroperitoneal  dermoids  may  be  of  comparatively  simple  structure, 
but  it  is  unusually  difficult  to  refer  such  growths  to  a  local  origin. 

MIXED  TUMORS 

The  scope  of  this  term  has  been  greatly  restricted,  especially  by  the  studies 
of  Wilms,  who  reviewed  the  once  numerous  group  and  demonstrated  the  tri- 
dermal  and  teratomatous  nature  of  many  of  the  tumors  included  therein. 
Through  his  work  and  that  of  many  later  observers  the  mixed  tumor  has 
largely  become  the  modified  teratoma,  and  the  idea  of  a  predominant  meta- 
plasia in  the  growth  of  many  tissues  has  been  replaced  by  the  conception  of  a 
natural  unfolding  of  embryonal  cell  potencies.  Hence  the  term  "mixed 
tumors"  is  now  confined  to  comparatively  simple,  chiefly  embryonal  growths, 
of  purely  local  origin,  resulting  from  overgrowth  of  embryonal  structures 
with  or  without  misplacement. 

Most  of  the  accepted  forms  of  mixed  tumors  do  not  contain  derivatives 
of  three  germ  layers,  but  are  bidermal  or  monodermal.  Yet  tridermal  tumors 
of  local  origin  are  observed,  especially  at  the  caudal  and  cephalic  ex- 
tremities. Since  it  is  not  always  possible  to  determine  whether  a  tumor  is  a 
poorly  developed  teratoma  of  heterochthonous  origin  or  a  complex  neoplasm 
of  local  origin,  a  rigid  classification  of  such  cases  cannot  be  accomplished. 
In  general  one  may  follow  the  rule  of  designating  as  mixed  tumors  growths  in 
which  embryonal  and  blastomatous  features  are  prominent,  and  grouping  as 
teratomas  those  growths  in  which  the  structure  is  more  complex  and  rudi- 
mentary organs  are  present.  It  is  obvious  that  the  mixed  tumors  are  closely 
related  in  origin  to  the  extensive  series  of  simple  embryonal  tumors  occurring 
in  many  regions. 

The  restricted  group  of  mixed  tumors  is  designated  by  Adami  as  terato- 
blastomas.  Yet  many  true  teratomas  are  blastomatous,  and  it  seems 
desirable  to  distinguish  as  far  as  possible  between  teratomas  and  mixed 
tumors. 

In  the  true  mixed  tumor  the  blastomatous  process  affects  both  germinal 
derivatives,  producing  adenosarcoma  or  carcinosarcoma,  etc.,  and  the  tend- 
ency of  one  element  to  overgrow  the  other  appears  to  be  less  marked  than 
with  teratomas. 

The  mixed  tumor  may  therefore  be  defined  as  a  complex  embryonal  tumor 
of  local  origin  which  reproduces  the  normal  development  of  the  tissues  and 
organs  of  the  affected  part.  They  may  be  classified  according  to  the  region 
in  which  they  occur,  as  renal,  genito-urinary,  salivary  and  facial,  and 
mammary. 

The  most  typical  examples  of  the  restricted  class  of  mixed  tumors  are 
found  in  a  series  of  complex  embryonal  and  congenital  tumors  of  the  kidney. 
These  are  mesodermal  growths  derived  from  the  primitive  kidney  and  neigh- 
boring tissues  and  reproduce  the  structure  of  the  nephrotome  and  sclero- 
tome.  They  are  called  adenomyosarcoma.  Muus  found  also  epidermal 


TERATOLOGY  963 

inclusions.  Certain  mixed  tumors  of  the  male  bladder  and  gubernaculum 
testis  are  probably  of  the  same  origin. 

The  congenital  sarcoma  of  the  vagina  contains  spindle-cells,  striated 
muscle-fibers,  and  myxomatous  tissue,  and  is  derived  from  mesoderm  mis- 
placed during  the  development  and  degeneration  of  the  Wolffian  duct.  More 
complex  sarcomas  of  the  adult  cervix  uteri  contain  muscle  and  cartilage. 
The  adenomyoma  uteri  and  its  malignant  derivatives  constitute  a  well- 
defined  variety  of  mixed  tumor  derived  from  the  mesonephros  or  paroophoron. 

The  salivary  and  lacrimal  glands  are  the  seat  of  mixed  tumors  contain- 
ing mesodermal  derivatives  and  basal-cell  carcinoma,  and  are  probably  de- 
rived from  buccal  ectoderm  with  a  possible  admixture  from  the  maxillary 
periosteum  or  bronchial  cartilages. 

The  mixed  tumors  of  the  breast  probably  originate  from  aberrant  and 
superfluous  material  derived  from  the  fetal  ectoderm  and  mesoderm  during 
the  early  development  of  the  breast.  They  contain  glandular  tissue  and 
carcinoma  and  various  mesodermal  derivatives.  It  is  probable  that  meta- 
plasia is  responsible  for  some  of  these  mesodermal  structures  (Beneke). 

Carcinoma  sarcomatodes  constitutes  a  miscellaneous  group  of  tumors  of 
variable  and  uncertain  origin  (Lippmann,  Herxheimer,  Lit.).  Most  of  these 
tumors  have  occurred  in  the  uterus,  but  out  of  a  considerable  number  Herx- 
heimer found  only  5  which  could  withstand  critical  analysis.  Others  have 
been  observed  in  the  ovary,  and  in  Lippmann's  case  there  were  both  carci- 
nomatous  and  sarcomatous  metastases. 

In  the  thyroid  several  cases  of  supposed  carcinosarcomas  are  reported. 
Especially  difficult  is  the  interpretation  of  Schmorl's  case,  of  thyroid  adenoma 
recurring  as  carcinoma  with  sarcomatous  stroma  and  with  sarcomatous  metas- 
tases. Tumors  of  the  esophagus  containing  epithelioma  and  sarcoma  are 
described  by  Hansemann  and  Herxheimer,  and  the  former  has  described 
similar  tumors  of  pharynx  and  gall-bladder.  Landsteiner  reports  a  tumor 
of  the  gall-bladder  in  which  acanthoma  and  myosarcoma  encroached  upon 
each  other.  Of  2  cases  occurring  in  the  stomach,  that  of  Lindemann  gave 
numerous  metastases  in  which  both  elements  were  intimately  mixed.  In  the 
liver  Lubarsch  cautiously  interpreted  a  large  tumor  as  an  adenocarcino- 
sarcoma.  In  many  respects  it  recalls  the  complex  pictures  of  primary  carci- 
noma of  liver-cells.  Michelsohn  believed  he  could  trace  the  origin  of  a  carci- 
nosarcoma  from  the  gland-cells  and  stroma  of  the  pancreas.  Arising  in  the 
nasopharynx  and  invading  the  orbit  Klein  found  a  vascular  round-cell  sar- 
coma containing  islands  of  acanthoma. 

In  the  lower  animals  tumors  of  mixed  structure  are  not  infrequently  ob- 
served, especially  in  the  mammae  of  dogs  and  in  the  thyroid  in  rats  (Wilms, 
Loeb). 

The  transformation  of  carcinoma  into  carcinosarcoma,  followed  by  elimination  of  the 
epithelial  element  in  the  course  of  transplantation  of  tumors  of  mice  and  rats,  observed 
by  Loeb,  Ehrlich  and  Apolant,  Bashford,  and  others,  is  an  interesting  experimental 
contribution  in  this  field.  Loeb  saw  the  sarcomatous  element  in  the  first  transplant, 
but  it  usually  occurs  much  later,  either  gradually  or  suddenly,  and  with  or  without  per- 
sistence of  the  carcinoma.  That  the  original  tumors  contained  mixed  tumor  elements 
is  improbable.  That  the  spindle-cells  are  modified  epithelium  is  rejected,  although 
transitions  of  cell  forms  have  occasionally  been  observed.  It  is  generally  assumed  that 
the  carcinoma  cells  exert  a  stimulating  influence  on  the  stroma-cells,  which  in  the  course 
of  the  transfers  yields  a  tumor  of  fibroblastic  origin. 

The  correct  interpretation  of  the  carcinosarcomatous  structures  in  man  and  lower 
animals  is  a  matter  of  much  difficulty.  No  single  explanation  will  probably  apply  to  all 
cases.  The  chief  source  of  these  structures  is,  I  believe,  the  transformation  of  epithelial 
cells  into  spindle-cells.  This  change  is  of  wide-spread  occurrence  in  epithelial  tumors, 
but  only  rarely  is  it  interpreted  as  carcinosarcoma.  It  is  frequently  observed  in  the 


964  NEOPLASTIC  DISEASES 

course  of  recurrences  and  metastases  of  melanoma,  basal-cell  epithelioma,  adaman- 
tinoma,  adenocarcinoma  of  thyroid  or  ovary,  primary  carcinoma  of  liver,  and  in  em- 
bryonal epithelial  tumors.  The  change  is  facilitated  by  rapid  growth,  relief  of  pressure, 
and  inflammatory  exudate.  Krompecher's  studies  of  the  metaplasia  of  squamous 
epithelium  have  an  important  bearing  on  this  subject.  The  change  may  often  be 
traced  in  the  same  tumor  where  polygonal  cells  merge  into  spindle  forms.  The  most 
striking  instances  are  furnished  in  the  recurrences  and  metastases  of  epithelial  tumors. 
Especially  in  thyroid  tumors  the  form  of  the  epithelial  cells  is  subject  to  wide  variations, 
a  fact  which  ren'ders  Schmorl's  interpretation  of  his  carcinosarcoma  very  questionable. 
I  have  seen  pure  spindle-cell  metastases  in  epithelioma  of  lip,  melanoma  of  skin,  ada- 
mantinoma,  and  other  epithelial  tumors.  In  experimental  tumors  of  mice  I  have  twice 
seen  convincing  indications  of  change  of  epithelial  cells  into  more  actively  multiplying 
spindle-cells  in  cases  now  figuring  as  carcinosarcoma.  Thus  in  several  departments 
there  is  reason  to  think  that  transformation  of  polygonal  into  spindle-cells  contributes 
a  share  of  carcinosarcomas. 

A  second  group  of  cases  may  be  referred  to  the  intermingling  of  contiguous  primary 
tumors  of  the  same  region,  and  on  this  ground  Herxheimer  rightly  discards  certain 
reported  cases  of  carcinosarcoma. 

That  certain  tumors  originate  through  neoplastic  growth  of  both  stroma 
and  epithelial  cells  of  a  tissue  complex,  the  epithelial  cells  at  first  outstripping 
the  fibroblasts,  must  be  conceded,  but  it  is  difficult  to  determine  which  if 
any  of  the  so-called  carcinosarcomas  originate  in  this  manner.  Known 
examples  of  this  type,  as  the  adenomyoma  uteri  and  its  malignant  forms,  are 
rather  well  defined.  It  is  possible  that  some  of  the  uterine  and  ovarian  adeno- 
sarcomas  originate  thus  and  constitute  a  special  variety  of  mixed  tumor. 

In  the  lower  animals  the  ready  response  of  fibroblasts  to  various  stimuli 
renders  more  acceptable  the  belief  that  transplanted  stroma  may  occasionally 
assume  neoplastic  properties  during  a  series  of  transfers,  but  does  not  guaran- 
tee the  existence  of  such  a  process  in  the  course  of  tumor  growth  in  man. 

SIMPLE  DERMOIDS  AND  EPIDERMOIDS 

The  simple  dermoid  consists  of  epidermis,  derma,  and  dermal  glands,  and 
usually  appears  in  the  form  of  a  cyst.  In  the  epidermoid  definite  dermal 
structures  are  wanting. 

The  simple  dermoid  commonly  originates  by  the  inclusion  of  a  portion  of 
ectoderm  during  the  closure  of  embryonal  fissures,  or  at  the  point  of  union 
of  ectodermal  with  other  structures,  along  the  course  of  ectodermal  invagina- 
tions  (hypophyseal  duct),  or  from  persistent  embryonal  ectodermal  struc- 
tures. In  the  sex  glands,  especially  the  ovary,  a  simple  dermoid  may  be  the 
sole  remnant  of  a  true  teratoma.  A  traumatic  origin  of  both  dermoids  and 
epidermoids  has  been  demonstrated  in  many  regions.  Epidermoids  are 
usually  of  traumatic  origin,  but  certain  well-defined  forms  are  of  embryonic 
derivation  and  produce  characteristic  tumors,  as  cholesteatoma.  A  defect 
of  the  overlying  skin  or  other  abnormality  is  sometimes  present  with  con- 
genital dermoids  (Heschl).  The  dermoid  cyst  is  single  or  multilocular,  and 
the  contents  are  sebaceous  material  and  hair.  The  character  of  the  hair 
corresponds  to  that  of  the  region  affected.  Torok  concluded  that  very  early 
separation  of  ectodermal  material  is  followed  by  the  development  of  dermal 
structures,  late  separation  giving  origin  to  the  epidermoid. 

Secondary  changes  in  dermoids  are  frequent  and  include  suppuration, 
rupture,  papillary  ingrowths,  overgrowths  of  dermal  structures,  and  neo- 
plastic changes. 

The  experimental  production  of  dermoids  has  been  successful  in  the  hands 
of  many  authors,  the  result  being  a  variable  period  of  growth  of  the  implanted 
skin,  a  long  period  of  quiescence,  followed  in  every  instance  by  slow  atrophy. 


TERATOLOGY 


965 


SPECIAL   FORMS   OF   EPITHELIAL   CYSTS,   DERMOIDS,    MIXED  TUMORS, 
TERATOMAS,  AND  FETAL  IMPLANTATIONS 

A  regional  classification  of  this  extensive  group  of  tumors  is  the  most 
serviceable,  and  is  rendered  almost  imperative  on  account  of  the  difficulty  of 
separating  the  different  types  on  the  basis  of  formal  genesis. 

Epithelial  Cysts  of  Skin. — The  variety  of  cystic  structures  lined  by  squa- 
mous  epithelium  in  skin  and  subcutaneous  tissues  is  considerable. 

(i)  Atheromatous  cysts  arising  from  retention  in  dermal  glands,  chiefly 
sebaceous,  are  of  frequent  occurrence.  They  are  usually  connected  with 
the  epidermis.  Chiari,  however,  from  the  study  of  a  notable  case,  showed 


FIG.  508. — Fat  crystals  in  a  dermoid  of  skin. 


that  the  common  multiple  cysts  of  the  derma  may  arise,  as  does  the  smaller 
comedo  or  milium,  by  retention  in  hair,  sebaceous  and  sweat-glands,  and  that 
these  retention  cysts  may  grow  deeper  as  they  enlarge  and  may  eventually 
lose  all  connection  with  the  epidermis.  The  lining  is  of  simple  stratified 
epithelium  which  is  compressed  and  atrophic. 

(2)  Congenital  Epidermoids. — The  origin  of  true  dermoids  of  the  skin 
from  ectodermal  cysts  was  established  by  Remak.  The  majority  of  small  or 
multiple  epithelial  cysts  of  the  skin  was  also  shown  by  Chiari,  Heschl,  and 
Franke  to  be  the  result  of  congenital  misplacements  of  epithelium.  The 
lining  of  these  cysts  is  of  well-formed  epidermis,  often  with  papillae,  but  with- 
out other  structure  of  the  derma.  On  account  of  the  simple  epidermal  lining 
Heschl  called  them  epidermoid  cysts.  It  is  probable  that  deep  epitheliomas 
of  the  skin  arise  from  such  cysts,  including  certain  reticulated  epitheliomas. 


966  N  EOF  LA  STIC  DISEASES 

(3)  Implantation  Dermoids  (Sutton).    Cystes  Epidermiques  (Reverdin). — 
Traumatic  misplacement  of  fragments  of  epidermis  produces  simple  cysts 
which  are  of  wide- spread  distribution  and  may  reach  considerable  dimensions. 
The  importance  of  this  origin  has  been  emphasized  especially  by  Reverdin, 
Jonnesco,  and  others,  who  have  pointed  out  their  occurrence  in  exposed 
portions  of  the  body,  as  the  palms  and  soles,  their  main  clinical  features, 
and  the  varying  character  of  the  lining.     Schwenninger,  Kaufmann,  and 
Dooremale  showed  that  such  cysts  may  be  produced  experimentally  by  im- 
planting portions  of  epidermis  in  deep  tissues,  or  in  the  interior  chamber  of 
the  eye.    The  character  of  the  resulting  cyst  depends  much  upon  the  con- 
formation of  the  displaced  fragment.     A  complete  fragment  of  skin  with 
epidermis  and  derma  yields  cysts  with  papillae,  while  the  epidermis  alone 
produces  smooth- walled  cysts  or  pearly  nodules   (Garre,  Le  Fort).     Yet 
Hoesch  and  Aschoff  concluded  that  definite  growth  of  displaced  epithelium 
and  cyst  formation  required  that  some  connective  tissue  must  accompany 
the  epithelium.    Fetal  epithelium  is  more  active  than  adult  (Nicholls).    The 
extent  of  the  misplacement  is  often  surprising,  and  the  original  injury  may 
excite  little  notice.    Although  usually  found  on  exposed  surfaces  in  working 
people,  traumatic  epidermoids  occur  in  the  cornea  and  iris  (Franke,  Graefe). 
Yet  the  origin  of  these  intra-ocular  cysts  is  not  fully  determined  (Collins, 
Greef).    A  traumatic  frontal  intracranial  dermoid  resembling  cholesteatoma 
is  described  by  Hartley.    The  growth  capacity  of  the  traumatic  dermoid  is 
moderate  and  malignant  changes  are  not  observed. 

(4)  True  Dermoids. — The  true  or  congenital  dermoid  is,  as  a  rule,  a  larger, 
more  complex,  and  more  deeply  situated  structure  than  the  retention  cysts 
and  traumatic  dermoids.     It  is  situated  in  locations  which  connect  it  with 
the  embryonal  disturbances  of  development  to  which  it  owes  its  origin 
(fissural  dermoids).     The  structure  presents  all  the  elements  of  the  skin, 
including  epidermis,  derma,  and  dermal  glands,  which  may  become  atrophic, 
but  usually  exhibit  overgrowth  or  at  times  malignant  changes.     Accessory 
structures  are  sometimes  added,  as  lymphoid  tissues,  fat  tissue,  muscle, 
bone,  cartilage,  and  normal  or  cystic  blood-  and  lymph- vessels. 

Dermoid  cysts  present  particular  clinical,  pathological,  and  embryological 
problems  in  the  several  situations  in  which  they  occur.  It  is  especially 
difficult  to  distinguish  between  certain  complex  dermoids  and  teratoid 
growths  with  predominance  of  ectoderm.  The  congenital  dermoids  occur  in 
the  scalp,  neck,  back,  along  median  line  of  chest  and  abdomen,  sacral  region 
and  buttocks,  where  they  are  readily  connected  with  embryonal  fissures,  clefts, 
and  junctures.  Teratomas  are  usually  found  in  deeper  organs  and  along  the 
vertebras  from  neck  to  coccyx.  Some  observers  give  a  very  wide  scope  to  the 
congenital  dermoid  at  the  expense  of  the  traumatic  forms  and  would  include 
not  only  those  which  occur  at  points  of  recognized  predisposition  (clefts, 
fissures),  but  those  in  many  other  regions,  especially  when  a  traumatic  history 
is  missing.  Thus  Labougle  found  a  traumatic  history  in  only  16  of  42  der- 
moids of  the  vola  manus;  the  others  he  would  refer  to  congenital  separation 
of  epidermis  at  interdigital  folds. 

Cervical  Dermoids. — An  extensive  variety  of  congenital  anomalies  in  the 
neck  results  from  irregularities  in  the  closure  of  the  branchial  clefts,  which 
give  rise  to  reduplication,  partial  or  complete,  of  organs;  fistulous  tracts; 
epidermoids;  dermoids:  blood-  and  lymph-cysts,  and  true  tumors.  Various 
combinations  of  these  conditions  may  be  observed,  as  multilocular  prolifer- 
ating cystoma  with  dermoid  cyst,  or  multilocular  cysts  of  various  types  with 
cystic  lymphangioma  (Samter).  The  location  of  the  different  clefts  and 
of  the  abnormalities  referable  to  them  may  be  seen  from  the  accompanying 


TERATOLOGY 


967 


sketch  from  Cusset.  This  subject  was  extensively  investigated  by  many 
early  observers,  more  recently  by  Kostaniecki  and  Mielecki,  who  conclude 
that  the  great  majority  of  cervical  dermoids  arise  from  the  second  cleft. 
Yet  many  fissures,  cysts,  dermoids,  and  tumors  in  particular  locations  are 
connected  with  each  of  the  other  clefts  (Virchow,  Konig). 

(1)  The  first  branchial  cleft  locates  a  series  of  abnormalities  which  are 
chiefly   found  in   the  aural  and  submaxillary  regions.     These  consist  of 
supernumerary  ears   (Sutton),  aural  fistulas,   chondromas  from  the  aural 
cartilages,  and  many  outgrowths  of  the  skin  which  often  contain  cartilage 
(Virchow,  Hermes).     It  is  probable,  however,  that  most  of  the  superficial 
anomalies  in  and  about  the  ear  result  from  secondary  disturbances  in  the 
formation  of  this  organ  and  are  not  connected  with  the  branchial  clefts. 
Congenital  epithelial  cysts  of  the 

external  ear  result  from  irregular 
closure  of  the  fistula  auris  con- 
genita  (Steinbrugge). 

Dermoid  cysts  from  the  first 
cleft  appear  to  be  relatively  rare. 
Hildebrand  out  of  20  epithelial 
cysts  of  neck  observed  one  which 
he  referred  to  the  first  cleft.  It 
lay  in  the  suprahyoid  triangle 
away  from  the  middle  line.  Konig 
reported  a  cyst  and  fistulous  tract 
probably  derived  from  the  first 
cleft,  which  ran  under  the  angle 
of  the  jaw  along  the  facial  nerve 
and  terminated  between  tragus 
and  antitragus.  Another  group  is 
found  along  the  floor  of  the  mouth, 
constituting  the  sublingual  der- 
moids (Kostanecki,  Lit.).  These 
are  lined  by  epidermis  and  con- 
tain sebaceous  material,  and  the 
walls  are  free  from  lymphatic 
tissue.  They  originate  from  the 
ectoderm  of  the  first  branchial 
arch  which  goes  to  form  the  lateral  portion  of  the  base  of  tongue.  Incomplete 
union  of  the  two  opposite  portions  of  the  first  branchial  arches  may  leave  a 
triangular  defect  beneath  the  skin  in  the  middle  line  in  the  submental  region 
(mesobranchial  space  of  His).  Thus,  portions  of  ectoderm  may  become 
adherent  to  entoderm  and  form  mesobranchial  dermoids  which  lie  at  base 
of  tongue  in  middle  line,  or  may  appear  anteriorly  in  suprahyoid  region. 

(2)  The  course  of  the  second  branchial  cleft  follows  the  stylohyoid  liga- 
ment from  the  styloid  process  to  the  lesser  cornu  of  the  hyoid  bone.    It  thus 
runs  from  beneath  the  ear  externally  and  from  the  tonsillar  fossa  internally, 
along  the  posterior  belly  of  the  digastric  muscle.    According  to  Kostanecki 
and  more  recent  observers,  the  great  majority  of  branchial  fistulae  and  cysts 
originate  from  this  cleft.     They  lie  anterior  to  the  sternomastoid  muscle 
and  may  develop  at  any  point  from  the  external  ear  to  the  sphenoid  bone, 
or  they  may  extend  along  the  whole  length  of  this  region.    Konig  suggests 
that  the  position  may  be  influenced  by  the  course  of  the  facial  nerve  or  artery. 
Portions  of  the  cyst  may  lie  within  the  parotid  gland  and  numerous  lateral 
sacculations  may  develop. 


FIG.  509. — Situations  of  congenital  fissures 
in  neck  [and  face:  I,  2,  3,  4,  First,  second, 
third,  and  fourth  clefts.  5,  Intermaxillary 
cleft.  6,  Frontomaxillary  cleft.  7,  Naso max- 
illary cleft.  (Cusset.) 


968  NEOPLASTIC  DISEASES 

Structure. — The  lining  reproduces  the  structure  of  ectoderm  or  of  entoderm. 
Both  embryonal  layers  may  be  represented  when  the  membranous  septum 
is  ruptured  and  both  inner  and  outer  layers  contribute  to  this  lining.  Some 
cysts  present  a  lining  of  epidermis  with  dermal  glands.  Their  contents  are 
usually  sebaceous  and  they  may  contain  hair.  Others  show  squamous 
epithelium  of  a  mucous  membrane  with  basal  layer  of  columnar  cells  and 
their  contents  are  mucoid.  A  third  group  shows  ciliated  epithelium  as  well 
as  squamous.  These  variations  depend  on  the  character  of  the  embryonal 
structures  involved,  the  mucous  membrane  and  ciliated  cells  being  derived 
from  the  entoderm  which  originally  possesses  a  ciliated  lining.  Foreign  body 
giant-cells  often  replace  much  of  the  epithelial  lining,  especially  when  the 
contents  are  fatty  or  oily.  Groups  of  thyroid  alveoli  may  be  present  in  the 
wall.  Lymphoid  tissue  is  abundant  in  the  embryonal  entoderm  and  reap- 
pears in  cysts  derived  from  this  layer,  but  is  absent  in  the  others.  In  the 
wall  may  be  found  striated  muscle,  mucous  glands,  and  islands  of  cartilage, 
derived  from  the  mesodermal  tissues  of  the  branchial  arches. 

Secondary  changes  in  cervical  dermoids  are  of  much  importance.  Extrav- 
asation of  blood  into  the  cyst  not  infrequently  occurs  from  the  small  vessels 
in  the  wall.  Rarely  a  communication  is  formed  with  the  jugular  vein,  pro- 
ducing a  blood-cyst  (Thomas).  The  dermal  glands  in  the  wall  may  become 
cystic  or  may  develop  cystadenomas  (Zahn,  Samter). 

Branchiogenic  Carcinoma. — That  many  cervical  carcinomas  and  primary 
epitheliomas  of  the  neck  arise  from  branchiogenic  cysts  and  epithelial  rests 
was  first  shown  by  Volkmann.  These  tumors  occur  usually  after  the  fortieth 
year,  producing  globular,  cystic  or  solid,  often  externally  ramifying  growths 
which  are  extremely  difficult  to  extirpate.  Pharyngitis,  difficulty  in  swallow- 
ing, inflammatory  edema,  and  lymphadenitis  often  mark  their  onset  and 
course.  Invasion  of  lymph-nodes  is  early  or  late,  depending  on  the  integrity 
of  the  cyst  capsule.  The  structure  is  commonly  that  of  adult  acanthoma. 
To  what  extent  other  carcinomas  of  the  neck  of  obscure  origin  are  referable 
to  branchial  remnants  is  at  present  undetermined.  Many  of  the  multilocular 
blood-cysts  of  the  neck  probably  arise  in  this  manner.  The  lymph-vessels 
may  be  highly  developed  and  it  is  probable  that  these  vessels  may  be  the 
source  of  hygroma  colli  (Lucke,  Zahn).  Virchow  designated  as  fissural 
angioma  certain  vascular  tumors  of  this  region.  The  fragments  of 
cartilage  in  the  wall  are  held  to  be  the  source  of  certain  branchiogenic 
chondromas. 

The  diagnosis  of  branchiogenic  carcinoma,  after  it  has  advanced  to  the 
cervical  lymph-nodes,  may  be  difficult.  It  should  be  emphasized  that  the 
usual  form  of  the  tumor  is  a  cystic  growth  in  and  about  which  are  carcinoma- 
tous  areas,  and  that  most  cases  are  encountered  when  the  cysts  are  recog- 
nizable, and  when  a  squamous-cell  cover  is  present  or  predominant.  In  the 
same  region  are  observed  carcinoma  of  the  lymph-nodes  secondary  to  lesions 
of  adjoining  mucosse,  buccal,  nasal,  ethmoidal;  carcinoma  from  aberrant 
thyroid  follicles;  tumors  of  the  carotid  gland;  and  primary  endothelioma 
of  lymph-nodes.  In  all  the  secondary  carcinomas  it  should  be  possible  to 
demonstrate  the  primary  growth.  The  structure  of  carotid  gland  tumors 
is  specific  and  that  of  endothelioma  is  partially  so.  There  remains  a  group 
of  apparently  primary  carcinomas  of  the  cervical  lymph-nodes  whose  origin 
is  obscure,  and  some  of  these  may  be  derived  from  the  entodermal  epithelium 
of  branchial  cysts.  Definite  observations  in  this  field  are  lacking,  but  in 
Samter's  case  of  complex  branchiogenic  cyst  there  were  adenomatous  pro- 
liferation in  several  of  the  compartments  and  infiltrating  carcinoma  with 
metastases  in  lungs  and  abdomen. 


TERATOLOGY  969 

Cervical  Teratoids  and  Teratomas. — Complex  teratoid  tumors  of  the 
neck  are  comparatively  rare  and  are  found  chiefly  in  connection  with  the 
branchial  clefts  and  the  thyroid  gland.  Partial  reduplication  of  the  lower 
jaw  has  given  rise  to  large  tumors  of  the  neck  containing  bone,  cartilage, 
teeth,  muscle,  connective  tissues,  and  fat  (Wilms).  More  complex  tumors 
containing  bone,  teeth,  muscle,  ectodermal  and  entodermal  cysts,  portions 
of  respiratory  tract,  and  brain  tissue,  are  described  by  Pupovac  and  Wetzel, 
and  interpreted  as  of  bigerminal  origin.  Several  cervical  teratomas  have 
been  connected  with  the  thyroid  gland  (Poult,  Lit.).  In  Henle's  case  a  large 
congenital  tumor  contained  nerve  tissue  and  choroid  plexus,  cysts  lined  by 
cuboidal  and  ciliated  epithelium,  thyroid  follicles,  and  connective  tissue. 
Some  cystic  sarcomas,  as  in  the  thyroid,  are  of  complex  structure  (Zahn). 
In  Pupovac's  case  the  lymph-nodes  contained  metastases  of  ganglionic  nerve 
tissue. 

"A  headless  but  otherwise  well-formed  fetus  was  found  embedded  in  the 
cervical  tissues  by  Rosenstiel,  and  Grass  observed  a  complete  fetus  of  the 
size  of  the  finger  lying  in  the  neck  of  a  woman.  Several  reports  of  fetal  im- 
plantation in  the  branchial  clefts  have  been  collected  from  the  older  litera- 
ture by  Heusinger. 

Cysts  of  Thyroglossal  Duct. — The  thyroglossal  duct  is  a  rare  source  of 
dermoid  cysts. 

When  the  base  of  the  tongue  is  formed  by  the  union  of  two  lateral  arches 
an  epithelial-lined  canal  persists,  leading  from  the  foramen  cecum"  to  the  mid- 
dle lobe  of  the  thyroid  The  upper  portion  of  the  duct  may  remain  patent 
(lingual  duct),  while  the  lower  region  from  thyroid  isthmus  to  hyoid  bone 
forms  the  thyroid  duct.  Bochdalek  in  several  cases  found  segments  of  this 
canal,  2  to  3  cm.  in  length,  patent  and  with  lateral  sacculations  lined  by  ciliated 
epithelium.  Streckeisen  found  small  mucous  cysts  lined  by  ciliated  cells 
along  this  tract,  and  Hildebrand  has  collected  other  similar  cases  in  some  of 
which  the  wall  contained  thyroid  tissue  (Berard,  Chalier,  Erdheim,  Lit.). 
Dermoid  cysts  in  the  middle  line  of  the  tongue  are  probably  derived  from 
portions  of  this  duct.  They  may  reach  a  large  size,  appearing  in  the  floor 
of  the  mouth  and  displacing  the  tongue  upward  (Bryck,  Dirmstrey).  Rarely 
cysts  are  found  behind  the  right  lobe  of  thyroid.  They  are  lined  by  ciliated 
epithelium,  and  are  probably  derived  from  the  esophagus,  the  upper  part  of 
which  in  the  early  embryo  is  covered  by  ciliated  epithelium. 

Mediastinal  Dermoids. — These  tumors  are  located  below  the  sternal 
notch  in  the  anterior  mediastinum  or  between  the  heart  and  root  of  lung 
or  in  the  lung,  or  they  occupy  the  pleural  cavity  (Christian,  Lit.;  Lambert 
and  Knox,  Lit.).  They  form  single  or  multilocular  cystic  growths  which  may 
reach  large  dimensions.  Most  of  them  appear  in  young  adults,  and  run  a  slow 
course  of  i  to  16  years.  Symptoms  may  be  wanting,  but  most  cases  show  the 
results  of  pressure  on  the  bronchi  and  trachea,  with  cough,  hemoptysis,  and 
in  8  cases  with  expectoration  of  hair,  as  well  as  sebaceous  material. 

According  to  structure  they  fall  into  two  classes:  (i)  Simple  dermoids. 
(2)  Teratoid  tumors. 

The  simple  dermoids  are  single  or  multilocular  cysts  with  smooth  or 
polypoid  epidermal  lining  containing  dermal  glands  and  with  contents  of 
hair  and  sebaceous  material.  Teeth  are  frequently  present.  The  epidermal 
lining  may  be  lost,  and  plates  of  bone  or  cartilage  may  be  present.  Some 
have  been  connected  with  portions  of  thymus  (Marchand).  The  complex 
tumors  are  tridermal  and  contain  besides  epidermis,  bone,  cartilage,  nervous 
tissue,  intestinal  tract,  respiratory  ciliated  epithelium  (Loewenmeyer),  and 
thyroid  (Mandelbaum)  (Dangschaat,  Lit.).  The  older  cases  have  been  col- 


970  NEOPLASTIC  DISEASES 

lected  by  Riegel.  Malignant  changes  were  observed  in  3  cases,  all  of  which 
were  probably  tera'toid.  Finders  described  lymphosarcoma  probably  from 
the  thymus,  Jores  spindle-cell  sarcoma  extending  into  lung,  and  Virchow 
carcinoma  and  sarcoma  with  nodules  in  liver. 

A  single  origin  through  one-sided  developments  of  teratomas  cannot 
be  excluded  for  the  entire  group.  Ekehorn  points  out  that  the  great  ma- 
jority of  mediastinal  dermoids  prove  to  be  tridermal  teratomas.  Yet  most 
authors  regard  the  simple  tumors  as  derived  from  the  third  branchial  arch 
which  produces  the  deep  sinus  cervicalis  and  the  thymus.  The  intimate 
relations  of  ectodermal  and  entodermal  layers  of  the  third  and  fourth  arches 
may  explain  the  variety  of  epithelium  and  the  connection  with  the  thymus 
and  thyroid,  while  the  descent  of  the  heart  may  carry  these  structures  deep 
into  the  thorax. 

Dermoids  of  the  lower  mediastinum  may  result  from  imperfect  closure 
of  the  anterior  chest  wall,  which  gives  origin  to  pr external  dermoids  (Andoly). 
Bergmann  observed  a  dermoid  divided  into  two  compartments  by  the  ster- 
num, but  joined  by  a  canal  through  the  bone. 

Congenital  dermoids  occur  along  the  orbitonasal  fissures:  (i)  At  the  outer 
angle  of  the  orbit  next  to  pericranium  covering  external  process  of  frontal 
bone.  (2)  At  inner  angle  of  orbit.  (3)  In  upper  eyelid  between  the  fronto- 
nasal  plate  and  the  cutaneous  fold  from  which  the  eyelid  is  formed. 

At  the  root  of  nose,  over  the  fontanels,  at  the  occipital  protuberance, 
and  elsewhere  in  the  scalp  congenital  dermoids  are  also  found  (Hartley). 
The  origin  of  these  dermoids  is  explained  by  the  imperfect  separation  of 
dura  and  skin  during  the  intramembranous  formation  of  the  cranial  bones. 
As  the  bone  forms  between  the  dura  and  skin  portions  of  the  latter  may 
adhere  to  the  dura,  become  enclosed  in  bone  and  form  dermoids  which  lie 
within  the  skull  and  may  be  connected  with  the  skin  by  a  pedicle.  With 
the  formation  of  intra-orbital  dermoids  the  invagination  of  ectoderm  in  the 
development  of  the  lens  is  prominently  concerned. 

Orbital  Teratomas. — Teratomas  occur  in  the  orbit,  usually  as  bulky 
growths  present  at  birth  (Hippel,  Lit.).  Their  analysis  reveals,  as  a  rule, 
derivatives  from  three  germ  layers,  but  only  two  layers  may  be  identifiable. 
The  development  of  rudimentary  organs  is  not  pronounced,  but  segments 
of  intestine,  ocular  cups,  and  portions  of  central  nervous  system  have  been 
identified.  Hippel  suggests  that  certain  orbital  dermoids  are  of  teratomatous 
nature,  since  ganglia  and  gland  alveoli  lined  by  mucous  cells  have  been 
found  in  the  wall  of  the  dermoid.  Monogerminal  mixed  tumors  of  the  orbit 
are  illustrated  by  the  case  of  Weigert,  Broer,  which  contained  fat,  bone, 
cartilage,  and  cysts  lined  by  cylindrical  or  ciliated  or  squamous  epithelium. 

Pharyngeal  Dermoids,  Teratomas,  and  Epignathi.— A  somewhat  numer- 
ous group  of  complex  tumors  and  developmental  anomalies  appears  in  the 
form  of  polypoid  growths  of  the  nasopharynx,  which  may  be  subdivided  into 
three  main  classes:  (i)  Dermoids,  (2)  teratoid  tumors,  and  (3)  epignathi 
(Arnold,  Lit.).  All  these  conditions  are  congenital  and  are  usually  encoun- 
tered in  deformed  stillborn  fetuses,  but  the  simpler  pharyngeal  polyps  may 
first  be  recognized  as  late  as  the  twenty-second  year. 

(i)  The  dermoids  are  usually  complex.  They  appear  at  birth  or  after 
some  years,  producing  dysphagia,  or  dyspnea,  or  are  described  as  cases  of 
hairy  tongue.  They  are  attached  to  the  hard  or  soft  palate,  or  wall  or  vault 
of  pharynx,  in  or  near  the  middle  line,  and  fill  the  nares  or  buccal  cavity. 
Some  may  show  an  intracranial  portion  connected  through  a  perforation  in 
the  skull  with  the  pharyngeal  tumor. 

The  tumors  are  covered  by  skin,  often  hairy,  and  containing  dermal  glands. 


TERATOLOGY 


971 


The  main  mass  is  composed  largely  of  fat  tissue,  with  occasional  fragments 
of  striated  muscle,  cartilage,  or  bone.  They  are,  therefore,  bidermal. 

(2)  The  teratoid  tumors  differ  from  the  dermoids  chiefly  in  the  greater 
complexity  of  structure,  larger  size  and  earlier  development,  and  they  are 
frequently  associated  with  extensive  deformities  of  the  skull,  as  anencephalus 
(Otto),  hemicrania  (Wollmann),  and  palatal  fissures  (Sonnenberg).  The 
presence  of  these  local  deformities  suggests  that  the  overgrowth  of  tissue 
constituting  the  teratoid  results  entirely  from  local  factors  and  that  they  are 
not  true  embryomas.  These  tumors  are  all  tridermal,  and  Schwalbe  further 
subdivides  them  into  two  groups,  in  one  of  which  the  three  germ  layers  pro- 
duce definite  organs,  i.  e.,  into  teratoids  and  teratomas. 

The  structures  which  form  the  basis  of  the  classification  as  teratoids 
consist  of  tridermal  elements,  fat,  muscle,  cartilage,  bone,  acinous  glands, 


FIG.  510. — Epignathus.     (Low,  Studies  in  Pathology,   Univ.  of  Aberdeen,  1906.) 

teeth,  cysts  lined  by  various  forms  of  epithelium,  and  nervous  tissue.  Cases 
in  which  the  bony  masses  imitate  a  rudimentary  skull  form  a  transition  to 
the  epignathi.  In  Koch's  case  the  growth  was  composed  chiefly  of  brain 
and  glia-tissue.  In  several  cases  the  structure  has  suggested  an  involvement 
of  the  branchial  arch,  as  when  there  are  deformities  of  tongue,  palate,  jaw, 
and  ear,  and  the  tumor  contains  rudiments  of  the  ear  (Wallmann). 

(3)  Epignathi. — These  remarkable  anomalies  differ  from  other  pharyn- 
geal  teratomas  in  presenting  well-formed  organs  and  limbs  of  a  parasitic 
fetus.  There  has  been  much  variation  in  the  criteria  demanded  for  identi- 
fication of  this  group,  but  since  the  studies  of  Arnold  and  Schwalbe  the  term 
"epignathus"  has  been  limited  to  the  growths  that  present  unmistakable 
parts  of  a  fetus.  Even  thus  the  observed  cases  are  rather  numerous.  The 
extent  to  which  the  fetal  organs  are  represented  varies  greatly.  In  some 


972  NEOPLASTIC  DISEASES 

the  main  tumor  consists  of  a  rudimentary  head  with  or  without  brain  tissue 
(Ahlfeld).  In  many  cases  well -formed  extremities  with  fingers,  toes,  and 
nails  are  present.  Otto  observed  a  cystic  growth  containing  portions  of 
intestine  and  a  rudimentary  testis.  Vrolich  found  intestinal  canal  with 
appendix,  long  bones,  and  a  placenta-like  mass.  Wegelin  identified  sacrum, 
foot  with  five  toes,  intestine,  crystalline  lens,  choroid,  and  brain.  Rind- 
fleisch  described  a  large  tumor  at  the  base  of  the  brain  attached  at  the  sella 
turcica,  and  containing  fetal  extremities  with  fingers  and  toes,  normal  liver, 
brain,  and  navel,  while  passing  through  a  fissure  in  the  base  of  the  skull  and 
projecting  from  the  mouth  was  a  bulky  polypoid  tumor  containing  chiefly 
mesodermal  structures.  He  assumed  an  origin  from  the  hypophysis  and 
characterized  this  organ  as  a  veritable  mine  of  undifferentiated  tissues. 

The  case  of  Baart  de  la  Faille  is  thus  reported  by  Schwalbe.  In  a  case 
of  quadruple  pregnancy  the  first  fetus  was  well  developed;  the  second  fetus 
formed  a  large  epignathus  hanging  from  the  mouth  of  the  first;  while  the 


FIG.  511. — Complex  epignathus.     (A  case  of  Baart  de[la  Faille.) 

third  and  fourth  were  joined  by  a  forked  umbilical  cord  to  the  palate  of  the 
first,  where  its  vessels  joined  with  the  sphenopalatine  branches. 

In  the  genesis  of  pharyngeal  dermoids  and  teratomas  various  theories  have  con- 
tended for  recognition.  In  the  extensive  discussions  of  this  subject  it  has  been  recog- 
nized not  only  that  the  general  principles  of  teratogenesis  are  involved,  but  that  special 
local  factors  in  development  must  be  considered. 

Arnold  maintained  that  the  simpler  bidermal  and  the  complex  tridermal  growths 
must  be  referred  to  local  disorders  of  development,  while  the  true  teratomas,  which 
according  to  his  definition  must  present  definite  rudimentary  organs,  were  true  fetal 
implantations.  Here  as  elsewhere  an  effort  has  been  made  to  distinguish  between  autoch- 
thonous teratomas  (developed  from  local  tissues)  and  heterochthonous  (developed  from 
sources  alien  to  the  locality).  From  this  point  of  view  two  entirely  different  embryonic 
disturbances  must  be  held  responsible  for  the  present  group  of  conditions:  (1)  Local 
disturbances  of  development  involving  the  buccal  cavity,  the  hypophyseal  duct,  and  the 
first  branchial  arch;  (2)  the  aberrant  growth  of  a  totipotent  blastomere,  polar  body, 
sex  cell,  or  tissue  bud. 

The  hairy  polyps  and  the  simpler  tridermal  teratoids  have  been  regarded  by  nearly 
all  authors  as  adequately  explained  by  the  first  mentioned  factors.  The  invagination 
of  ectoderm  in  the  formation  of  the  buccal  cavity  and  the  fusion  of  this  cavity  with  the 


TERATOLOGY  973 

fore-gut  through  the  primitive  pharyngeal  membrane  give  opportunity  for  the  separa- 
tion of  ectodermal  and  mesodermal  rests  which  may  explain  some  of  the  growths  at- 
tached to  the  palate.  Rather  more  definite  sources  are  provided  in  the  course  of  devel- 
opment of  the  hypophysis  and  its  duct,  for  some  of  the  pharyngeal  growths  are  clearly 
connected  with  these  structures  and  many  of  them  are  attached  at  the  sella  turcica  or 
perforate  the  skull  at  this  point.  The  hypophysis  may  be  missing.  That  the  first 
branchial  arch  may  also  be  concerned  in  some  cases  is  indicated  by  the  occurrence  of 
other  anomalies  in  the  course  of  this  arch  and  by  the  complex  teratoids  and  epignathi 
located  in  the  course  of  other  arches.  Finally,  the  theory  of  local  origin  is  favored  by 
analogy  with  parallel  conditions  at  the  caudal  extremity  and  by  the  series  of  simpler 
embryonal  tumors  of  the  nasopharynx.  The  definite  teratomas  and  epignathi  Arnold, 
Askanazy,  and  others  interpret  as  forms  of  fetal  implantation  without  designating  their 
particular  history. 

Somewhat  definite  discrepancies,  however,  exist  between  the  above  theory  and  the 
observed  facts.  The  sharp  separation  attempted  between  complex  autochthonous  and 
only  slightly  more  complex  heterocthonous  growths  proves  extremely  difficult,  for  no 
sharp  distinction  in  morphology  exists.  In  fact,  in  the  not  overnumerous  series  every 
gradation  seems  to  be  represented,  from  the  simple  bidermal  polyps  up  to  the  well- 
formed  epignathi,  so  that  a  single  origin  for  the  entire  group  is  strongly  indicated. 
Hence,  Schwalbe  concludes  that  all  the  complex  pharyngeal  growths  are  derived  from 
isolated  blastomeres,  and  that  the  varying  structure  of  the  growths  depends  upon  the 
stage  of  development  of  the  blastomeres  at  the  time  of  their  isolation.  It  is  more  prob- 
able that  they  result  from  early  budding.  He  employs  the  term  "teragogenic  termina- 
tion-point" to  indicate  the  stage  of  differentiation  which  the  separated  blastomere  or 
originating  cell  group  must  possess  in  order  to  produce  just  the  particular  form  of  tera- 
toid,  teratoma,  or  parasitic  fetus  observed.  When,  however,  Schwalbe  includes  with 
isolated  blastomeres  more  complex  and  differentiated  cell  complexes,  his  theory  closely 
approaches  the  standpoint  of  Arnold. 

Adami  explains  epignathi  and  sacral  monstrosities  as  the  result  of  overgrowth  of  cells 
at  the  two  "growing  points"  of  the  embryo,  after  the  rudiments  of  the  local  organs  have 
been  laid  down.  After  the  brain  vesicles  are  formed  any  further  growth  of  the  superior 
growing  point,  which  lies  in  the  region  of  the  sella  turcica,  would  produce  superfluous 
tissue  involving  three  germ  layers. 

In  the  origin  of  the  naso pharyngeal  dermoids  three  possible  sources  must  be  con- 
sidered: (1)  Incomplete  absorption  of  the  membrane  separating  buccal  cavity  (stoma- 
deum)  and  fore-gut.  (2)  The  ectodermal  pouch,  hypophysis.  (3)  The  first  branchial 
cleft  in  its  relations  especially  to  the  Eustachian  tube,  which,  however,  is  wholly  endp- 
dermal  in  origin.  The  relation  of  the  hairy  pharyngeal  dermoids  to  the  complex  teratoid 
tumors  of  this  region  remains  undetermined,  but  since  their  structure  is  comparatively 
simple  and  they  contain  only  such  elements  as  may  arise  from  normal  tissues  in  that 
neighborhood,  they  probably  originate  from  a  local  disturbance  in  the  first  branchial 
cleft  and  not  from  a  totipotent  cell  or  cell  group  (Askanazy). 

Hypophyseal  Dermoids. — Closely  related  to  the  pharyngeal  growths  is 
a  group  of  more  complex  intracranial  dermoids  lying  at  the  base  of  the  skull, 
in  the  sella  turcica  (Beck),  near  the  olfactory  lobes  (Bonorden),  or  at  optic 
chiasm  (Rokitansky).  The  neighboring  pineal  gland  may  be  hyperplastic. 
These  tumors  are  lined  by  epidermis  and  filled  with  granular  or  lamellated 
detritus  as  in  cholesteatoma  and  the  wall  may  contain  bone,  cartilage,  muscle- 
tissue,  and  fat.  Bonorden  found  14  teeth,  cysts  lined  by  ciliated  epithelium, 
and  fragments  of  thyroid  tissue,  in  a  case  which  suggests  a  teratoid  origin. 
These  tumors  are  commonly  referred  to  buccal  ectoderm  misplaced  in  the 
development  of  the  hypophysis  (Wilms,  Lit.).  While  there  are  some  grounds 
for  assuming  a  teratoid  origin  of  the  entire  group,  the  structural  scope  is 
somewhat  limited,  and  represents  chiefly  the  local  organs  from  which  differ- 
ent elements  might  well  be  contributed  by  some  early  embryonal  disturbance, 
such  as  budding  at  the  cephalic  extremity.  The  alternative  hypothesis  would 
explain  these  growths  as  abortive  epignathi. 

A  few  cases  of  intracranial  teratoid  tumors  have  been  referred  to  the 
hypophysis.  Beck  found  in  the  sella  turcica  a  small  tumor  containing 
cartilage,  bone,  myxoma,  cysts  with  ciliated  epithelium,  and  14  teeth. 

Intracranial  Dermoids. — The  relations  of  the  medullary  groove  to  the 


974  NEOPLASTIC  DISEASES 

ectoderm,  the  complex  steps  in  the  formation  of  the  brain  and  ventricles, 
and  the  formation*  and  union  of  the  cranial  bones  give  abundant  sources 
for  the  development  of  epidermal  growths  in  the  skull.  The  interpretation 
of  these  tumors  is  further  complicated  by  certain  properties  of  endothelial 
growths  to  copy  the  structure  of  cholesteatoma,  and  finally  traumatic  im- 
plantation of  portions  of  ectoderm  accounts  for  a  small  proportion  of  intra- 
cranial  processes.  Several  types  of  epidermal  tumors  are  included  in  this 
group. 

(1)  Cholesteatoma  is  a  tumor  composed  of  lamellated  waxy  or  scaly  ma- 
terial enclosed  in  a  wall  of  stratified  squamous  cells.    It  occurs  in  all  parts 
of  the  brain,  ventricles,  and  basal  regions,  usually  near  the  midline,  and  is 
regularly  connected  with  the  meninges.     Bostroem,  in  an  elaborate  study, 
concludes  that  all  cholesteatomas  arise  from  embryonal  epidermal  inclu- 
sions.   Beneke  and  Bonorden  support  this  view,  and  refer  a  basal  cholestea- 
toma to  an  inclusion  from  the  pharyngeal  wall  connected  with  the  hypoph- 
ysis.   Erdheim  reports  13  cholesteatomas  at  the  base  of  brain,  none  of  which 
seemed  to  be  connected  with  the  hypophysis  and  few  were  in  the  median 
line.    He  finds  only  one  case  of  cholesteatoma  of  the  infundibulum  (Beneke's). 
Blasius,  in  a  tumor  of  the  convexity,  found  epithelium  resembling  that  of 
the  skin.    A  traumatic  origin  must  be  accepted  for  Hartley's  frontal  choles- 
teatoma.   An  endothelial  origin  for  the  deep  tumors  is  assumed  by  Glaeser, 
H.  Frank,  and  others,  and  Borst  distinguishes  intracranial  dermoids,  epider- 
moids,   and  endothelial   cholesteatomas.     Finally,   Benda  holds  the  epen- 
dymal  epithelium  responsible  for  some  deep  cholesteatomas.     In  several 
cases  I  have  found  no  evidence  of  any  other  than  an  epithelial  origin. 

(2)  The  intracranial  dermoids  are  walled  by  epidermis  and  derma  with 
sebaceous  and  hair  glands,  and  contain  sebaceous  material  and  hair.    They 
lie  (i)  between  the  olfactory  lobes  and  corpora  mammillaria,  or  (2)  between 
medulla  and  pons,  and  their  positions  indicate  that  the  embryogenic  dis- 
turbance occurred  at  the  formation  of  the  second  brain  vesicle.     Bostroem 
collected  18  cases,  all  of  which  were  connected  with  dura  or  pia. 

(3)  Dural  dermoids  lie  close  to  the  skuU,  but  grow  deeply,  pushing  the 
pia  before  them.    They  usually  lie  in  the  median  line  in  tentorium  cerebelli, 
at  internal  occipital  protuberances  or  torcular  herophili,  or  they  may  be 
epicranial.    They  are  often  connected  with  the  skin  by  an  epithelial  canal  or  a 
fibrous  strand,  and  there  may  be  a  defect  in  the  skull  or  an  absence  of  hair 
in  the  overlying  scalp  (Heschl).    They  must  arise  late  after  the  skin  is  formed, 
from  adhesions  between  skin  and  dura,  and  they  are  observed  at  birth  or  in 
infancy  (Bostroem,  Ziegler).     Some  of  the  tumors  of  the  hypophyseal  duct 
described  by  Erdheim  contained  cysts  lined  by  derma  in  which  were  bony 
trabeculae.      Benda  has   also  described  a  hypophyseal  dermoid   containing 
bone  in  its  wall. 

Multiple  complex  dermoids  scattered  over  pia  of  cord  and  brain  and  in 
ventricles,  appearing  as  yellowish  nodules  of  connective  tissue,  fat,  nerve- 
cells  and  fibers,  smooth  muscle,  and  flat  epithelium,  occurred  in  a  remarkable 
case  recorded  by  Trachtenberg.  The  large  complex  intracranial  dermoids 
are  probably  to  be  interpreted  as  teratomas  (Askanazy). 

Intracranial  teratoids  and  teratomas  have  been  observed  in  a  few  cases, 
the  position  of  which  it  has  often  been  difficult  to  determine.  Arnold  de- 
scribed a  frontal  tumor  partly  extracranial,  but  extending  into  the  ventricles, 
which  contained  fat,  cartilage,  and  bone,  and  which  he  interpreted  as  a 
fissural  mixed  tumor.  Eberth  observed  an  intracranial  tumor  connected 
by  a  pedicle  with  the  dura,  and  composed  of  fat,  muscle,  lymphoid  tissue, 
and  nerves. 


TERATOLOGY  975 

In  the  ventricle  Strassmann  and  Streker  described  in  a  boy  of  3  years 
a  tumor  of  the  right  choroid  plexus,  composed  of  connective  tissue,  fat,  bone, 
cartilage,  muscle,  nerve-cells,  glands,  and  cysts  lined  by  epithelium.  In  the 
third  ventricle  of  an  infant  Saxer  found  a  complex  teratoid  containing  carti- 
lage, bone,  muscle,  chorda  tissue,  gland  alveoli,  cysts  lined  by  cylindrical 
or  ciliated  or  squamous  epithelium,  pigmented  retinal  epithelium,  choroid 
plexus,  and  fetal  brain  tissue  and  ganglia.  Both  of  these  tumors  may  be 
referred  to  complex  portions  of  the  medullary  plate. 

Certain  intracranial  teratoids  and  teratomas  arise  in  connection  with 
the  hypophysis  and  the  pineal  gland  (q.  v.). 

Teratoma  of  Pineal  Gland. — (See  Pineal  Gland.) 

Peritoneal,  Mesenteric,  and  Omental  Cysts,  Dermoids,  and  Terato- 
mas.— A  comprehensive  resume  of  this  subject  was  first  contributed  by  Hahn 
in  1887.  A  more  minute  analysis  and  history  were  given  by  Braquehaye 
(1892),  who  recognized  especially  the  dermoids  and  cysts  derived  from  neigh- 
boring organs.  Dowd  (1900)  pointed  out  the  probable  identity  and  embryo- 
nal origin  of  many  glandular,  serous,  and  blood-cysts.  A  complete  resume  of 
the  entire  subject  with  reference  to  184  cases  is  presented  by  Niosi. 

Four  main  varieties  of  cystic  tumors  appear  in  the  peritoneum:  (i) 
Lymphatic  or  chylous  cysts.  (2)  Enteric  cysts.  (3)  Urogenital  cysts.  (4) 
Dermoids  and  teratoids.  Hydatid  cysts  and  cysts  of  neighboring  organs 
complicate  the  clinical  diagnosis. 

(1)  Chylous  cysts  form  very  large,  single,  usually  multilocular  tumors,  or 
very  numerous  small  swellings  of  mesentery,  omen  turn,  intestinal  wall,  and 
retroperitoneal  regions  (Klemm,  Lit.).    The  contents  are  clear  fluid  or  chyle, 
or  more  inspissated  fatty  material,  and  blood  is  often  added.     The  walls 
are  of  fibrous  tissue  in  which  are  many  round  cells  or  lymph-follicles,  and 
often  dilated  lymph  spaces.    Bundles  of  smooth  muscle  tissue  may  be  present, 
as  in  enteric  cysts.    The  lining  of  recognizable  endothelium,  which  may  be 
hyperplastic  (Tilger).     Many  giant-cells  may  form  about  fatty  detritus,  or 
the  cellular  lining  may  be  lost. 

Klemm  and  Rittner  interpret  all  mesenteric  chylous  cysts  as  cystic  lymph- 
angiomas.  That  some  represent  merely  dilated  lymphatics  is  shown  by 
Kostlivy's  study  and  by  the  cases  of  lymph-cysts  arising  after  occlusion  of 
local  lymphatics  in  cancer.  In  some  cases  the  cyst  appears  to  involve  chiefly 
certain  lymph-nodes  (Lion,  Spaeth).  Since  enteric  cysts  may  contain  chy- 
lous fluid  a  sharp  distinction  from  chylous  lymph-cysts  is  not  always  possible. 

The  so-called  serous  cysts  probably  represent  rare  forms  of  other  varieties 
of  this  group.  Turner  found  clear  fluid  in  one  compartment  and  chylous 
fluid  in  two  other  portions  of  a  lymph-cyst.  The  presence  of  muscle-fibers  in 
the  walls  of  serous  cysts  suggests  an  enteric  origin. 

Blood-cysts  usually  arise  from  extravasation.  Wagener  has  described  a 
true  cystic  hemangioma  of  the  mesentery. 

(2)  Enteric  cysts  constitute  a  rather  well-defined  group  of  intraperitoneal 
cysts.    They  form  single  or  multiple  large  or  small  cysts  lying  usually  along 
the  lower  end  of  the  ileum,  in  the  wall  of  the  intestine,  at  the  point  of  Meckel's 
diverticulum  (Roth),  in  the  mesentery,  or  near  the  navel  (Wyss).     When 
originating  within  the  muscular  wall  of  the  intestine  they  usually  remain 
connected  with  this  organ  and  are  enclosed  by  a  muscular  wall.    Arising  in  the 
subserosa  they  remain  attached  to  the  convex  side  or  project  into  the  mesen- 
tery.    There  may  be  definite  malformation  of  the  intestine  (Nasse).     The 
cavity  is  usually  single  and  the  contents  are  mucinous,  colorless,  yellowish,  or 
brownish  fluid.    The  wall  resembles  that  of  the  intestine,  and  may  contain 
smooth  muscle,  mucosa,  crypts,  lymphoid  tissue,  and  a  lining  of  cylindrical 


976  NEOPLASTIC  DISEASES 

or  cuboidal  or  stratified  epithelium  (Colmers).  The  epithelium  may  show 
papillary  proliferation.  Secondary  changes  in  the  cyst  may  destroy  much  or 
possibly  all  the  epithelial  lining,  and  many  stages  of  the  atrophy  of  muscle 
tissue  have  been  observed  (Niosi).  Both  cylindrical  and  squamous  cells 
may  be  found  in  the  same  cyst  (Gfeller). 

There  are  probably  several  modes  of  origin  of  enteric  cysts.  Many 
originate  from  Meckel's  diverticulum  and  are  located  at  the  lower  ileum  where 
they  may  communicate  with  the  bowel  (Ruge,  Roth).  At  the  navel  they 
may  be  referred  to  the  omphalomesenteric  duct  (Wyss).  The  term  "ento- 
dermoid"  has  been  employed  by  Beneke  to  designate  enteric  cysts  which 
arise  from  definitely  misplaced  portions  of  intestine.  Many  of  these  lie  in 
the  mesentery,  and  are  multiple.  Roth  and  Hennig  found  a  large  cyst  in 
mesentery  and  one  in  posterior  mediastinum,  both  in  infants.  Sanger  and 
Klopp,  in  a  newborn  infant,  found  5  cysts,  in  the  walls  of  2  of  which 
were  portions  of  liver  tissues.  Honl  has  reported  2  remarkable  cases  of 
multiple  enteric  cysts  in  which  there  were  37  and  89  small  cysts  lined  by 
intestinal  mucosa. 

(3)  Intraperitoneal  cysts  of  nephrogenic  origin  form  a  less  definite  and  less 
numerous  group,  of  which  Niosi  collected  5  cases.    Many  other  cases  in  which 
the  structure  was  obscure  are  held  by  Dowd  and  Niosi  to  belong  in  this  group. 
These  cysts  are  of  large  size,  single  or  multilocular,  involving  mesentery 
and  adjacent  regions  or  extending  into  the  pelvis,  and  occur  chiefly  in  adult 
women.     The  contents  are  brownish  serous  fluid  containing  pseudomucin. 
The  wall  is  composed  of  fibrous  tissue  and  the  lining  is  of  high  cylindrical 
or  cuboidal  glandular  epithelium,  which  may  be  deficient  in  some  areas. 
In  Niosi's  case  the  structure  was  complex  and  the  wall  contained  definite 
portions    of    adrenal    cortex,    and    structures    resembling    the    embryonal 
kidney. 

The  origin  of  these  cysts  presents  a  difficult  problem,  but  it  seems  probable 
that  they  are  derived  from  aberrant  remnants  of  the  Wolffian  body  and  that 
the  embryogenic  disturbance  occurs  at  various  periods  in  the  history  of  this 
structure.  Dowd  regarded  his  case  as  arising  from  an  ovarian  rest,  while 
Niosi's  case  must  have  included  more  complex  elements. 

(4)  Dermoid  cysts  of  the  mesentery  and  peritoneum    are  rare    (Niosi, 
Lit.).     They  are  located  in  any  portion  of  the  mesentery  from  celiac  axis 
to  pelvis  and  their  dimensions  may  be  considerable.    In  Fraenkel's  case  the 
cyst  was  attached  to  the  diaphragm.     The  epithelial  lining   may  be  lost 
(Marie).     They  are  usually  lined  by  squamous  epithelium  and  contain  hair 
and  sebaceous  material.    Ruysch  and  Martel  observed  in  the  omen  turn  large 
cysts  containing  hair.    Others  are  very  complex  and  contain  hair  and  teeth. 
In  a  large  cyst  extending  in  mesentery  from  ribs  to  pelvis  of  an  infant  of 
2  years  Dickinson  found  connective  tissue,  fat,  bone,  and  cartilage. 

A  few  peritoneal  teratoid  tumors  have  been  reported.  Bonfigli  describes 
a  cyst  adherent  to  liver  and  stomach  containing  19  loose  teeth  and  2  em- 
bedded in  well-formed  bone.  The  wall  was  lined  by  hairy  skin.  A  very 
similar  case  is  that  of  Schutzer. 

Various  sources  appear  to  contribute  to  these  tumors.  Many  simple 
intraperitoneal  dermoids  are  referred  by  Wilms  to  imperfect  closure  of  the 
abdominal  plates.  Others  are  commonly  regarded  as  derived  from  the  ovary, 
by  separation  of  an  original  ovarian  tumor,  or  by  development  from  a  super- 
numerary ovary,  or  by  implantation  from  a  ruptured  ovarian  dermoid. 

The  position  of  the  complex  dermoids  strongly  suggests  that  many  of 
them  belong  in  the  group  of  abdominal  teratomas  and  that  more  complete 
examination  would  have  revealed  a  tridermal  structure. 


TERATOLOGY  . 977 

Abdominal  Fetal  Implantations  and  Teratomas. — Seventeen  cases  of 
definite  fetal  implantation  in  the  abdomen  have  been  collected  by  Lexer. 
They  occurred  in  newborn  infants  or  in  subjects  between  the  ages  of  a  few 
months  and  61  years.  Their  location  in  the  transverse  mesocolon  or  behind 
liver  in  bursa  epiploica  indicates  that  they  were  originally  celomic  implanta- 
tions. The  vascular  supply  is  from  the  aorta  or  the  vessels  of  the  colon. 
Rudimentary  limbs  and  organs  and  well-formed  membranes  and  umbilical 
cords  have  been  recognized. 

Several  cases  of  tridermal  teratomas  of  the  peritoneum  have  been  collected 
by  Lexer  and  by  Askanazy,  and  to  these  may  be  added  other  bidermal  growths 
which  are  probably  of  similar  origin.  Their  position  has  been  behind  the 
liver  and  extending  downward  behind  the  kidney. 

A  sharp  separation  between  peritoneal  and  retroperitoneal  teratomas 
cannot  be  made.  The  tumors  occur  in  young  or  adult  subjects  and  reach 
large  dimensions.  The  scope  of  structure  includes  solid  portions  composed 
of  bones  with  marrow  cavity,  cartilage,  fat  tissue,  muscle,  and  connective, 
and  cystic  portions  with  cavities  containing  hair  or  mucus,  and  lined  by 
epidermis  or  cylindrical  or  ciliated  epithelium.  Hosmer  found  a  portion 
of  intestine  with  mesentery.  Marchand  observed  intestine  with  calculi, 
prostate  gland,  and  rudimentary  brain.  Ahren's  case  consisted  chiefly  of  a 
segment  of  gastro-intestinal  canal,  with  lining  of  intestinal  mucosa,  or 
squamous  or  ciliated  cells.  There  was  ulceration,  and  pepsin  and  acid  were 
demonstrated  in  the  contents  of  the  cyst.  Whether  this  case  was  a  tera- 
toma  reduced  to  gastro-intestinal  canal,  or  a  derivative  of  misplaced  ento- 
derm,  it  is  difficult  to  determine.  Yet  Englander's  case,  containing  intestine, 
cartilage,  and  fat,  furnishes  a  transition  to  genuine  tridermal  teratoma.  Pil- 
liet  describes  sarcomatous  areas,  and  in  Montgomery's  case  the  original 
sarcomatous  and  carcinomatous  areas  recurred.  In  Goebell's  case  adeno- 
sarcoma  derived  from  the  entoderm  produced  numerous  metastases.  The 
peritoneum  is  occasionally  the  seat  of  malignant  embryonal  tumors  of  carci- 
nomatous or  sarcomatous  structure  whose  position  suggests  a  relation  to 
the  malignant  forms  of  peritoneal  teratoma.  Fleischmann  found  pure  neuro- 
epithelioma  in  the  metastases  of  a  complex  malignant  tumor  of  the  omentum. 

Primary  abdominal  chorioma  in  the  male,  located  in  the  omentum,  is 
described  by  Bonney,  and  other  abdominal  tumors  have  been  interpreted 
as  chorioma  by  Bostroem  and  Djewitsky. 

Retroperitoneal  Dermoids  and  Teratoids. — Three  varieties  of  epidermal 
tumors  occur  in  retroperitoneal  regions: 

(1)  Tridermal  teratomas.     These  may  be  unattached  teratomas,  as  in 
Brouha's  or  Schonholzer's  cases,  or  derived  from  the  ovary,  normal,  displaced, 
or  supernumerary  (Borst,  Bolzano).    Funke  would  derive  all  retroperitoneal 
dermoids  from  germ  epithelium,  or  from  ovary,  or  from  supernumerary 
testes,  of  which  Merkel  has  collected  several  cases. 

(2)  Epidermal  rests  derived  from  the  Wolffian  duct  are  probably  the 
source  of  certain  dermoids  of  kidney  (Schlegtendal,  Wedeman),  ligamentum 
latum,  spermatic  cord,  and  epididymis  (Wilms,  Lexer,  R.  Meyer).     They 
contain  no  dermal  glands. 

(3)  True  dermoids  are  derived  from  imperfect  closure  of  abdominal  folds. 
Ruge  describes  a  large  cyst  with  two  compartments,  one  lined  by  skin  with 
dermal  glands  and  containing  hair,  the  other  reproducing  intestinal  mucosa, 
which  he  would  derive  from  a  remnant  of  the  vitelline  duct.    Of  the  abdom- 
inal fetal  implantations,  Lexer  finds  2  cases  (Buhl,  Phillips)  in  which  the 
location  was  retroperitoneal.    The  tumors  lay  on  the  aorta  behind  pancreas, 
and  extended  from  diaphragm  downward  and  behind  kidney. 

62 


978  •  NEOPLASTIC  DISEASES 

Dermoid  cysts  of  the  pelvic  connective  tissues  are  rare  but  well-recognized 
conditions  giving  rise  to  pelvic  symptoms  (Germain,  Lit.).  They  appear 
chiefly  in  women  in  the  childbearing  period,  and  are  commonly  situated 
behind  the  rectum  and  above  the  levator  ani  muscle,  and  reach  the  size  of  a 
hen's  egg,  or  child's  head,  or  larger.  Six  cases  have  occurred  in  male  subjects. 
Sanger  collected  n  cases  in  which  the  tumors  were  found  in  various 
positions,  chiefly  in  contact  with  and  behind  the  rectum.  The  presence  of 
hair  in  the  stools  has  been  the  first  symptom  observed,  or  the  bladder  may  be 
reached  and  hair  appear  in  the  urine  (Le  Gendre).  The  occasional  presence 
of  muscle  tissue  and  renal  structures  suggest  a  teratoid  origin,  but  it  is  more 
probable  that  they  result  from  misplacement  of  portions  of  ectoderm  and 
mesoderm  during  the  formation  of  the  anus,  rectum,  and  urinary  passages 
(proctodeal  membrane  and  neurenteric  canal).  As  a  group  they  correspond 
to  the  pharyngeal  and  cervical  dermoids  of  the  cephalic  extremity.  They 
differ  in  location,  origin,  and  symptoms  from  the  more  superficial  dermoids 
which  project  externally  and  are  usually  present  at  birth.  Some  very  exten- 
sive pelvic  and  retroperitoneal  dermoids  probably  belong  in  this  group. 
Zweifel  removed  a  large  cyst  lined  by  hairy  skin,  which  extended  from  dia- 
phragm behind  kidney  and  into  pelvis,  and  Bardenhauer's  cystic  tumor  was 
even  more  extensive  in  the  same  regions. 

Ciliated  Epithelial  Cysts.  Enterocystomas. — In  many  regions  of  the 
body  occur  small  or  large  cysts  lined  by  ciliated  epithelium,  the  origin  of  which 
has  given  rise  to  much  speculation.  One  group  of  these  cysts  is  relatively 
numerous  along  the  gastro-intestinal  canal,  and  since  they  are  usually  lined 
by  mucous  membrane  resembling  that  of  the  intestine  they  are  commonly 
named  enteric  cysts.  Others,  while  of  much  the  same  structure,  are  widely 
distributed  in  organs  where  an  enteric  origin  is  improbable,  as  in  brain, 
thorax,  pharynx,  lung,  and  genital  organs,  and  in  each  situation  they  are 
probably  referable  to  local  disorders  of  development.  They  seem  to  represent 
an  endodermal  parallel  of  the  dermoid  cysts,  but  the  presence  of  ciliated 
cells  does  not  necessarily  indicate  an  endodermal  origin.  In  general,  their 
structure  may  be  explained  by  the  fact  that  many  embryonal  canals  are 
originally  lined  by  ciliated  epithelium,  as  the  neural,  enteric,  respiratory, 
and  genital,  and  that  an  early  misplacement  of  cell  groups  from  these  struc- 
tures would  naturally  have  the  lining  cells  in  an  embryonal  state.  In  fact, 
all  undifferentiated  epithelium  is  generally  ciliated.  In  the  brain  the  cysts 
occur  in  the  region  of  the  ventricles,  with  which  they  may  be  connected  by 
cell  strands.  Their  origin  is  probably  from  the  epithelium  of  the  neural 
canal  (Eberth).  In  the  regions  of  the  branchial  clefts,  nasopharynx,  mouth, 
neck,  tongue,  and  mediastinum  many  cysts  of  this  type  are  observed.  Their 
origin  may  be  traced  to  the  same  conditions  that  lead  to  branchiogenic  der- 
moids, with  which  they  are  often  combined.  In  the  skin  Hess  has  described 
a  number  of  cysts  with  ciliated  lining,  for  which  no  explanation  is  apparent. 

Along  the  esophagus  in  the  fibrous  or  submucous  coats  the  cysts  have 
frequently  been  observed  and  referred  to  misplacements  of  the  embryonal 
epithelial  lining  which  is  originally  ciliated  (Wyss,  Zahn,  Trespe).  In  the 
pleura,  hilus  of  lung,  arch  of  aorta  (Stilling),  and  in  mediastinum  between 
diaphragm  and  lung,  simple  or  complex  cysts  occur,  often  associated  with 
mucous  glands,  muscle,  or  cartilage.  They  have  been  referred  to  misplaced 
portions  of  the  respiratory  tract  (Virchow,  Zahn).  In  the  liver  the  cysts 
have  appeared  on  the  anterior  surface,  near  the  suspensory  ligament,  and 
along  the  inferior  border.  They  lie  between  the  peritoneum  and  capsule  of 
the  organ  (Zahn),  and  their  origin  is  not  readily  explained. 

About  the  female  generative  organs,  internal  and  external,  the  cysts  are 


TERATOLOGY 


979 


particularly  frequent,  and  may  be  referred  to  the  several  embryonal  struc- 
tures connected  with  these  organs. 

Sacrococcygeal  Dermoids,  Mixed  Tumors,  and  Teratomas. — The  com- 
plex embryonal  processes  occurring  in  the  caudal  extremity  form  the  basis 
of  a  series  of  fistulas,  cysts,  and  tumors  in  this  region.  Very  similar  con- 
ditions exist  at  the  cephalic  extremity  with  parallel  results. 

In  the  sacrococcygeal  region  the  abnormalities  resulting  from  embryonal 
disorders  include:  (i)  Simple  dermoids,  (2)  complex  dermoids,  (3)  teratoid 
tumors,  (4)  teratomas,  (5)  fetal  implantations.  In  many  cases  these  condi- 
tions are  associated  with  various  defects  of  the  spinal  cord  and  its  membranes 
and  the  spinal  column  (spina  bifida). 

While  some  of  these  conditions  are  simple  and  readily  referable  to  par- 
ticular embryonal  structures,  others  are  complex,  difficult  of  interpretation, 
and  seem  to  involve  more  than  one  embryonal  structure.  In  dealing  with 


Intestine 
Colon 

Duct,  omphaloenteric 
Duct,  allantoideus 

Membrana  cloacae 
Post-anal  gut 
Spinal  column 


Mesonephros 
Mesenterium  dors. 
Extremitas  inf. 

Intestine 
Opening  of  Wolffian  duct 

Aorta 
Chorda 

FIG.  512. — Model  of  caudal  extremity  of  embryo.     (After  Kollmann.) 

the  more  complex  growths  one  encounters  teratoid  tumors  which  seem  to 
have  a  purely  local  origin  and  transitional  cases  which  seem  to  belong  to  the 
true  bigeminal  teratomas,  among  which  are  also  pronounced  forms  of  fetal 
implantation.  Thus  the  entire  group  is  not  only  numerous  but  complex,  and 
a  rigid  classification  is  at  present  impossible  (Borst,  Lit.). 

The  embryonal  structures  which  give  rise  to  these  growths  are  chiefly: 
(i)  The  fovea  coccygea  and  the  coccygeal  vestiges  of  the  neural  canal,  (2) 
the  neurenteric  canal,  (3)  the  postanal  gut,  (4)  the  proctodeal  membrane. 
The  location  of  these  structures  and  the  general  conformation  of  the  caudal 
extremity  is  partially  indicated  in  the  accompanying  sketch. 

Fovea  Coccygea.  Coccygeal  Vestiges  of  Neural  Canal. — Up  to  the  third 
month  the  spinal  cord  reaches  to  the  third  coccygeal  vertebra,  beyond  which 
it  is  continued  to  the  tip  of  coccyx  and  to  the  overlying  skin  as  a  fibrous  cord 
containing  groups  of  epithelial  cells.  Up  to  the  fifth  month  or  later  there 


980  NEOPLASTIC  DISEASES 

is  further  growth  of  the  cells  of  this  structure,  producing  irregular  spaces 
lined  by  polyhedral* or  pavement  cells.  The  later  development  of  the  soft 
parts  about  the  anus  and  the  gradual  atrophy  of  the  remannt  of  cord  often 
produces  a  superficial  depression  over  the  coccyx — ihefovea  coccygea  (Tourneux, 
Hermann,  Mallory).  Fistulas  lined  by  pavement  or  polyhedral  cells,  der- 
moids,  and  more  complex  tumors  may  develop  from  these  structures.  Tour- 
neux has  found  remnants  of  gland  tissue  along  with  these  coccygeal  vestiges. 
Perman  describes  a  large  tumor  resembling  a  meningomyelocele  which  was 
not  connected  with  the  spinal  canal,  but  contained  much  neuroglia  tissue 
and  cysts  lined  by  cubical  or  stratified  squamous  epithelium.  Nasse  de- 
scribes a  simple  fistula  lined  with  epidermis  and  many  sweat-glands,  and 
Wendelstadt  reports  a  case  in  which  the  tract  contained  skin  and  hair. 
Wette  observed  a  dermoid  in  the  coccygeal  canal,  with  a  fistula  leading  to  the 
skin.  Schmidt  found  a  sacral  dermoid  with  several  fistulous  openings,  asso- 
ciated with  a  complex  mesodermal  tumor  in  which  were  tubules  lined  by 
cylindrical  cells.  Mallory  has  collected  a  series  of  cases  of  fistulous  tracts. 
cysts,  dermoids,  and  a  glioma  in  this  region,  and  demonstrated  in  several 
fetuses  the  embryonal  structures  from  which  they  spring.  Bergmann 
pointed  out  that  the  dermoid  tumors  in  this  locality  show  no  free  communica- 
tion with  the  spinal  canal,  which  is  regularly  present  with  meningocele.  Yet 
some  spinal  dermoids  are  connected  with  the  canal  by  a  narrow  pedicle. 

Neurenteric  Canal. — In  the  lower  vertebrates  there  is  constantly  present  a 
short  narrow  canal  connecting  the  lower  end  of  the  medullary  groove  with  the 
hind-gut.  This  neurenteric  canal  has  been  observed  by  Graf  Spec  in  a  human 
embryo  with  still  widely  open  medullary  groove,  and  Eternod  has  repeated 
this  observation.  Although  the  canal  is  a  very  minute  structure  and  there 
is  no  evidence  that  it  exists  in  any  form  in  the  adult  (Keibel  and  Mall),  it 
has  been  drawn  into  the  possible  sources  of  certain  tumors  of  the  ventral 
side  of  the  coccyx,  especially  those  which  combine  cysts  lined  by  intestinal 
wall  with  portions  of  nervous  tissue. 

Of  these  tumors  Hildebrand's  case  may  serve  as  an  example.  A  female 
infant  of  6  months  presented  a  tumor  as  large  as  its  head,  lying  between  rec- 
tum and  sacrum  and  protruding  externally.  It  was  composed  of  many  cysts 
lined  by  cuboidal  or  cylindrical  or  ciliated  or  hornifying  squamous  epithelium. 
In  some  cysts  the  lining  closely  resembled  the  intestinal  mucosa,  and  into 
these  cysts  projected  two  papillary  masses  of  neuroglia  tissue.  Other  com- 
plex cases  which  seem  to  belong  in  this  group  are  reported  by  Jantreboff  and 
Ritchl.  Bergmann  described  sarcomatous  changes,  and  cases  in  which  the 
course  is  rapid  and  the  tumor  exhibits  several  types  of  sarcoma,  but  without 
metastases  (cystosarcoma). 

Postanal  Gut. — The  proctodeal  portion  of  the  anal  canal,  formed  by  an 
invagination  of  the  ectoderm,  does  not  meet  the  lower  end  of  the  intestine, 
but  joins  the  intestinal  wall  at  some  distance  anterior  to  its  extremity.  The 
terminal  portion  of  the  intestine,  lying  on  the  ventral  side  of  the  coccyx, 
becomes  closed  and  atrophic,  and  this  embryonal  remnant  appears  to  be 
connected  with  many  tumors  lying  between  coccyx  and  rectum.  It  was 
first  employed  by  Middledorpf  in  explanation  of  a  cystic  tumor  containing  a 
convoluted  portion  of  intestine  surrounded  by  much  fat  tissue. 

These  tumors  are  observed  at  birth.  They  form  papillary  external  tumors 
between  anus  and  coccyx,  displacing  the  genitals,  and  they  extend  upward 
behind  the  rectum,  and  occasionally  outward  over  the  coccyx. 

Simple  tumors  of  this  group  are  composed  of  segments  and  convoluted 
folds  of  intestinal  wall  and  mucosa.  Middledorpf's  tumor  had  an  external 
fistula  and  was  adherent  to  rectum.  Ganz  found  a  segment  of  intestine  7 


TERATOLOGY  981 

cm.  long,  and  other  similar  cases  are  described  by  Freyer  and  Nasse.  Wid- 
ened sacral  vessels  coursing  over  the  tumor  may  yield  a  bruit  (Jordan).  The 
well-developed  muscular  walls  may  yield  spontaneous  or  electrically  excited 
peristaltic  movements  (Preuss,  Bergmann,  Stolper).  Striated  muscle-fibers 
from  the  sacral  region  may  be  added  to  the  capsules  and  contribute  to  the 
movements  (Ahlfeld). 

Cloacal  Membrane. — The  various  steps  in  the  union  of  anus  with  gut, 
the  absorption  of  the  cloacal  membrane,  and  the  formation  of  bladder  and 
external  genitals,  are  concerned  with  tumors  of  these  organs  and  may  lead 
to  formation  of  dermoids.  Some  of  these  appear  in  the  pelvic  connective 
tissue  (Germain,  Lit.).  Small  nodules  along  the  raphe  of  penis  and  scrotum 
composed  of  epithelial  pearls  are  referred  to  imperfect  closure  of  the  dermal 
cleft  at  this  point  (Epstein) . 

A  variety  of  cysts  lined  by  epidermis  or  by  cylindrical  or  mucous  cells, 
and  probably  derived  from  cloacal  remnants,  have  been  collected  by  Mermet 
and  Marchadier. 

A  dermoid  of  the  bladder  with  atresia  ani  et  urethrae  is  described  by 
Martini. 

There  are  thus  four  somewhat  definite  groups  of  tumors  which  may  be 
referred  with  considerable  certainty  to  single  embryonal  structures  in  the 
sacrococcygeal  regions.  Yet  the  majority  of  congenital  tumors  of  this  area 
are  most  complex  and  seem  to  involve  more  than  one  of  the  embryonal  rem- 
nants or  some  additional  anomalies  of  development. 

Sacrococcygeal  teratoid  tumors  constitute  a  somewhat  heterogeneous  group 
in  this  field  (Braune,  Stolper,  Lit.).  These  are  solid  and  cystic  large  nodular 
congenital  tumors  lying  at  the  lower  end  of  the  spinal  column  in  front  of 
sacrum  and  coccyx.  They  project  below,  displacing  the  anus  forward,  and 
may  extend  over  the  dorsal  surface  of  coccyx  and  sacrum.  A  definite  con- 
nection with  the  bones  is  occasionally  seen  (Kummel),  and  the  sacrum  may 
be  rudimentary  (Pannwitz).  The  spinal  dura  is,  as  a  rule,  not  involved.  In 
these  features  they  differ  from  the  tumors  on  the  dorsal  surface  of  the  sa- 
crum. The  hypertrophied  sacral  arteries  and  the  branches  of  the  nerves  of 
the  sacrococcygeal  plexus  course  over  the  tumors.  One-third  of  the  subjects 
are  born  dead,  and  90  per  cent,  of  the  others  die  in  the  first  few  days. 

The  structure  is  very  varied  and  complex,  a  histological  potpourri  which 
is  yet  sufficiently  restricted  for  a  local  origin,  although  three  germ  layers 
are  represented. 

The  solid  portions  contain  cellular  connective  tissue,  fat,  smooth  and 
striated  muscle,  bone,  and  cartilage.  Chorda  rests  were  identified  by  Hen- 
nig.  Portions  of  central  nervous  system  are  often  observed  in  the  form  of 
masses  of  glia  tissue  or  ganglia.  The  cysts  are  of  numerous  types,  being 
lined  by  cubical,  cylindrical,  ciliated  epithelium,  or  with  pavement  cells, 
or  they  resemble  true  dermoids  with  hornification,  epithelial  papillae,  seba- 
ceous material,  hair,  and  sweat-glands  (Nasse).  The  cyst  walls  are  composed 
of  fibrous  tissue  or  contain  cartilage,  bone,  adenoid  tissue  with  lymph-follicles 
or  nervous  tissue.  Areas  of  glia  tissue  may  contain  small  cysts  lined  by  neuro- 
epithelium  (Perman,  Stolper).  Very  large  cysts  lined  by  cuboidal  cells  prob- 
ably represent  a  distended  neural  canal  simulating  a  cerebral  ventricle.  Borst 
describes  a  cystic  tumor  which  he  interpreted  as  a  rudimentary  caudal  brain. 
Pigmentation  of  various  tissues  is  frequent  and  certain  pigmented  epithelial 
structures  have  been  interpreted  as  rudimentary  retinal  vesicles  (Spondly, 
Kummel).  Well-defined  retinal  structures  are  described  by  Hennig,  and 
fully  developed  or  rudimentary  teeth  by  Port,  Kronlein,  and  Danzel.  Fetal 
bones  have  also  been  identified  by  Kiderlen,  Borst,  and  Menzel. 


982 


NEOPLASTIC  DISEASES 


Sacral  Teratomas, — The  presence  of  definite  organs  or  their  rudiments 
which  cannot  well  be  referred  to  neighboring  structures  constitute  the  basis 
of  classification  in  this  group  of  tumors.  This  principle  was  first  employed 
by  Nasse  and  its  validity  will  be  considered  later. 

The  general  relations  of  these  growths  are  very  similar  to  those  of  the 
teratoid  tumors.  They  are  bulky  masses,  present  at  birth,  lying  on  the  dor- 
sal surface  of  the  sacrum  and  coccyx  and  adherent  to  or  enclosed  within  the 
periosteum  or  connected  to  the  bone  by  a  pedicle.  Others  lie  anterior  to  the 
sacrum  and  connected  with  this  bone  (Kauffmann),  or  with  the  rectum  (Feld- 
mann),  and  projecting  into  the  pelvis.  The  structure  presents  cystic  and 
solid  portions  similar  to  those  of  the  teratoid  tumors,  including  cysts  lined 


FIG.  513. — Structure  of  a  congenital  sacral  teratoma:  a,  b,  c,  Dermal  layers;  d,  smooth 
muscle;  e,  intestinal  epithelium;  g,  glia  tissue.     (After  Stolper.} 

by  various  types  of  epithelium,  dermoids,  segments  of  intestinal  mucosa, 
gland  structures,  fat,  muscle,  cartilage,  and  bone,  and,  finally,  portions  of 
nervous  and  glia  tissue. 

In  addition,  a  great  variety  of  rudimentary  organs  are  observed.  These 
include  segments  of  intestine  with  mesentery,  rudimentary  esophagus, 
stomach,  and  buccal  cavity  with  salivary  glands  (Linser,  Kleinwachter) ; 
pulmonary  parenchyma,  bronchi  with  cartilaginous  rings  (Piper,  Linser); 
thyroid  (Hagenthorn),  pancreas,  spleen,  adrenal  (Stroh),  kidney,  brain  with 
ventricles  and  choroid  plexus  (Sperling,  Stroh).  The  bones  may  reproduce 
well-formed  extremities,  as  forearm  and  hand  (Bohm),  tibia,  femur,  and 
joint  (Kaufmann),  pelvis  and  extremities  (Kleinwachter),  toes  (Feldmann), 


TERATOLOGY 


983 


eyes  (Frank)  (Depaul).  In  fact,  Askanazy  regards  the  sacral  teratomas  as 
the  most  prolific  in  the  production  of  rudimentary  organs.  An  abortive 
fetus  enclosed  in  amniotic  membrane  lay  under  the  skin  in  a  case  of  Jordan's. 
Thus  many  transition  stages  up  to  definite  fetal  implantations  are  provided. 
Secondary  changes  of  importance  occur  in  sacral  teratomas,  giving  rise 
to  simple  malignant  tumors.  Overgrowth  of  muscle-cells  led  Virchow  to 
speak  of  myosarcoma  in  these  tumors.  Bergmann  described  a  variety  of 
sarcomatous  changes.  Nakayama  observed  infiltrating  endothelioma  and 
myxo-angiosarcoma,  and  a  metastatic  growth  consisting  of  fetal  brain  tissue. 
In  a  sacral  tumor  reported  by  Buzzi  as  angiosarcoma  Perrier  afterward 
found  teratoid  structures.  A  recurring  sarcomatous  teratoma  described 
by  Hinterstoisser  gave  extensive  metastatic  tumors,  "alveolar  sarcoma," 
in  lungs,  liver,  and  lymph-nodes.  Askanazy  suggests  that  more  thorough 


FIG.  514. — A  case  of  spina  bifida,  with  meningocele. 

examination  of  other  simple  tumors  of  the  sacral  region  might  disclose  tera- 
toid elements.  The  sacral  and  ischiorectal  region  is  a  frequent  seat  of  angio- 
sarcomas,  whose  origin  may  thus  be  explained.  The  sacral  neurogliomas 
constitute  a  definite  subdivision  (Mallory,  Keller,  Scheuermann). 

Tumors  Associated  with  Spina  Bifida. — While  the  common  meningocele, 
myelocele,  myelocystocele,  etc.,  have  no  neoplastic  character,  spina  bifida 
is  often  associated  with  tumor  processes.  The  association  with  spina 
bifida  throws  some  light  on  the  pathogenesis  of  the  entire  group  of  sacral 
teratomas,  since  spina  bifida  signifies  a  lack  of  coherence  of  embryonal  parts, 
and  a  failure  of  growth  momentum,  which  is  favorable  to  spasmodic  and 
aberrant  growth  of  the  type  of  budding. 

Sacral  hygroma  or  cystic  lymphangioma  is  the  simplest  tumor  of  this 
class  and  arises  from  extensive  cystic  dilatation  of  the  spinal  subarachnoid 


984  NEOPLASTIC  DISEASES 

spaces.  Such  a  cystic  tumor  may  show  extensive  connection  with  the  spinal 
canal  (Marchand,  Kroner),  or  these  connections  may  be  lost  and  the  tumor 
appear  as  an  isolated  lymphangioma  lying  on  the  dorsal  or  ventral  side  of  the 
spine.  Marchand  describes  hernial  protrusions  of  spinal  meninges  between 
vertebrae,  and  Borst  believes  that  many  cervical  and  sacral  hygromas  arise 
in  this  manner,  referring  to  cases  of  Lotzbeck  and  Brauner,  and  to  one  of  his 
own  observation  in  which  the  spinal  connection  was  reduced  to  a  narrow 
canal. 

Dilatation  and  overgrowth  of  lymph-  and  blood-vessels  in  the  walls  of 
such  cysts  may  lead  to  the  growth  of  angioma  and  lymphangioma  associated 
with  spina  bifida  (Hildebrand),  and  overgrowths  of  fibrous  or  fat  tissue  may 
produce  fibroma  or  lipoma.  Such  lipomas  may  contain  cysts  or  a  canal  lead- 
ing to  the  spine. 

Spina  bifida  occulta  is  a  condition  in  which  the  original  fissure  in  the  spinal 
column  has  become  closed  by  a  fibrous  or  bony  membrane,  while  the  hernial 
sac  and  its  accompanying  tissues  persist.  This  condition  has  been  observed 
with  a  variety  of  malformations,  sacral  hypertrichosis,  club-foot,  congenital 
luxation  of  hip,  with  atrophy  of  limbs,  elephantiasis,  syndactyly,  disturbances 
of  innervation,  mal  perforant,  and  in  a  series  of  cases  it  has  been  associated 
with  sacral  tumors  (Recklinghausen).  Most  of  these  tumors  consist  of  fibro- 
lipoma  with  areas  of  nerve-fibers  and  striated  muscle,  and  are  connected 
by  a  fibrous  or  fatty  tissue  pedicle  with  the  sacral  fissure.  The  so-called 
"false  tail"  is  a  pendulous  lipoma  which  is  often  connected  by  a  strand  of 
fibrous^or  muscular  tissue  with  the  sacral  dura  (Arnold,  Bartels,  Hagenbach). 
The  spinal  cord  may  be  extensively  deformed  (Bohnstadt).  The  nerve  plexus 
in  the  tumor  may  show  myxomatous  changes  (Borst).  Muscatello  described 
cases  with  extensive  defects  in  sacral  and  dorsal  spine  and  cord,  with  a  dermoid 
in  the  dorsal  region  and  an  epidermoid  at  the  sacrum. 

On  the  convexity,  at  the  base  of  the  skull,  and  in  the  dorsal  region  hairy 
lipomas  are  described  which  probably  have  the  same  origin  (Arnold,  Virchow, 
Bartels).  That  portions  of  brain  and  cord  may  be  displaced  with  the  mem- 
branes in  spina  bifida  is  indicated  in  the  reports  of  glioma  with  meningocele 
(Hildebrand).  Much  more  complex  tumors  and  deformities  arising  from 
spina  bifida  and  imperfect  development  of  the  spinal  cord  are  described  by 
Arnold  and  Borst. 

Origin  of  Congenital  Sacral  Mixed  Tumors. — The  recent  tendency  has  been 
to  regard  the  congenital  mixed  tumors  of  the  sacral  region  as  forms  of  true 
teratoma,  a  view  which  is  favored  by  many  considerations.  It  has  long  been 
recognized  that  many  gradations  exist  between  the  comparatively  simple 
mixed  tumors,  teratoids,  teratomas,  and  fetal  implantations  in  this  region, 
and  that  there  are  no  definite  anatomical  features  on  which  they  can  readily 
be  separated.  The  resemblances  to  teratomas  of  the  sex  glands  have  often 
been  pointed  out.  Nakayama  has  recently  reviewed  the  subject,  with  the 
conclusion  that  all  or  nearly  all  sacral  mixed  tumors  are  of  tridermal  structure 
and  arise  from  totipotent  material,  and  Askanazy  accepts  this  conclusion. 

Against  the  sweeping  application  of  this  view  there  stand,  however,  the 
well-known  embryogenic  disturbances  peculiar  to  the  caudal  and  cephalic 
extremities.  It  seems  quite  clear  that  certain  complex  growths  must  be 
referred  to  the  coccygeal  vestiges  of  the  neural  canal,  the  postanal  gut,  prob- 
ably also  to  the  neurenteric  canal,  while  the  complex  forms  of  spinal  rachis- 
chisis  doubtless  account  for  other  complex  tumors.  Many  other  special 
factors  pertaining  to  the  mechanics  of  development  of  the  caudal  extremity 
have  been  adduced  in  support  of  the  local  origin  of  sacral  tumors  (Borst, 
Lit.). 


TERATOLOGY  985 

Therefore,  in  view  of  the  several  important  possible  sources  of  complex 
sacral  tumors,  it  seems  necessary  to  continue  the  attempt  to  analyze  each 
case  and  place  it  in  a  proper  category  and  not  merge  the  group  into  one  class 
of  teratomas.  As  previously  pointed  out,  there  are  special  reasons  for  at- 
tributing many  of  the  sacral  growths  as  well  as  the  cervical  to  budding  proc- 
esses. In  this  aspect  the  sacral  tumors  differ  from  those  of  the  sex  glands, 
which  probably  always  arise  from  totipotent  sex  cells. 

The  difficulty  of  accomplishing  this  separation  is  illustrated  in  a  case 
described  by  Borst.  A  large  congenital  antesacral  tumor,  composed  of  solid 
and  cystic  portions,  was  connected  by  a  pedicle  with  the  spinal  column.  It 
appeared  to  represent  an  immature  brain  with  gyri,  bilateral  ventricles, 
choroid  plexus,  and  pigmented  ganglia.  Small  cysts  were  lined  by  cubodial 
or  flat  epithelium.  The  solid  parts  contained  much  cellular  connective, 
fat  tissue,  and  glandular  alveoli,  nerve-trunks,  and  ganglia.  Borst  refers 
this  tumor  exclusively  to  derivatives  of  the  medullary  groove  and  its  mesen- 
chymal  investments. 


BIBLIOGRAPHY 

NOTE. — The  bold-face  figures  refer  to  page  numbers  in  this  book. 
KEY  TO  ABBREVIATIONS  OF  JOURNALS  CITED 

The  common  names  of  journals,  rather  than  their  official  titles,  are  usually  employed. 

Articles  are  not  entered  more  than  once  in  the  bibliography  of  one  chapter,  although 
they  may  be  cited  twice  in  the  text  of  that  chapter.    Accordingly,  if  a  reference  appears 
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Arch.  gen.     Archives  generale  de  Medecine. 

B.  M.  J.        British  Medical  Journal. 

B.  B.  Bruns'  Beitrage  z.  kl.  Chirurgie. 

B.  W.  Berliner  kl.  Wochenschrift. 

C.  B.  Centralblatt  f.  Bacteriologie. 
C.  C.  Centralblatt  f.  Chirurgie. 

C.  G.  Centralblatt  f.  Gynsecologie. 

C.  P.  Centralblatt.  f.  allg.  Pathologic. 

D.  A.  Deutsches  Arch.  f.  kl.  Med. 

D.  P.  G.  Deutsche  patholog.  Gesellschaft. 

D.  W.  Deutsche  med.  Wochenschrift. 

Erg.  Path.  Ergenbnisse  d.  allg.  Pathol.  Lubarsch,  Ostertag. 

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J.  C.  D.  Journal  of  Cutaneous  and  Genito-urinary  Diseases. 

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L.  A.  Lagenbeck's  Archiv.  f.  Chirurgie. 

M.  G.  Mittheilungen  a.  d.  Grenzgebieten  d.  Med.  u.  Chir. 

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S.  G.  O.  Surgery,  Gynecology,  and  Obstetrics. 

Soc.  Anat.  Bulletin  d.  Soc.  Anat.,  Paris. 

Soc.  Chir.  Bulletin  d.  Soc.  Chir.,  Paris. 

V.  A.  Virchow's  Archiv. 

W.  Wochenschrift. 

Z.  B.  Ziegler's  Beitrage  z.  path.  Anat. 

Z.  G.  G.  Zeitschrift  f.  Geburtshilfe  u.  Gynecologic. 

Z.  K.  Zeitschrift  f.  Krebsforschung. 

Z.  M.  Zeitschrift  f.  kl.  Medezin. 

Z.  N.  Deutsche  Zeitschrift  f.  Nervenheilkunde. 

Z.  C.  Deutsche  Zeitschrift  f.  Chirurgie. 

HISTORICAL 

The  author  has  made  no  research  in  the  older  literature  of  cancer.    Most  of  the  older 
titles  cited  in  this  section  are  taken  from  Gurlt,  Geschichte  d.  Chir.,  Berlin,  1898;  from 

987 


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998  BIBLIOGRAPHY 

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OSTEOMA 

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MYOMA 

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Theilhaber,  Hollinger,  A.  G.,  73,  i.  Vassmer,  A.  G.,  75,  668.  553  Thorn,  Z.  G.  G.,  28, 
75.  554  Gessner,  Z.  G.  G.,  34,  387.  Ladinski,  S.  G.  O.,  1915,  20,  325.  555  Gebhard. 
Z.  G.  G.,  24,  i.  Flaischlen,  Z.  G.  G.,  32,  347.  Ruge,  C.,  Z.  G.  G.,  31,  471.  Benckiser, 
Z.  G.  G.,  22,  337.  556  Doca,  Z.  G.  G.,  58,  i.  Noble,  Amer.  Jour.  Obstet.,  1904,  49,  306. 
Flaischlen,  Z.  G.  G.,  58,  343.  Roily,  V.  A.,  155,  555.  Dillmann,  Z.  K.,  2,  333.  Schwab, 
Hegar's  Beitr.,  12,  102.  557  Gebhard,  Z.  G.  G.,  24,  i.  Werth,  A.  G.,  49,  369.  Kauf- 
mann,  C.  G.,  1906,  1071.  Zeller,  Z.  G.  G.,  //,  56.  Borst,  D.  P.  G.,  7,  1907.  Meyer, 

A.  G.,  91,  579.    Heurlin,  C.  G.,  1898,  38.    Oeri,  Z.  G.  G.,  57,  384.    Winter,  Die  Bekamp- 
fung  des  Uteruskrebses,  Stuttgart,  1904.     Taylor,  H.  C.,  Amer.  Gyn.  Soc.,  37,  313. 
Mackenrodt,  Z.  G.  G.,  54,  514.    Waldstein,  A.  G.,  61,  52.    559  Scheib,  A.  G.,  87,  I.    Veit, 

B.  W.,  1889,  701.    Bumm,  Z.  G.  G.,  55,  173.    Fromme,  A.  G.,  79,  197.    Sappey,  Traite 
d'Anat.,  188.     Kroemer,  A.  G.,  73,  57.    Poirier,  Le  Progress  Med.,  1889,  2,  491;  1890, 
/,  41.     Lucas-Championniere,  These,  Paris,  1875.     Bruhns,  Arch.  f.  Anat.  u.  Phys., 
Anat.  Abt.,  1898,  57.    Baisch,  A.  G.,  75,  273.    Kroemer,  A.  G.,  73,  57.    Veit,  A.  G.,  13, 
470.     Doederlein,  Hegar's  Beitr.,  9,  173.    Fritsch,  A.  G.,  29,  359.    Landau,  A.  G.,  44, 
567.    Kundrat,  A.  G.,  69,  355.    Kermauner,  Lameris,  Hegar's  Beitr.,  5,  87.    Schauta, 
Mon.  G.  G.,  19,  475.    v.  Herf,  Corresp.  Schweitz.  Arzte,  1904.    560  Blau,  I.  D.,  Berlin, 
1870.    Lubarsch,  Erg.  d.  allg.  Path.,  2.    Meyer,  Z.  G.  G.,  49,  54.    561"  Ruhle,  Z.  G.  G., 
74,321.    Williams,  Brit.  Gyn.  J.,  2,  529.    Beckmann,  Z.  G.  G.,  45,  492.    Offergeld,  A.  G., 
87,  298;  Mon.  G.  G.,  22,  514.    Willinsky,  I.  D.,  Berlin,  1904.    J.  H.  Jacobson,  Trans. 
A.  M.  A.,  Section  Obst.  Gyn.,  1910,  188;  cf.  J.  A.  M.  A.,  67,  1219.     Ries,  S.,  Am.  Jour. 
Obst.,  44,  29.     Clark,  J.  G.,  Johns  Hopkins  Hosp.   Bull.,  July-August,   1895.     562 
Mackenrodt,  C.  G.,  1902,  808.    Peterson,  B.  B.,  34.    J.  W.  Miller,  A.  G.,  89,  76.    Alder- 
gott,  I.  D.,  Leipzig,  1905.    Sampson,  Amer.  Gyn.  Soc.,  31,  387.    Gellhorn,  Ibid,  30,  137. 
R.  Peterson,  Ibid,  37,  295. 

VULVA 

Gurlt,  L.  A.,  25,  446.  Dittrich,  Amer.  J.  M.  S.,  1905,  130  (Lit.).  Arnot,  London  P. 
S.,  1873,  24.  Fromme,  Beitr.  G.  G.,  p,  382.  Sitzenfrey,  Z.  G.  G.,  58,  363.  563  Weir, 
Amer.  J.  M.  S.,  1875,  21,  240.  Butlin,  B.  M.  J.,  1901,  2,  61.  P.  Jung.  Mon.  G.  G.,  17, 
985.  v.  Franque,  Z.  G.  G.,  60,  237.  Peter,  Mon.  G.  G.,  j.  Schwarz,  I.  D.,  Berlin, 
1893.  Fritsch,  cit.  by  Veit.  Kustner,  Z.  G.  G.,  7,  70.  H.  Schulze,  I.  D.,  Leipsig,  1903. 
Teller,  Z.  G.  G.,  61.  Rupprecht,  Z.  G.  G.,  72.  564  L.  Pick,  V.  A.,  175.  H.  Ruge,  Z. 
G.  G.,  56.  Veit,  Handb.  d.  Gyn.,  1910,  IV,  2,  724,  741.  P.  Meyer,  A.  G.,  85.  Hinsel- 
mann,  Z.  G.  G.,  62.  Chaboux,  Les  turn.  mal.  prim.  d.  glande  Barth.,  Lyone,  1906. 

VAGINA 

Schwarz,  U.  d.  Erfolg.  d.  Oper.  Vul.  u.  Vag.,  Berlin,  1893.  Wille,  I.  D.,  Erlangen, 
1903.  West,  Lessons  on  the  Dis.  of  Women,  London,  1870.  Reclus,  Gaz.  hebdom.,  1887. 
Bex,  These,  Paris,  1887.  Bernard,  These,  Paris,  1895  (Lit.),  v.  Franque,  Z.  G.  G.,  60. 
Pozzi,  Traite  de  Gyn.  Schwarz,  Deut.  Cong.  Gyn.,  1886.  Olshausen,  Cent.  Gyn., 
1895,  *•  Poirier,  Prag.  Med.  W.,  1889,  491.  Bruhns,  Arch.  A.  u.  P.,  A.  Abt.,  1898. 
565  Lohnberg,  Z.  G.  G.,  73,  755.  R.  Williams,  N.  Y.  M.  Rec.,  1901,  60,  841.  R.  Meyer, 
Erg.  P.,  9,  518  (Lit.);  Z.  G.  G.,  71.  Davidsohn,  A.  G.,  61.  Cullen,  Johns  Hopk.  Hosp. 
Bull.,  16.  Pintor,  Ac.  d.  Med.  Torino,  1900.  Pollasson,  Violet,  Ann.  de  Gyn.,  32,  675. 
Hoehne,  Z.  G.  G.,  67.  Hirsch,  Z.  G.  G.,  67. 


1012  BIBLIOGRAPHY 

CHORIOMA  (CHORIONEPITHELIOMA) 

566  R.  Volkmann,  V.  A.,  61.  Sanger,  A.  G.,  44.  Pestalozza,  II  Morgagni,  1891,  33. 
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1351.  Ladinsky,  Amer.  J.  Obstet.,  45.  Olliveir  Bauregard,  These,  Paris,  1904.  Curtis, 
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Outerbridge,  Amer.  J.  Obs.,  72.  Ries,  Ibid.,  57.  Caturani,  Ibid.,  63.  Waldo,  Ibid.,  62. 
Huguenin,  An.  de  Gyn.,  1905,  2,  649.  Engstrom,  Mitt.  gyn.  klin.  Engstrom,  10.  568 
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Fleischman,  Mon.  G.  G.,  1903,  17.  574  Lebret,  These,  Paris,  1911.  Fraenkel,  D.  W., 
1899,  177.  575  v.  Velits,  Z.  G.  G.,  52,  56.  577  R.  Meyer,  Z.  G.  G.,  58.  Bauereisen, 
Z.  G.  G.,  53.  580  H.  Schmidt,  C.  G.,  1900;  Wien,  kl.  W.,  1901,  1077.  Lindfors,  Upsala 
Lak.  For.,  6,  177.  Walthard,  Z.  G.  G.,  59.  Patellani,  C.  G.,  1905,  388.  581  Stockel, 
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Orthmann,  D.  Ges.  Gyn.,  1897,  351.  Seitz,  A.  G.,  75.  Fraenkel,  Anat.  Anz.,  20;  A.  G., 
68.  Pick,  Berl.  W.,  1902,  1189.  Wallert,  Z.  G.  G.,  53.  Dunger,  Z.  B.,  37.  Risel,  Z. 
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C.  G.,  1902.  Lubarsch,  Arbeit,  path.  Inst.,  Posen,  1901.  Bock,  Soc.  Beige  de  Gyn., 
1899,  113. 

CYSTS  AND  EPITHELIAL  TUMORS  OF  THE  OVARY 

582  Felix,  Embryology  (Keibel  &  Mall).  Bulius,  Hegar's  Festschr.,  1889.  Nagel, 
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49,  233.  Babo,  V.  A.,  161,  311.  v.  Franque,  Z.  G.  G.,  39,  326.  Pick,  Berl.  W.,  1900, 
219.  Schickele,  V.  A.,  169  (Lit.),  v.  Franque,  Z.  G.  G.,  43.  R.  Meyer,  V.  A.,  171. 
583  Bulius,  Z.  G.  G.,  75.  Klob,  Path.  Anat.  weibl.  Sexorg.  Wien.,  1864.  Waldeyer, 
A.  G.,  I.  Olshausen,  Krankh.  d.  Ovar.,  1886.  Rokitansky,  Allg.  Wien.  m.  Zeit.,  1859, 
253.  584  Zahn,  V.  A.,  151  (Lit.).  Martin,  Krankh.  weibl.  Adnexorg.,  1899.  Garkisch, 
Z.  G.  G.,  63.  Lunzer,  Z.  f.  Heilk.,  28.  Langer,  A.  G.,  49,  87.  E.  Fraenkel,  A.  G.,  48, 
57,  511.  585  Orthmann,  Verh.  Gyn.  Gesell.,  1897.  L.  Fraenkel,  A.  G.,  56,  355.  L. 
Pick,  Cent.  Gyn.,  1903.  Pfannenstiel,  Handb.  d.  Gyn.  (Veit),  IV.  Kroemer,  D.  W., 
1907,  1246.  Patellani,  Cent.  Gyn.,  1905,  388.  Stoeckel,  Fest.  f.  Fritsch,  1902,  136. 
Albert,  Cent.  Gyn.,  1900,  1328.  Voight,  A.  G.,  49.  586  Grousdew,  A.  G.,  70.  Michel- 
azzi,  La  Riforma  med.  Roma,  3.  Santi,  Annali  di  Ost.  e.  Gin.,  Milano,  27.  Seitz,  A.  G., 
75.  Schaller,  Pforringer,  Beitr.  G.  G.,  2.  Wendeler,  Martin's  Handb.,  1899,  2,  416. 
Seitz,  A.  G.,  77.  587  Jayle,  Bender,  Rev.  de  Gyn.,  7,  755.  Nebesky,  Cent.  Gyn.,  1895, 
1052.  Odebrecht,  Z.  G.  G.,  54,  160.  Hoffmeier,  Frauenkrankheiten,  1908.  588  Pye- 
Smith,  cit.  by  Pfannenstiel.  Peaslee,  Ovarian  tumors,  N.  Y.,  1872.  Troschel,  Arb.  a. 
d.  Mackenrodt's  Klin.,  H.  3.  589  E.  Fraenkel,  Mon.  G.  G.,  21,  67.  Werder,  Amer.  J. 
Obst.,  38,  668.  Olshausen,  D.  m.  W.,  1902,  750.  H.  Freund,  Z.  G.  G.,  17.  Malcolm, 
London  Obst.  Soc.,  1899,  226.  Opitz,  Z.  G.  G.,  42.  Pozzi,  Rev.  de  Gyn.,  1904,  407. 
Holzapfel,  D.  Gyn.  Ges.,  1905,  358.  Schroeder,  Z.  G.,  54,  19.  Marchand,  Beitr.  z. 
Kennt.  Ovarialtum,  1879,  Halle,  v.  Velits,  Z.  G.  G.,  17.  Wagner,  A.  F.  Heilk.,  5.  H. 
Freund,  Saml.  kl.  Vort.,  301,  362.  590  Virchow,  V.  A.,  75,  348.  Flaischlen,  Z.  G.  G.,  7, 
434.  591  Glockner,  A.  G.,  83.  Tauffer,  D.  Gyn.  Gesell.,  1905,  374.  592  Zacharias, 
M.  W.,  1904,  1386  (Lit.).  Bauer,  Z.  G.  G.,  75,  617.  L.  Pick,  A.  G.,  64,  670  (Lit.).  R. 
Meyer,  V.  A.,  772.  593  Pfannenstiel,  A.  G.,  38,  407  (Lit.).  Mitjukoff,  A.  G.,  49,  278. 
Kretschmar,  Mon.  G.  G.,  19,  389.  E.  Herter,  Martin's  Handb.,  1899,  2,  615.  Gebhard, 
Path.  Anat.  weibl.  Geschl.,  1899.  Waldeyer,  A.  G.,  I,  252.  594  Olshausen,  Z.  G.  G.,  41, 
278.  Fromme,  I.  D.,  Tubingen,  1902.  Frank,  Prag.  m.  Woch.,  1891,  266.  Martin, 


BIBLIOGRAPHY  1013 

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N.  Y.  M.  J.,  49,  609.  Jacobs,  Le  Prog.  med.  Beige.,  1905.  Sanger,  Cent.  Gyn.,  1886,  601. 

v.  Kahlden,  Z.  G.  G.,  21. 

•» 

THE  OVARIAN  TERATOMA 

613  Kroemer,  Veit's  Handb.,  Gyn.,  1908,  4  (Lit.);  A.  G.,  57,  322.  Hohne,  D.  Ges.  f. 
Gyn.,  n,  360.  Neuhauser,  A.  G.,  79,  696.  614  Falk,  Mon.  f.  Gyn.,  12,  351.  Arn- 
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4,  354.  Opitz,  Z.  G.  G.,  42,  188;  47,  118.  Pfannenstiel,  Veit's  Handb.  Gyn.,  1908,  4. 
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Wilms,  Hygeia,  6,  300.  Flaischlen,  Z.  G.  G.,  6.  Baumgarten,  V.  A.,  107.  617  Sutton, 


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TUMORS  OF  PANCREAS 

702  Lazarus,  Z.  kl.  M.,  51,  52.  Edling,  V.  A.,  182.  Sotti,  Arch.  p.  sci.  med.,  1906. 
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MAXILLARY  TUMORS  OF  DENTAL  ORIGIN 

707  Magitot,  Arch.  gen.  de  Med.,  1872-73.  Barnes,  Med.  Trans.,  London,  1813,  316. 
Guzack,  Dublin  Hosp.  Rep.,  1826,  29.  Delpech,  Chir.  clin.,  1828.  Dupuyten,  Chir. 
clin.,  1833.  Forget,  These,  Paris,  1840.  Nelaton,  Soc.  anat.,  1856.  Robin,  C.  R.  S.  B., 
1862.  Wedl,  Path.  d.  Zahne,  1870.  Broca,  Gaz.  hebdom.,  1868,  70.  Traite  d.  Turn., 
1886.  Malassez,  Arch,  de  Physiol.,  1885.  709  Galippe,  Le  debris  epit.  parad.,  Paris, 
1910  (Lit.).  Bryck,  L.  A.,  25.  711  Benneke,  Z.  C.,  42.  Albarran,  Rev.  de  Chir.,  1888. 
Kruse,  V.  A.,  124.  Flaubert,  These,  Paris,  1857.  Chibret,  Arch.  med.  exper.,  1894. 
Bernays,  N.  Y.  M.  Rec.,  1885,  28,  l.  712  Guibout,  Un.  Med.,  1847.  d'Amiens,  Bull, 
soc.  chir.,  1878.  Buchteman,  L.  A.,  26.  Eve,  B.  M.  J.,  1883,  I,  l.  Heath,  Inf.  and 
Dis.  of  Jaws,  London,  1872;  B.  M.  J.,  1887,  J,  777.  Haasler,  L.  A.,  53,  749.  713 
L'Esperance,  N.  Y.  Path.  Soc.,  1912.  714  Coate,  Lancet,  1857,  2,  363.  Bornig,  V.  A., 
190,  421.  Kruse,  V.  A.,  124.  Albarran,  C.  R.,  Soc.  Biol.,  1887.  Pincus,  L.  A.,  72. 
B.  Fischer,  Frank.  Z.  Path.,  12, 422.  715  Sirantoine,  These,  Nancy,  1903.  Witzel,  Mon. 
f.  Zahnh.,  1896,  305.  Mickulicz,  Wien.  m.  W.,  1876,  952.  716  Gosselin,  Bull.  soc. 
Chir.,  1860,  185.  Vitalis,  Bull.  soc.  anat.,  1858,  326.  Ancelot,  Gaz.  d.  hop.,  1869.  Sour- 
ier,  Ibid.,  134.  Berger,  Bull.  soc.  chir.,  1881,  422.  Albarran,  Soc.  anat.,  1887,  497. 
Legouest,  Soc.  chir.,  1862,  345.  Broca,  Rev.  de  mal.  de  1'Enfance,  1906,  521.  Bayer, 
Rev.  de  Stomatol.,  1904,  414.  Nelaton,  Soc.  anat.,  1856,  149.  Grosse,  L.  A.,  51,  436. 
Remy-Duret,  Soc.  anat.,  1873,  401;  1874,  686.  717  Allgayer,  B.  B.,  440.  M.  B. 
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EPITHELIAL  TUMORS  OF  THE  SALIVARY  GLANDS 

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TUMORS  OF  THE  KIDNEY  AND  ADRENAL 

738  Ebstein,  Ziemssen  Encyc.,  1877,  Vol.  15.  G.  Konig,  1826,  cit.  by  Kuster;  Deut- 
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807  Boyle,  Rech.  s.  1.  phthisie  pulmon.,  Paris,  1810.  Stokes,  Dublin  J.  Med.  Sci,, 
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EPIDERMOID  CARCINOMA  OF  SKIN,  LIP,  TONGUE,  AND  LARYNX 

Selberg,  V.  A.,  145.  Krompecher,  Z.  B.,  28;  Die  Basalzellenkrebs,  Jena,  1903;  Z. 
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1024  BIBLIOGRAPHY 

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CARCINOMA  OF  ESOPHAGUS 

857  Kraus,  Nothnagel's  Handb.,  1902,  16.  Heimann,  L.  A.,  57.  Mehnert.  Heller, 
Arndt,  I.  D.,  Kiel,  1901.  Ritter,  D.  A.,  55.  Schaffer,  V.  A.,  177.  Hewlett,  J.  Exper. 
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BIBLIOGRAPHY  1025 

135.  Stoeber,  Z.  B.,  52,  512.  Kathe,  V.  A.,  190,  80.  Grabowski,  Z.  B.,  56,  266.  Seelig, 
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1901,  V.  B.,  240.  Coplin,  Phila.  P.  S.,  1904.  Caesar,  M.  W.,  1904,  944.  859  Borrmann, 
Z.  B.,  48,  576.  Diirr,  C.  P.,  3,  38.  Francke,  V.  A.,  174.  Norris,  N.  Y.  P.  S.,  1912. 
Herxheimer,  Z.  B.,  44  (Lit.).  Donath,  V.  A.,  194. 

EPITHELIAL  TUMORS  OF  BLADDER 

860  Albarran,  Les  tumeurs  de  la  vessie,  Paris,  1891.  Fenwick,  Tumors  of  Bladder, 
London,  1897.  Hadda,  L.  A.,  88.  Rauenbusch,  V.  A.,  182.  861  Keyes,  Jour.  Cut. 
Dis.,  1887,  242.  Guyon,  Ann.  d.  mal.  d.  org.  gen.  ur.,  1884.  Adenot,  Ibid.,  1895.  863 
Fluss,  W.  Id.  W.,  1907,  1227.  Stein,  Tumors  of  Bladder,  N.  Y.,  1881.  864  Venulet,  V. 
A.,  196.  Buerger,  S.  G.  O.,  1915,  179.  Kaltenbach,  L.  A.,  30.  Virchow,  V,  A.,  5. 
Aschoff,  V.  A.,  138.  Lubarsch,  Arch.  micr.  Anat.,  41.  v.  Brunn,  Ibid.  Prezowsky,  V. 
A.,  116.  865  Montfort,  These,  Paris,  1902.  Kuster,  L.  A.,  42,  864.  Voelcker,  London 
P.  S.,  46,  133.  Drew,  London  P.  S.,  1897.  Fenwick,  Tumors  of  Bladder,  London,  1897. 
Rundle,  London  P.  S.,  1895.  Fere,  These,  Paris,  1881.  Stow,  An.  Surg.,  46, 233.  Goebel, 
Z.  K.,  j.  Stoerk,  Z.  B.,  26  (Lit.).  Cohen,  V.  A.,  113.  Rehn,  L.  A.,  50.  866  Wendel, 
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353-  Seyberth,  M.  W.,  1907,  1573.  Beneke,  V.  A.,  161.  W.  Fischer,  Arb.  path.  Instit., 
Tubingen,  1908.  Monckberg,  V.  A.,  187.  Terrier,  Hartmann,  Rev.  d.  Chir.,  1895. 
Husler,  Jahrb.  f.  K.,  1905,  62.  R.  F.  Miiller,  I.  D.,  Leipsig,  1904. 

TUMORS  OF  PENIS 

867  Creite,  Z.  C.,  79.  C.  Kaufmann,  Deut.  Chir.,  5oa.,  163.  Barney,  Mass.  Gen. 
Hosp.  Rep.,  1908,  2,  275.  Thomson,  B.  M.  J.,  1897,  2,  1841.  Hottinger,  Cor.  Schweiz. 
Aertze.,  1897.  Demarquay,  Mal.  Chir.  d.  Penis,  Paris,  1877.  Martin,  J.  Cut.  Dis., 
1895,  13.  Buday,  L.  A.,  49.  Schuchardt,  S.  Id.  V.,  257.  Taylor,  J.  Cut.  Dis.,  1889,  7. 
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1889.  Mitchell,  Med.  News,  1888,  53,  152.  Lewin,  V.  A.,  112.  Heath,  B.  M.  J.,  1883, 
2,  327.  Bell,  Edin.  M.  J.,  1876,  22,  135.  Cameron,  Glasgow  M.  J.,  12,  40. 

MELANOMA 

871  Demieville,  V.  A.,  82.  Recklinghausen,  Fibrome  d.  Haut,  1882.  Unna,  Berl. 
k.  Woch.,  1893,  14;  V.  A.,  143;  Histopath.  d.  Hautk.,  1894.  Delbanco,  Monatsh.  f.  p. 
Derm.,  22,  105.  Hodara,  Ibid.,  25,  205.  Scheuber,  A.  D.,  44,  175.  Gilchrist,  J.  Cut. 
Dis.,  1899,  17.  Bauer,  V.  A.,  142.  Judassohn,  A.  D.,  33.  Lubarsch,  Erg.  P.,  1895,  588. 
Hannsemann,  Bosartig.  Gesch.,  13.  Borst,  Geschwulste,  I,  116,  447.  Favera,  Z.  B., 
43  (Lit.).  872  Kromayer,  Z.  B.,  22;  Monatsh.  f.  p.  Derm.,  41.  Lowenbach,  V.  A.,  157. 
Walsch,  A.  D.,  39.  Riecke,  Ibid.,  65.  Pini,  Ibid.,  61.  Judalewitsch,  A.  D.,  58.  Herx- 
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THE  THYMUS  AND  ITS  TUMORS 

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924  Marie,  Rev.  de  med.,  1886;  Brain,  1889.  Courtellemont,  Des  Turn.  d.  Corps 
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INDEX 


ABDOMINAL  fetal  implanta- 
tions, 977 
teratomas,  977 
Hodgkin's  granuloma,  370 
Acanthoma,  474 

adenoides  cysticum,  834 
of  skin,  Demodex  follicu- 

lorum  in,  822 
etiology,  820 
secondary  changes,  820 
structure,  819 
types,  818 
of  vocal  cords,  855 
tubular,  819 
Acidemic  coma  in  cancer  of 

stomach,  656 
Acidosis  of  cancer,  74 
Acinar  carcinoma,  471 
of  breast,  508,  521 
fibrous,  522 
following  fibro-aden- 

pma,  521 
primary,  522 

Acoustic  neurofibroma,  432 
Acrpmegaly,  942 
diabetes  with,  943 
glycosuria  with,  943 
Adamantinoma,  49,  709 
clinical  features,  714 
glandular,  713 
of  tibia,  715 
structure,  712 
Adeno-acanthoma  of  uterus, 

547 

Adenocarcinoma,  456,  470 
of  adrenal  gland,  770 
of  breast,  508,  510 

forms,  512 

histogenesis,  512 

small  cystic,  517 

structure,  511 
of  cervix  uteri,  547 

mucous,  549 
of  kidneys,  alveolar,  748 

embryonal,    in    adults, 

749 

in  infants,  749 
multiple,    in    sclerosis, 

746 
papillary,  742 

histogenesis,  746 

structure,  748 

with    granular   cells, 

746 

tubular,  750  ^ 
of   large  intestine,  gelat- 
inous, 671 


Adenocarcinoma   of    ovary, 

cystic,  597 
papillary  serous,  589 
pseudomucinous,  595 
of  pituitary  gland,  932 
metastases,  933 
structure,  933 
of  prostate,  787 
of  stomach,  627 

occurrence,  656 
of  thyroid  gland,  898 

small  alveolar,  large 

cell,  901 
papillary,       of      choroid 

plexus,  418 
Adenofibroma,  149 
edematodes,  166,  167 
of  breast,  495 
of  ovary,  597 
Adenoid  carcinomas,  464 
epithelioma  of  skin,  834 
cystic,  834 
simple,  835 

Adenoma,  28,  446,  452 
alveolare  a  cellules  claires, 

745 
clinical       characteristics, 

453 

destruens  of  large  intes- 
tine, 669 
endotheliale,  746 
functional  capacity,  454 
gelatinosum,  893 
gross  appearance,  453 
in  colitis  polyposa,  458 
in  gastritis  polyposa,  458 
malignum,  453,  455 

of  adrenal  gland,  770 
mode  of  growth,  455 
of  adrenal  gland,  769 
of  bile-ducts,  cystic,  689 

multiple,  690 
of  bladder,  864 
of  cervix  uteri,  simple,  549 
of  kidney,  739 

alveolar,  740 

histogenesis,  741 

papillary,  739 

tubular,  741 
of  larynx,  850 
of  liver,  multiple,  686 

solitary,  68 1 
of  ovary,  586 

everted  papillary,  597 

solid,  596 

superficial,  597 

testicular,  610 
1033 


Adenoma  of  pancreas,  702 
of  prostate,  786 
of  salivary  glands,  725 
of  stomach,  simple,  629 
of  testis,  802 

of  thyroid  gland,  fetal,  895 
interacinous,  894 
malignant,  898 
papillary  cystic,  455 
physiological   conception, 

457 

sebaceum,  461 
structure,  455 
tubular,  455 
Adenomatoid     hyperplasia, 

functional,  459 
inflammatory,  457 
Adenomyoma,  212 
mesonephric,  214 
of  ovary,  610 
psammopapillare,  215 
Adenomyomatosis    of    cor- 
pus uteri,  diffuse,  556 
Adenomyosarcoma    of    kid- 
ney, 220 
embryonal,  753 
anatomy,  753 
histogenesis,  754 
structure,  753 
Adenosarcoma  of  breast,  501 

of  pituitary  gland,  934 
Adiposogenital     dystrophy, 

theories,  946,  947 
Adrenal    gland,     adenocar- 

cinoma  of,  770 
adenoma  of,  769 
malignum,  770 
cancer  of,  769 

fully  developed,  770 
hyperplasia  of,  768 
melanoma  of,  778 
neurocytoma  of,  77? 
clinical  types,  774 
sarcoma  of,  in  infants, 
congenital,  (Pep- 
per type),  775 
with    cranial   met- 
astases   (Hutch- 
inson  type),  774 
tumors  of,  768 
classification,  768 
medullary,  771 

chromaffin  cell,  776 
with  adrenalin  con- 
tent  and    neph- 
ritic   symptoms, 
776 


1034 


INDEX 


Adrenal  melanoma,  890 
rests,   extrarenal,   tumors 

of,  761 
tumors  of,  755 

carcinomatous,  759 
gross  appearance,  758 
lateral       retroperito- 

neal,  762 
occurrence,  756 
peritheliomatous,  759 
renal  tumors  and,  dif- 
ferentiation, 760 
sarcomatous,  759 
structure,  758 
trabecular,  759 
tumors,  hepatic,  672 
of    female    genital    or- 
gans, 762 
of  ovary,  610 
of  spermatic  cord  and 

testis,  762 
of  testis,  803 
Adult  tumors,  26,  48 
Albuminuria  in  cancer,  75 
Aleukemic  systemic  lymph- 

omatosis,  376 
Alimentary    tract,    myoma 

of,  216 
Alkalescence    of    blood    in 

cancer,  69 
Allantoid  type  of  papilloma 

of  bladder,  863 
Altruism  of  cells,  100 
Alveolar  adenocarcinoma  of 

kidneys,  748 
adenoma  of  kidney,  740 
cancer,  large,  471 

small,  471 
endothelioma,  305 
sarcoma,  983 
tumor,  346 
Alveoli,  pulmonary,  cancer 

arising  from,  812 
Amitosis  in  tumors,  39 
Amphipyrenin,  46 

in  tumor-cells,  46 
Ampulla  of  Vater,  cancer  of, 

700 

Amyloid  tumors,  167 
Anaplasia    of    cancer-cells, 

467 

of  tumor-cells,  101 
Anemia     from     Hodgkin's 

granuloma,  368 
in  cancer  of  stomach,  655 
infantum,  379 
Anemic  type  of  cancer,  67 
Angiocholitis       proliferans, 

679 

Angiochondroma,  186 
Angio  -  endothelioma         of 
bones,      telangiectatic, 

323 

of  skin,  331 
Angiofibroma,  149 

blood-vessels  in,  151 
Angioma,  27,  223 

arteriale  racemosum,  233 


Angioma,  cavernous,  227 
clinical  features,  231 
course,  229 
cutaneous,  231 
histogenesis,  230 
multiplicity  of,  228 
neoplastic  nature,  231 
of  liver,  232 
of  ovary,  232 
of  tongue,  231 
structure,  230 
submucous,  231 

fissural,  225 

histogenesis,  226 

of  bone,  231 

of  brain,  232 

of  breast,  505 

of  glands,  232 

of  larynx,  850 

of  muscles,  225 

of  orbit,  231 

of  spinal  cord,  441 

plexiform,  224 
Angioplastic   endothelioma, 

334 
Angiosarcoma,  303,  304,  342 

of  pituitary  gland,  934 

orbital,  885 
Antigen,  autogenous  tumor, 

complement        deviation 

with,  91 
Antitryptic  power  of  blood, 

92 

Antra,  osteoma  of,  199 
Antrum,     maxillary.       See 

Maxillary  antrum. 
Aplastic  leukemia,  361 
Aponeuroses,  giant-cell  sar- 
coma of,  256 
Appendix,  cancer  of,  665 
anatomy,  665 
structure,  665 
Astrocytes,  401,  403      ,i 
Astrocytoma,  416 
Astromas,  401 
Ateliosis,  942 
Atheromatous  cysts  of  skin, 

965. 

Athletic  stomach,  652 
Atypical  leukemia,  360 
Auricular  chondroma,  191 
Autogenous  tumor  antigen, 

complement        deviation 

with,  91 


BACTERIA  in  cancer,  115 
Bartholin's  gland,  tumors  of, 

564 
Basal-cell    carcinoma,    474, 

833  . 

epithelioma  of  skin,  830 
Bathing  trunk  type  of  nevus, 

873 

Benign  giant-cell  sarcoma  of 
bone,  280 

Bile-ducts,  adenoma  of,  cys- 
tic, 689 


Bile-ducts,     ademoma     of, 

multiple,  690 
cysts  of,  688 
intrahepatic,     cancer    of, 

multiple,  690 
larger,  cancer  of,  698 
anatomy,  699 
etiology,  699 
location,  699 
structure,  700 
tumors  of,  689 
Bird's-eye  inclusion  in  can- 
cer,  115 

Bladder,  adenoma  of,  864 
cancer  of,  etiology,  865 

glandular,  864 
leiomyoma  of,  866 
myoma  of,  216 
osteochondrosarcoma    of, 

866 

papilloma  of,  860 
allantoid  type,  863 
structure,  863 
rhabdomyoma  of,  866 
sarcoma  of,  865 
tumors  of,  epithelial,  860 

miscellaneous,  865 
Blastomycetes     in     cancer, 

117 
Blood,    alkalescence    of,    in 

cancer,  69 

antitryptic  power  of,  92 
changes  in,   in   leukemia, 

359 
in  cancer,  67 

hyperglycemia  in,  70 
in  chloroma,  363 
in  stools  in  cancer,  72 
in   true    pseudoleukemia, 

377 
regeneration  ol,  in  cancer, 

69 

total    quantity  of,  in  tu- 
mors, 69 

Blood-vessels  in  dissemina- 
tion of  cancer,  81 
of  breast,  531 
in  gliomas,  405 
relation    of,    to    tumors, 

56 

Bochdalek's  gland,  910 
Bones,  angioma  of,  231 
endothelioma  of,  308,  322 
classification  of,  323 
multiple,  324 
solitary    bulky    cystic, 

.323 

diffuse,  326 
fibroma  of,  163 
formation,    heteroplastic, 

201 

myeloma  of,  292 
myxoma  of,  174,  175 
perithelioma  of,  345 
sarcoma  of,  244,  269.   See 

also  Sarcoma  of  bone. 
telangiectatic  angio-endo- 

thelioma  of,  323 


INDEX 


1035 


Bone-marrow      lesions      in 
Hodgkin's  disease,  371 
multiple  myeloma  of,  292 
sarcoma  of,  269 

primary  multiple,  293 
Bone-sarcoma,  telangiectat- 

ic,  273 

Brain,  angioma  of,  232 
cholesteatoma  of,  974 
melanoma  of,  885 
sarcoma  of,  424 
diffuse,  424 
gross  anatomy,  424 
malignancy  of,  426 
structure,  425 
tumors  of,  393.     See  also 

Tumors  of  brain. 
Branchiogenic  cancer,  968 

chondromas,  190 
Breast,  acinar  carcinoma  of, 

52i 

fibrous,  522 
following  fibre-aden- 
oma, 521 
primary,  522 
adenocarcinoma   of,    508, 

5io 

small  cystic,  517 
adenofibroma  of,  495 
adenosarcoma  of,  501 
angioma  of,  505 
cancer  of,  506.     See  also 

Cancer  of  breast. 
carcinosis  of,  acute,  533 
chondroma  of,  192 
cystadenocarcinoma      of, 

532 

cystadenoma  of,  496 
cysts  of,  dermoid,  505 

sebaceous,  505 
epithelial  tumors  of,  484 
epithelioma  of,  506 
fibre-adenoma  of,  495 
fetal,  499 
papillary       intracystic, 

496 
fibrocarcinoma     of,     518, 

.,535 
fibroma  of,  165 

hypertrophy  of,  484 

diffuse,  of  adults,  484 

infantile,  484 

of  male,  484 
leiomyoma  of,  505 
lipoma  of,  505 
melanoma  of,  505 
osteochondromyxosar- 

coma  of,  505 
papilloma  of,  505 
perithelioma  of,  345 
sarcoma  of,  pure,  503 
spindle-cell,  504 

round-cell,  503 

senile  involution  of,  487 
tumors     of,     ectodermal 
mixed,  500 

mesodermal,  499 

miscellaneous,  505 


Breast,   tumors    of,    mixed, 

494 

teratoid  mixed,  499 
Bronchial      cancer     arising 
from     mucous 
glands,  811 
structure,  812 
of     lining     epithelium, 

809 

structure,  810 
papilloma,  813 
Buccal    papillomatosis,    dif- 
fuse, 452 

Byzantine  period,  cancer  in, 
18 


CACHEXIA  in  cancer,  demin- 
eralization  in,  75 

of  stomach,  654 
in  uterine  cancer,  561 
Cancer,  28,  446,  461 
a  deux,  85,  114 
acidosis  of,  74 
acinar,  471 
adenoid,  464 
albuminuria  in,  75 
alkalescence  of  blood  in, 

69 
alveolar,  large,  471 

small,  471 
anemic  type,  67 
arising    from    pulmonary 

alveoli,  812 
atypical  qualities  of  cells, 

466 

bacteria  in,  115 
basal-cell,  474,  833 
bird's-eye  inclusion  in,  1 15 
blastomycetes  in,  117 
blood  in,  67 

hyperglycemia  in,  70 

in  stools  in,  72 
blood-vessels   in   dissemi- 
nation of,  8 1 
branchiogenic,  968 
bronchial,     arising     from 
mucous 
glands,  811 
structure,  812 

of  lining  epithelium,  809 

structure,  810 
cachexia  of,  demineraliza- 

tion  in,  75 
cell  autonomy,  theory  of, 

97 

cellular  overgrowth  in, 
466 

changes  in  urine  in,  72 

character  of  affected  tis- 
sue, 480 

chemical  agents  in  pro- 
duction of,  119 

chimney-sweeps',  870 

chorionic,  571 

cicatricial  character,  463 

classification,  470 

coccidia  in,  115 


Cancer,  Cohnheim's  theory 

of,  94 

limitations  of,  97 
collateral  hyperplasia  in, 

481 

coma,  74 
congenital,  95 
contact  infection  in,  85 
contagiousness  of,  114 
cystic,  471 
desmoplastic     properties, 

468 

diffuse,  472 
distribution  of  nutriment 

in,  99 

embryonal,  472 
theory  of,  94 

limitations  of,  97 
en  cuirasse,  463,  473,  525, 

534 

epidermoid,  28,  474,  857 
glandular,  475 
tubular,  474 

epiphanin  reaction  in,  93 

families,  105 

following  intestinal  poly- 
posis,  662 

from  chronic  inflamma- 
tion, 476 

from  physiological  invo- 
lution of  organs,  477 

from  regenerative  hyper- 
trophy, 478 

from  transformation  of 
benign  into  malignant 
tumors,  478 

fully  developed,  471 

genius  loci  in,  85 

gross  anatomy,  463 

groups  of,  462 

hemorrhage  in,  67 

heredity  in,  105 

heterotopia  in,  467 

histological  period,  21 

historic  study  of,  17 

in  ancient  times,  17 

incidence  of,  113 

induration  in,  463 

inflammatory  reaction  in, 
50 

influence  of  intestinal  di- 
gestion on,  72 
of  mechanical  pressure 

in,  98 

of  mode  of  origin,  480 
of  organization  on,  100 
of  specialized  functions 

on,  99 
on  gastric  digestion,  70 

invasion    of   serous   cavi- 
ties by,  80 
of  thoracic  duct  by,  79 

leukocytosis  in,  68 

local  invasion  in,  481 
invasive    and    destruc- 
tive properties,  467 

loss  of  polarity  in,  469 

marantic  type,  67 


1036 


INDEX 


Cancer,  mechanical  pressure 
of   contracting   mtfs- 
cle-fibers  in,  468 
separation  of  epithelial 

cells  in,  102 
meiostagmin  reaction  in, 

92 

metastases  in,  469 
microorganisms  in,  115 
microscopic  structure,  465 
mode  of  extension  of,  480 
mycetozoa  in,  116 
of  adrenal  gland,  769 

fully  developed,  770 
of  ampulla  of  Vater,  700 
of  appendix,  665 
anatomy,  665 
structure,  665 
of  bladder,  etiology,  865 

glandular,  864 
of  breast,  506 
acinar,  508 
fibrous,  522 
following  fibro-aden- 

pma,  521 
primary,  522 
age  incidence,  506 
blood-vessels  in  dissem- 
ination, 531 
cerebral  metastases  in, 

.530 

clinical  varieties,  532 
development  of  surgical 

treatment,  537 
developmental   anoma- 
lies in,  507 
dissemination,  525 
duct,  508,  514 

gross  anatomy,  514 
histogenesis,  519 
small  cystic,  517 
structure,  516 
effective  causation,  508 
encephaloid,  532 
etiology,  506 
extension  to  lungs  in, 

529 

general  prognosis,  538 
generalization,  528 
gross  anatomical  diag- 
nosis of,  522 
heredity  in,  507 
in  males,  536 

incidence,  506 
incidence,  506 
invasion  of  skin  in,  525 
involvement  of  pleura 

1    ir\5^    •         •       • 
lymphatic  invasion  in, 

525 

medullary,  532 
modes  of  extension,  523 
mucoid,  513 
pathological    anatomy, 

508 

position  of,  538 
peritoneal  invasion  in, 

530 


Cancer  of  breast,    previous 
exudative   inflamma- 
tion in,  507 
radium  in,  541 
recurrences,  538 
regressive     phenomena 

in,  531 
scirrhous,  534 
x-ray  in,  541 
of  cervix  uteri,  544 
anatomy,  544 
atypical  forms,  549 
erosion  in  cause,  548 
sarcomatoid       struc- 
tures in,  550 
scirrhous,  549 
of  corpus  uteri,  551 
anatomy,  551 
histogenesis,  555 
precancerous  changes 

in,  556 

structure,  553 
of  duodenum,  66 1 
of  esophagus,  857 
anatomy,  858 
etiology,  857 
structure,  859 
of  Fallopian  tubes,  610 
etiology,  611 
structure,  611 
of  gall-bladder,  693 
anatomy,  694 
clinical  features,  697 
squamous-cell,  696 
structure,  695 
surgical  results  in,  701 
of  hypophyseal  duct,  epi- 

dermoid,  936 
of  ileum,  662 
of  intestine,  66 1 
of  intrahepatic  bile-ducts, 

multiple,  690 
anatomy,  690 
incidence,  690 
structure,  691 
of  jejunum,  662 
of  kidney,  742 

metastases  in,  744 
papillary,     with     clear 

cells,  743 

tubular  structure,  752 
of  large  intestine,  667 

anatomical  varieties, 

669 

developing  from  soli- 
tary polyps,  671 
etiology,  667 
histogenesis,  669 
squampus-cell,  674 
statistical,  667 
of  larger  bile-ducts,  698 
anatomy,  699 
etiology,  699 
location,  699 
structure,  700 
of  larynx,  851 
anatomy,  852 
course,  855 


Cancer  of  larynx,  larval,  853 
lymphatic  extension,  855 
structure,  854 
of  lining  epithelium,  bron- 
chial, 809 
structure,  810 
of  lip,  838 
of  liver-cells,  multiple,  684 

primary  massive,  682 
of  lung,  807 

arising  from  pulmonary 

alveoli,  812 
classification,  809 
etiology,  808 
histogenesis,  813 
metastases,  812 
symptomatology,  815 
of  maxillary  antrum,  721 
clinical  course,  723 
deformation       stage, 

724 

invasion  stage,  724 
latent  stage,  724 
of  ovary,  597 

clinical  course,  605 
solid,  597 
structure,  599 
of  pancreas,  702 
anatomy,  703 
etiology,  703 
origin,  705 
structure,  704 
symptoms,  706 
of  pituitary  gland,  atypi- 
cal, 934 
of  prostate,  781 

age  of  incidence,  782 
clinical  course,  785 
course,  785 
etiology,  782 
gross  anatomy,  783 
heredity  in,  782 
lymphatic      extensions 

in,  783 
scirrhous,  788 
skeletal        osteoplastic 

metastases  in,  784 
structure,  786 
variations  in  structure, 

788 
of  salivary  glands,  725 

round-cell,  727 
of  scrotum,  870 
paraffin,  870 
of  skin,  epidermoid,  818 
of  small  intestine,  662 
of  stomach,  625 

acidemic  coma  in,  656 
age  in  etiology,  625 
alcoholism  in,  626 
anatomy,  627 
anemia  in,  655 
cachexia  in,  654 
curability,  659 
cylindrocellulare  micro- 

cysticum,  629 
diffuse,  635 

scirrhous,  637 


INDEX 


1037 


Cancer  of  stomach,  etiology, 

625 
experimental,     in     rat, 

133 

extensions  of,  646 
following  peptic  ulcer, 

630 

anatomy,  635 
clinical  features, 

658 

gastric  mucosa  in,  644 
gelatinous,  629 

clinical  features,  658 
structure  of,  630 
heredity     in     etiology. 

626 

histogenesis,  650 
idiosyncrasy    in    etiol- 
ogy, 626 
location,  654 

in  etiology,  626 
lymphatic  invasion  in, 

648 
lymphatics  involved  in, 

668 

medullary,  635 
metastases  in  ovary  in, 

649 

onset,  652 
operability,  659 
operative  mortality,  659 
pathogenesis,  653 
relation     to     anatomic 

varieties,  656 
scirrhous,    clinical    fea- 
tures, 658 
simplex,  635 

clinical  features,  658 
statistics,  625 
structure,  629 
surgical  treatment,  659 
symptomatology,  652 
telangiectatica,  635 
trauma  in  etiology,  626 
of  testis,  embryonal,  with 

lymphoid  stroma,  795 
of  thymus  gland,  920 
of  thyroid  gland,  901 
histogenesis,  906 
metastases,  902,  904 
structure,  905 
of  tongue  and  mouth,  epi- 
dermoid, 840 
clinical  course,  846 
embryonal    forms, 

846 

etiology,  841 
gross  anatomy,  842 
lymph-node         in- 
volvement      in, 
844 

metastases  in,  844 
prognosis,  847 
structure,  846 
syphilis  in  etiology, 

841 

tobacco    in    etiol- 
ogy, 841 


Cancer  of   ureter,  primary, 

865 

of  urethra,  870 
of  uterus,  267 

age  in,  544 

cachexia  in,  561 

classification,  543 

clinical  course,  561 

course,  557 

effect  of  pregnancy  on, 
560 

etiology,   543 

evertens,  546 

frequency,  543 

histogenesis,  545 

invertens,  546 

lymphatic  invasion  in, 

559 

mortality,  562 

structure,  545 

symptoms,  558 

termination,  561 

visceral  metastases  in, 

56i 
of  vagina,  epidermoid,  564 

histogenesis,  565 

prognosis,  565 

structure,  565 
of  vulva,  course,  563 

epidermoid,  562 

pruritus  in,  563 

structure,  564 
papillary,  464,  470 
paraffin,  of  scrotum,  870 
parasitic  theory  of,  113 
theoretic     objections 

to,  120 

percentage  of  urea  in,  72 
precancerous    lesions    in, 

475 

protozoa  in,  115 
Ransohoff  s  test  in,  93 
rapidity  of  growth,  480 
regeneration  of  blood  in, 

69 
research,       experimental, 

126 

sarcomatodes,  963 
scope  of  relation  of  para- 
sites" to,  122 
simplex,  471 
specific  degenerative 

changes  in,  464 
spirochgtae  in,  116 
squamous-cell,  of  choroid 

plexus,  419 

Stammler's  reaction  in,  93 
structural     classification, 

470 
structure,  466 

primary  versus  second- 
ary, 466 

theories  of  nature  of,  94 
tissue  tension  theory  of, 

98 

tubular,  471 

ulcerative  lesions  in,  464 
uric  acid  increase  in,  72 


Cancer,  urobilin  in,  74 
varia,  472 
Wassermann  reaction  in, 

91 

x-ray,  102 

dermatitis  and,  823 
clinical  course,  824 
structure,  824 
Capsular  lipoma,  181 

sarcoma,  275 
Carcinoma.     See  Cancer. 
Carcinomatous  cirrhosis  of 

liver,  686 

structure    in    cystic    tu- 
mors, 464 

Carcinome  villeux,  510 
Carcinosarcoma,  963 
of  esophagus,  859 
Carcinosis,  acute,  of  breast, 

533 

miliary,  464 
Cardiac  lipoma,  184 
Carotid  gland,  perithelioma 

of,  346 

Cavernous  angioma,  227 
clinical  features,  231 
course,  229 
cutaneous,  231 
histogenesis,  230 
multiplicity  of,  228 
neoplastic  nature,  231 
of  liver,  232 
of  ovary,  232 
of  tongue,  231 
structure,  230 
submucous,  231 
Cell    autonomy,    theory   of 

cancer,  97 

division  in  tumors,  38 
Cells,  altruism  of,  100 
endothelial,     origin     and 

functions,  299 
pathology  of,  300 
physiology,  300 
Paget's,  827 

syncytial  wandering,  568 
Cellular  nevus,  331 
Cellules       dyskeratosiques, 

827 

Central  spinal  sarcoma,  440 
Cephalic  tumors  of  pituitary 

gland,  939 
Cephalopagi,  955 
Cerebral  gliomas,  410 

meninges,  sarcoma  of,  dif- 
fuse, 424 
metastases   in    cancer   of 

breast,  530 

Cervical  dermoids,  966 
teratoids,  969 
teratomas,  969 
Cervix     uteri,     adenocarci- 

noma  of,  547 
mucous,  549 
adenoma  of,  simple,  549 
cancer  of,  544.    See  also 
Cancer  of  cervix  uteri. 
cystadenoma  of,  549 


1038 


INDEX 


Cervix   uteri,  endothelioma 

of,  55p 

perithelioma  of,  550    • 
precancerous      changes 

.in,  550 

Chemical  agents  in  produc- 
tion of  cancer,   119 
Chemistry  of  tumors,  89 
Chimney-sweeps'        cancer, 

870 
Chloroma,  362 

blood  in,  363 

form,  363 

gross  anatomy,  363 

occurrence,  362,  363 

structure,  364 

symptoms,  363 
Choanal  polyp,  167 
Choked  disk  in  tumors  of 

brain,  398 
Cholangioma,  688 
Cholesteatoma,  766 

of  brain,  974 
Chondroma,  27,  185 

auricular,  191 

branchiogenic,  190 

clinical  types  of,  190 

cystic  papillary,  187 

etiology  of,  189 

heredity  in,  189 

matrix,  187 

multiple  character  of,  186 

of  breast,  192 

of  larynx,  850 

of  respiratory  tract,  192 

of  salivary  glands,  193 

of  scapula,  190 

of  testis,  80 1 

of  uterus,  192 

ossification  of,  187 

osteoid,  190 

Ranvier's      classification, 
187 

rickets  in  etiology,  189 

skeletal,  190 
location  of,  186 

structure  of,  187 

subperiosteal,  capsule  of, 
1 86 

teratoid,  193 

trauma  in  etiology,  190 
Chondromyxoma,  176 
Chondrosarcoma,  187,  188 

of  ovary,  262 
Chordoma,  27,  193 

coccygeal,  195 

identification  of,  195 

malignant,  194 
Chorio-adenoma,  566 

destruens,  567 

clinical  course,  577 

differential      diagnosis, 
569 

metastases  in,  569 

structure,  568 

uterine  contents  in,  568 
Choriocarcinoma,  566,  570 

clinical  course,  578 


Choriocarcinoma,        metas- 
tases in,  575 
structure,  571 
Chorioma,  566 

clinical  course,  577 
deportation      of      normal 
chorionic    elements    in, 

579 

etiology,  567 
gross  anatomy,  567 
historical  note,  566 
of     Marchand,     atypical, 

575 

ovarian  changes  in,  580 
ovarii,  621 
recovery  after  curetage  or 

partial  removal,  578 
structure,  567 
testis,  797 

Chorionepithelioma,  566 
Chorionic  carcinoma,  571 
Choroid     plexus,     papillary 
adenocarcinoma     of, 
418 

squamous-cell    carci- 
noma of,  419 
tumors  of,  415 
Chromatophores,  origin  and 

function,  887 
Chromatophoroma,     Rib- 

bert's,  872 
Chylangioma  of  mesentery, 

238 

Chylous  cysts,  975 
Ciliated  epithelial  cysts,  978 
Cirrhosis  mammae,  486 
of  liver,  cancer  with,  686 
carcinomatous,  686 
relation  of  primary  epi- 
thelial tumors  to,  678 
Cirsoid  neurofibroma,  156 
Coccidia  in  cancer,  115 
Coccygeal  chordoma,  195 
Cohnheim's  theory  of  can- 
cer, 94 

limitations  of,  97 
Colitis  polyposa,  673 
adenoma  in,  458 
cancer  following,  662 
Collateral     hyperplasia     in 

cancer,  481 
hypertrophy    in    tumors, 

3.7 

Colloid  degeneration  of  tu- 
mors, 45 
goiter,  891 

metastasizing,  903 
struma,  460 
Collonema,  180 
Coma,  acidemic,  in  cancer 

of  stomach,  656 
cancer,  74 

Complement  deviation  with 
autogenous  tumor  anti- 
gen,  91 

Complex  dermoids,  961 
Condyloma       acuminatum, 
450 


Condyloma  latum,  451 
Congenital   hypertrophy   of 
thyroid,  459 

myxoma  of  navel,  175 

nevus,  871 

rhabdomyoma    of    heart, 
222 

tumors,  26 

Connective-tissue  tumors,  27 
Contact  infection  in  cancer, 

85 

Cornu  cutaneum,  450 
Coronodental  cysts,  716 
Corpus  adiposum  malse,  182 
cavernosum   penis,   endo- 
thelioma of,  331 
luteum  cysts,  584 
uteri,      adenomyomatosis 

of,  diffuse,  556 
cancer    of,    551.       See 
also  Cancer  of  corpus 
uteri. 

Corpuscles,  Hassall's,  913 
Cranial  lipoma,  182 
Crateriform    rodent     ulcer, 

831 
Cutaneous  lymphosarcoma, 

387 

neurofibroma,  153 
warts,  448 
Cylindroma,  305 
Cystadenocarcinoma          of 

breast,  532 
Cystadenoma,  malignant,  of 

kidney,  742 
of  breast,  496 
prognosis,  498 
structure,  497 
of  cervix  uteri,  549 
of    kidney,    malignant 
transformation   in,   748 
of    ovary,    pseudomucin- 

ous,  591 
course,  593 
structure,  593 
serous,  586 
course,  588 
implantation    metas- 
tases in,  588 
structure,  588 
Cystes  epidermiques,  966 
Cystic    adenocarcinoma    of 

breast,  small,  517 
of  ovary,  597 
carcinoma,  471 
duct  carcinoma  of  breast, 

small,  517 
goiter,  893 
lymphangioma,  983 
mastitis,  489 
tumors,  464 

of  carcinomatous  struc- 
ture, 464 
Cystoma  of  ovary,   simple 

serous,  583 
simple,  582 
Cystosarcoma    phyl lodes, 

497 


INDEX 


1039 


Cysts,  chylous,  975 
coronodental,  716 
corpus  luteum,  584 
dentigerous,  716,  717 
dermoid.       See    Dermoid 

cysts. 

enteric,  975 
entodermoid,  976 
epidermoid,  965 
epithelial,  ciliated,  978 

special  forms,  965 
implantation  dermoid, 

966 

in  lipoma,  180 
in  tumors,  31 
intraperitoneal,   of   neph- 

rogenic  origin,  976 
mesenteric,  975 
of  bile-ducts,  688 
of  hypophyseal  duct,  936 
of  maxillary  antrum,  721 
of  ovary,  582 

dermoid,  atypical  forms, 
619 

small  multiple,  582 

simple  follicular,  582 
of  parathyroid  gland,  910 
of   pelvic   connective   tis- 
sue, dermoid,  978 
of  peritoneum,  975 

dermoid,  975 
of  pineal  gland,  949 
of  skin,  atheromatous,  965 

epithelial,  965 
of  thymus  gland,  915 
of  thyroglossal  duct,  969 
of  thyroid  gland,  910 
omental,  975 
radiculodental,  715 
sebaceous,  of  breast,  505 
serous,  975 
tubo-ovarian,  584 


DEAD  osteoma,  200 
Debris  epitheliaux  paraden- 

taires,  707 
Deciduoma,  566 
malignum,  566 
Degeneration,  fatty,  in  tu- 
mors, 43 
Demineralization      in      ca- 

chexia  of  cancer,  75 
Demodex     folliculorum     in 

acanthoma  of  skin,  822 
Dentigerous  cysts,  716,  717 
Dermatomyoma,  216 
Dermoid  cysts,  cervical,  966 

structure,  968 
complex,  961 
fissural,  966 
from      first      branchial 

cleft,  967 
hypophyseal,  973 
implantation,  966 
intracranial,  973 
mediastinal,  969 
mesobranchial,  967 


Dermoid     cysts    of    breast, 

505 

of  mesentery,  976 
of  omentum,  975 
of  orbitonasal  fissures, 

970 

of  ovary,  atypical  forms, 
619 

etiology,  623 

malignant  characters 
in,  620 

multiple,  619 

secondary  changes  in, 
620 

with  cystoma,  614 
of     pelvic     connective 

tissue,  978 
of  peritoneum,  975 
pharyngeal,  970 
presternal,  970 
retroperitoneal,  977 
sacrococcygeal,  979 
simple,  964 
special  forms,  965 
sublingual,  967 
true,  966 
tumors,  164 
Diabetes   with   acromegaly, 

.943 
Diffuse    buccal    papilloma- 

tosis,  452 
carcinoma,  472 
endothelioma,  339 
hypertrophy  of  breasts  in 

adults,  484 
melanoma    of    meninges, 

439 
sarcomatosis  of  meninges, 

438 
spindle-cell     sarcoma     of 

lung,  816 

Digestion,  influence  of  can- 
cer on,  70 

Double  monsters,  955 
asymmetrical,  956 
symmetrical,  955 
Duct  carcinoma  of  breast, 

508 
thyroglossal,      cysts      of, 

969 

Duodenum,  cancer  of,  661 
Dystrophia     adiposogenita- 

lis,  944 

Dystrophic  tumors  of  pitui- 
tary gland,  940 
Dystrophy,    adiposogenital, 
theories,  946,  947 


ECCHONDROSES,    185 
Ecchondrosis       physalifora, 
194 

spheno-occipitalis,  193 
Ectodermal    mixed    tumors 

of  breast,  500 
Edema  in  tumors  of  brain, 

397 
Elephantiasis,  158 


Elephantiasis,  acquired,  159 
angiomatosa,  159 
dura,  486 
durum,  158 
fibrosarcomatosa,  267 
hemangiomatosa,  225 
lymphangiectatica,      158, 

237 

molle,  158 
telangiectatica,  159 
Emaciation     from    tumors, 

65 
Embolism,  pulmonary  rnet- 

astatic,  84 
paradoxic,  84 
secondary,  84 
tertiary,  84 
Embryoid  tumors  of  testis, 

794 

Embryoma,  28,  959 
of  testis,  adult,  790 

complex,  790 

Embryonal      adenomyosar- 
coma    of    kidneys, 

753 

anatomy,  753 
histogenesis,  754 
structure,  753 
cancer  of  testis  with  lym- 

phoid  stroma,  795 
carcinoma,  472 
theory  of  cancer,  94 

limitations  of,  97 
tumors,  26,  49 
of  testis,  795 
Embryos,    post  -  generation 

of,  957 

Encephaloid        cancer       of 
breast,  532 

tumors,  511 

Enchondroma,  185,  186 
Endometrial  sarcoma,  struc- 
ture, 267 

Endometritis,  hypertrophic, 
458. 

mterstitiahs,  458 

syncytial,  566,  575,. 577 
Endothelial  cells,  origin  and 

functions,  299 
pathology  of,  300 
physiology  of,  300 

myeloma,  323 

psammoma  of  skin,  331 

sarcoma  of  spleen,  390 

tumors,  27 
Endothelioma,  27,  299,  342 

alveolar,  305 

angioplastic,  334 

calcification  in,  311 

classification,  305 

clinical  types,  313 

diagnosis,  differential,  312 

diffuse,  305,  339 

etiology,  313 

gross  anatomy,  308 

growth,  305 

histological  types  of,  305 

history  of,  302 


1040 


INDEX 


Endothelioma,    hyaline    de- 
generation in,  310 
interfascicular,  305 
mucinous  degeneration  in, 

3ii    . 

multiplicity,  309 
nomenclature,  305 
of  bones,  308,  322 

classification,  323 

multiple,  324 

solitary    bulky    cystic, 

323 

diffuse,  326 
of  cervix  uteri,  550 
of     corpus     cavernosum 

penis,  331 
of  ganglia,  318 
of  lymph-nodes,  309,  335, 

.341 

clinical  types,  336 

frequency,  336 

gross  anatomy,  337 

histogenesis,  339 

localized,  336 

metastases  in,  337 

structure,  338 

systemic  form,  336 
of  meninges,  315 

course,  318 

forms,  315 

location,  315 

structure,  315 
of  nerve-trunks,  318 
of  orbit,  318 
of  ovary,  309,  331 

appearance,  333 

clinical  course,  333 

diagnosis,  333 

structure,  333 
of  serous  membranes,  319, 

320 

of  skin,  309,  328 
of  stomach,  335 
of  testis,  308 
of  uterus,  334 
origin,  305 
papillary,  305 
peritoneal,  320 

classification,  322 

structure,  320 
perivascular,  305,  339 
pleural,  319 

classification  of,  322 

clinical  course,  320 

origin,  319 

structure,  319 
plexiform,  305,  339 
sarcoma    and,    combina- 
tion of,  311 
structure  of,  310 
Endothelium,        pathology, 

300 
tumor-like  hyperplasia  of, 

313 

Enteric  cysts,  975 
Enterocystomas,  978 
Entodermoid  cysts,  976 
Ependyma,  tumors  of,  415 


Ependyma,   tumors    of,   in- 
fundibular, 415,  420 
Ependymal  glioma,  420 
of  pineal  gland,  950 
gliomatpsis,  410 
neuroglioma      of      pineal 

gland,  951 

Ependymitis  granularis,  415 
Epidermoid  cancer,  28,  474, 

857 

glandular,  475 
of    hypophyseal    duct, 

936 

of  skin,  818 
of  tongue  and  mouth, 

840 

of  vagina,  564 
of  vulva,  562 
tubular,  474 
cysts,  965 
Epidermoids,  964 
congenital,  965 
Epignathi,  970 
Epiphanin  reaction  in  can- 
cer, 93 
Epithelial     cysts,     ciliated, 

978 

of  skin,  965 
special  forms,  965 
hyperplasia  of  liver,  675 
papilloma     of     maxillary 

antrum,  721 
pearls,  474 
proliferation,  influence  of 

lipoid  solvents  on,  128 
tumors,  28 

general    pathology    of, 

446 

of  bladder,  860 
of  breast,  484 
of  kidney,  738 
of  liver,  primary,  678 
of  ovary,  582 
of     renal     pelvis     and 

ureter,  763 
of  salivary  glands,  7 
of  thyroid  gland,  papil- 
lary, 899 
structure,  900 
of  vulva,  562 
Epithelipma,  21,  28,  474 
adenoides  cysticum,  329 
chorio-ectodermale,  622 
of  breast,  506 
of  lip,  papillary,  837 
ulcerative     infiltrating, 

837 
of  penis,  866 

course,  869 

established  disease,  867 

extensions,  868 

initial  lesion,  867 

structure,  869 
of     prostate,     squamous, 

788 
of  renal  pelvis,  papillary, 

763 
of  skin,  adenoid,  834 


Epithelioma  of  skin,  adenoid, 

cystic,  834 
simple,  835 
basal-cell,  830 
reticulated,  830 
of  ureter,  papillary,  763 
petrified,  820 
plexiform,  475 
reticulated,     histogenesis, 

833 
Epitheliome     intracanalicu- 

laire,  510 
kystique       intra-acineux, 

486 

luminaire,  564 
Epithelium,     lining,     bron- 
chial, cancer  of, 
809 

structure,  810 
Epopphoron,  tumors  of,  609 
Erosion  as  cause  of  cancer 

of  cervix  uteri,  548 
Esophagus,  cancer  of,  857 
anatomy,  858 
etiology,  857 
structure,  859 
carcinosarcoma  of,  859 
leiomyoma  of,  216 
sarcoma  of,  258 
Everted   papillary  adenoma 

of  ovary,  597 
Exophthalmic  goiter,  896 

stages,  897 
Exostoses,  197 
Exostosis  bursata,  198 
cartilaginea,  198 
clayata,  197 
clinical  groups,  198 
de  croissance,  198 
eburnea,  197 
medullaris,  197 
multiple,  198 
of  trachea,  198 
spongiosa,  197 
traumatic,  198 
Extradural  tumors  of  spinal 

cord,  444 
Extramedullary    plasma-cell 

tumors,  388 

tumors  of  spinal  cord,  444 
Extrarenal     adrenal     rests, 

tumors  of,  761 
Eye,  lymphangioma  of,  237 
osteoma  of,  202 


FACIAL    bones,  osteoma   of, 

199 
Fallopian      tubes,      adrenal 

tumors  of,  762 
cancer  of,  610 
etiology,  611 
structure,  611 
tumors  of,  612 
adrenal,  762 
False  tail,  984 

Family  incidence  of  cancer, 
105 


INDEX 


1041 


Fasciae,  fibroma  of,  163 

Fats  in  tumors  90 

Fatty    degeneration    in   tu- 
mors, 43 

Febiger's  experimental  gas- 
tric cancer  in  rat,  133 

Ferments  in  tumors,  67,  90 

Fetal   adenoma   of   thyroid 

gland,  895 
nbro-adenoma   of  breast, 

499 

implantations,        abdom- 
inal, 977 

special  forms,  965 
teratomas        abdominal, 

977 

Fetus,  parasitic,  958 
Fibro-adenoma    of    breast, 

495 

acinar    carcinoma    fol- 
lowing, 521 
fetal,  499 
papillary      intracystic, 

496 

Fibroblastic  sarcoma,  249 
Fibrocarcinoma,  473 
of  breast,  518,  535 
of    large    intestine,    ste- 

nosing,  670 

of  stomach,  diffuse,  639 
sclerosing,  clinical  fea- 
tures, 659 
pyloric,  639 
Fibrolipoma    of    spermatic 

cord,  801 
Fibroma,  27,  149 

blood-vessels  in,  149,  151 
clinical  types,  152 
edematodes        cysticum, 

i 66,  167 

simplex,  166,  167 
etiology,  160 
gross  appearance  of,  149 
juvenile    nasopharyngeal, 

1 68 

course,  169 
lipomatodes,  162 
lymph- vessels  in,  151 
matrix,  150 
molluscum,  149,  153 
clinical  course,  155 
typical,  154,  155 
natural  history  of,  151 
of  bones,  163 
of  breast,  165 
of  fasciae,  163 
of  glandular  organs,  165 
of  kidney,  165 
of  larynx,  850 
of  nares,  166 
of  ovary,  166 
of  periosteum,  163 
of  spermatic  cord,  plexi- 

form,  801 
of  testis,  165,  801 
origin  of,  151 
papillary,  149 
structure  of,  150 
66 


Fibromatosis,  diffuse,  158 

uteri,  267 

Fibromyoma,  uterine,  207 
Fibroneuroma,  true,  427 
Fibro-osteoma,  200 
Fibrosarcoma,  150,  251 

mucocellulare  carcinoma- 

todes  of  ovary,  262,  603 

Fibrous  acinar  carcinoma  of 

breast,  522 
Fissural  angioma,  225 

dermoids,  966 

Fistula  auris  congenita,  epi- 
thelial  cysts  of  external 

ear  from,  967 
Folliculoma  malignum  ova- 

rii,  602 
Frontal  sinus,   osteoma  of, 

200 

Functional   activity   in    tu- 
mors, 53 

adenomatoid  hyperplasia, 

459 
Fungus  hematodes,  19,  30 


GALEN'S  theory  of  cancer, 

17 

Gall-bladder,  cancer  of,  693 
anatomy,  694 
clinical  features,  697 
squamous-cell,  696 
structure,  695 
surgical  results  in,  701 
sarcoma  of,  697 
Gametoid  mitosis  in  tumors, 

39 
Ganglia,    endothelioma    of, 

318 

Gangliocellulare,  399 
Ganglionic    neuroma,    427, 

430 

etiology,  432 
Gasserian  ganglion,  tumors 

of,  434 

Gastric    cancer,    625.      See 
also  Cancer  of  stomach. 
digestion,  influence  of  can- 
cer on,  70 
Gastritis  polyposa,  adenoma 

in,  458 
Gastro-intestinal  Hodgkin  s 

granuloma,  369 
lipoma,  184 
pseudoleukemia,  378 
sclerostenosis,  640 
tract,  lymphosarcoma  of, 

385 
Gelatinous  adenocarcinoma 

of  large  intestine,  671 
cancer  of  stomach,  629 
Genius  loci  in  cancer,  85 
Giant-cell  sarcoma,  250 
of  aponeuroses,  256 
of  bone,  benign,  280 
prognosis,  287 
structure,  282 
of  tendon-sheaths,  256 


Giantism,  940 

Glandular     adamantinoma, 

713 

cancer  of  bladder,  864 

epidermoid  carjcijnoma, 
475. 

mastitis,  chronic,  489 

organs,  fibroma  of,  165 

tumors,  28 
Glans  penis,   melanoma  of, 

870 
Glioma,  27,  399 

blood-vessels  in,  405 

cerebral,  410 

clinical  types,  410 

differential  diagnosis,  407 

durum,  399 

ependymal,  410,  420 

etiology  of,  408 

ganglionare,  399 

gross  anatomy,  399 

growth  of,  406 

intracranial,     histological 
classification,  410 

molle,  399 

nasal,  411 

of  pineal  gland,  ependy- 
mal, 950 

of  posterior  lobe  of  pitui- 
tary, "939 

of  retina,  421 
etiology,  423 
structure,  422 

of  spinal  cord,  411 

pial,  414 

sarcoma  and,  differentia- 
tion, 407 

secondary      degeneration 
in,  400 

structural  forms,  399 

structure  of,  401 

telangiectaticum,  400 

teratomatous,  415 
Gliosarcoma,  399,  405,  424 
Glycogenic  degeneration  of 

tumors,  44 
Glycosuria  with  acromegaly, 

943 

Goiter,  colloid,  891 
metastasizing,  903 

congenital,  894 

cystic,  893 

exophthalmic,  896 
stages  of,  897 

parenchymatous,  894 
acquired,  895 

simple,  460,  891 
Granuloma,  benign,  of  thy- 
roid gland,  908 

Hodgkin's,  367,  443 
abdominal,  370 
anemia  from,  368 
clinical  course,  368 

types,  368 
etiology  of,  375 
gastro-intestinal,  369 
mediastinal,  370 
structure,  371 


1042 


INDEX 


Granuloma,  Hodgkin's,  tu- 
berculous lesions  in,. 

375 

with    chronic    general- 
ized lesions,  368 
malignum,  381 
Graves'  disease,  459,  896 
Gynecomastism,  484 


HAMARTOMA,  231 

Hassall's  corpuscles,  913 

Heart,  myxoma  of,  175 
rhabdomyoma     of,     con- 
genital, 222 
sarcoma  of,  primary,  176 

Hemangio  -  endothelioma, 
226,  307 

Hemangioma,  223 
hypertrophicum,  226 
simplex,  224,  736 

Hematodes,  fungus,  30 

Hemorrhage  in  cancer,  67 

Hemorrhagic  sarcoma,  mul- 
tiple, 252 

Hepatic  adrenal  tumors,  762 

Hepatoma,  68 1 
multiple,  684 
solitary,  68 1 
with  cirrhosis,  686 

Hereditary  tumors,  26 

Heredity  in  cancer,  105 

Heterolytic  action  of  tumor 
ferments,  67 

Heteroplastic    bone    forma- 
tion, 20 1 

clinical  forms,  201 
deposits  in  leukemia,  355 

Heterotopia  in  cancer,  467 

Highmore,  antrum  of,  tu- 
mors of,  720 

Hippocrate's  theory  of  can- 
cer, 17 

Histoid  tumors,  48 

Hodgkin's     disease,     bone- 
marrow     lesions     in, 

37.1 
mediastinal  tumors  in, 

370 

skin  lesions  in,  371 
splenic,  368 

granuloma,  367,  443.  See 
also  Granuloma,  Hodg- 
kin's. 

sarcoma,  373 
Homologous  tumors,  48 
Homotypic  tumors,  48 
Hunter's  theory  of  cancer, 

*9 

Hutchinson's  type  of  sar- 
coma of  adrenal  gland  in 
infants,  with  cranial  met- 
astases,  774 

Hyaline  changes  in  tumors, 

45 

Hydatid  disease,  485 
Hydrocystoma      tuberosum 
multiplex,  329 


Hydropic    degeneration     in 

tumors,  43 

Hydrops  follicularis,  582 
Hygroma  cysticum,  159 
colli,  238 

sacral,  239,  983 
Hylomata,  29 
Hyperglycemia  in  blood  in 

cancer,  70 
Hypernephroma,    738,    744, 

755 

Hyperostosis,  197 
Hyperplasia,    adenomatoid, 

functional,  459 
inflammatory     adenoma- 
toid, 457 
neoplastic,       morphology 

of,  41 
versus       inflammatory 

hyperplasia,  40 
of  adrenal  gland,  768 
of     interstitial     cells     of 

testis,  803 
of  liver,  epithelial,  675 

multiple  nodular,  677 
of    pituitary    gland,    dif- 
fuse, 930 
tumor-like,    of     endothe- 

lium,  313 
Hyperplastic  lymphadenitis, 

350 
Hypertrophic  endometritis, 

458 

granulation  tissue,  224 
Hypertrophy  of  breast,  484 
diffuse,  of  adults,  484 
infantile,  484 
of  male,  484 
of  prostate,  459,  779 
adenomatous,  780 
carcinomatous,  780 
etiology,  780 
productive      inflamma- 
tion in,  779 
structure,  779 
of  thymus  gland,  simple, 

914 

of  thyroid,  congenital,  459 
regenerative,  cancer  from, 

478 
Hypophyseal  dermoid  cysts, 

973 
duct,    cancer    of,    epider- 

moid,  936 
cysts  of,  936 
teratoids  of,  935 
tumors  of,  935 
Hypophysis     cerebri.       See 
Pituitary  gland. 


ILEUM,  cancer  of,  662 
Implantation  dermoid  cysts, 

966 

metastases  in  serous  cyst- 
adenoma  of  ovary,  588 
Induration     chronique     en 
masse,  486 


Infantile     hypertrophy     of 

breasts,  484 
Infantilism,  941 
reversif,  942 
tardif,  942 
Infants,  adenocarcinoma  of 

kidneys  in,  749 
sarcoma  of  adrenal  gland 
and  liver  in,  con- 
genital    (Pepper 
type),  7.75 
with   cranial    met- 
astases   (Hutch- 
inson  type),  774 
Infection  by  contact  in  can- 
cer, 85 

Infiltrative   growth   in   ma- 
lignancy, 62 

Inflammation,    chronic,    in 
experimental     production 
of  tumors,  131 
Inflammatory  adenomatoid 

hyperplasia,  457 
hyperplasia    versus    neo- 
plastic hyperplasia,  40 
reaction  in  cancer,  50 
Infundibular  ependyma,  tu- 
mors of,  420 
Interacinous     adenoma     of 

thyroid  gland,  894 
Interfascicular     endothelio- 
ma, 305 

Intermuscular  lipoma,  182 
Interstitial    cells    of    testis, 

hyperplasia  of,  803 
mastitis,  chronic,  488 
Intestinal     indigestion,     ef- 
fect of  cancer  on,  72 
polyposis,  673 

cancer  following,  662 
Intestine,  cancer  of,  661 
large,  adenocarcinoma  of, 

gelatinous,  671 
cancer  of,  667.    See  also 
Cancer    of   large    in- 
testine. 
fibrocarcinoma  of,  ste- 

nosing,  670 
leiomyoma  of,  216 
lymphomatous  tumors  of, 

260 

lymphosarcoma  of,  387 
melanoma  of,  886 
sarcoma  of,  260 

spindle-cell,  260 
tumors   of,    multiple    be- 
nign embryonal  carcin- 
oid,  663 

Intoxication,  general,  in  ma- 
lignancy, 63 
Intracranial  dermoid  cysts, 

973 

teratoids,  974 
teratomas,  974 

Intracystic      fibro-adenoma 
of  breast,  papillary,  496 

Intrahepatic  bile-ducts,  can- 
cer of,  multiple,  690 


INDEX 


1043 


Intramedullary    tumors    of 

spinal  cord,  444 
I  ntra  peritoneal      cysts      of 

nephrogenic  origin,  976 
Involution  of  breasts,  senile, 

487 

Irritation  group,  475 
Ischiopagi,  955 


JEJUNUM,  cancer  of,  662 
Juvenile  nasopharyngeal  fi- 
broma,  1 68 
course,  169 


KANGRI  cancer,  821 
Keloid,  1 60 

from  trauma,  1 60 
in  negro,  160 
neoplastic  properties,  162 
spontaneous,  160 
Kidneys,      adenocarcinoma 

of,  alveolar,  748 
embryonal,    in    adults, 

749 

in  infants,  749 
multiple,     in    sclerosis, 

746 

papillary,  742 
histogenesis,  746 
structure,  748 
with    granular    cells, 

746 

tubular,  750 
adenoma  of,  739 
alveolar,  740 
histogenesis,  741 
papillary,  739 
tubular,  741 

adenomyosarcoma  of,  220 
embryonal,  753 
anatomy,  753 
histogenesis,  754 
structure,  753 
cancer  of,  742 

metastases  in,  744 
papillary,     with     clear 

cells,  743 

tubular,  structure,  752 

fibroma  of,  165 

leukemic   infiltrations   in, 

355 

lymphosarcoma  of,  388 
myoma  of,  217 
myxoma  fibromatosum  of, 

165 

perithelioma  of,  346 
spotted,  741 
tumors  of,  738 

adrenal     tumors     and, 

differentiation,  760 
epithelial,  738 

classification,  739 
Krunkenberg's  fibrosarcoma 
mucocellulare  carcinama- 
todes  of  ovary,   262,  603 


LACHRYMAL  gland,  tumors 
of,  319,  725 

Lactic  acid  in  tumors,  89 

Langenbeck's  theory  of  can- 
cer, 22 

Large    alveolar    carcinoma, 

471 

Larval  cancer  of  larynx,  853 
Larynx,  adenoma  of,  850 
angioma  of,  850 
cancer  of,  851 
anatomy,  852 
course,  855 
larval,  853 
lymphatic       extension, 

855 

structure,  854 
chondroma  of,  850 
fibroma  of,  850 
leukoplakia  of,  851 
lipoma  of,  850 
lymphosarcoma  of,  856 
papilloma  of,  847 

structure,  847 
sarcoma  of,  856 
tumors  of,  847 
benign,  850 
Leiomyoma,  27,  203 
cavernosum,  203 
clinical  types,  207 
course  of,  205 
diagnosis,  205 
durum,  203 
molle,  203 
of  bladder,  866 
of  breast,  505 
of  esophagus,  216 
of  intestine,  216 
regressive  changes  in,  205 
structure  of,  204 
Lentigo,  873 

maligna  juvenilis,  823 
Leontiasis  ossea,  197 
Lepidomata,  29 
Leukanemia,  360 
Leukemia,  aplastic,  361 
atypical,  360 
changes  in  blood  in,  359 
heteroplastic  deposits  in, 

355 
infiltrations  in  kidney  in, 

355 

lymph-nodes  in,  354 

lymphoid-cell,  362 

mixed-cell,  361 

nature  of,  364 

plasma-cell,  364 

splenic  lesions  in,  354 
Leukemic  lymphoma,  353 
Leukocytosis  in  cancer,  68 
Leukoplakia  of  larynx,  851 

uteri,  557 

Leukosarcomatosis,  361,  362 
Linin,  46 

in  tumor-cells,  46 
Linitis    plastica,     .  35,    639, 

640 
clinical  features,  659 


Linitis  plastica,  leather-bot- 
tle stomach  in,  644 

Lip,  cancer  of,  838 

epithelioma  of,  papillary, 

837 
ulcerative     infiltrating, 

837 
Lipoid  solvents,  influence  of, 

on  epithelial  proliferation, 

128 
Lipoma,  27,  178 

annulare  colli,  182 

arborescens,  182 

capsular,  181 

cardiac,  184 

cavernosum,  179 

clinical  types,  182 

combined  with   myxoma, 
176 

connection     with     blood- 
vessels, 179 

cranial,  182 

cysts  in,  180 

etiology,  180 

gastro-intestinal,  184 

intermuscular,  182 

mediastinal,  184 

microscopical   structure, 
179 

molle,  178 

myelogenous,  184 

of  breast,  505 

of  larynx,  850 

of  posterior  lobe  of  pitui- 
tary, 939 

of  renal  hilus,  766 

of  spinal  cord,  441 

pelvic,  184 

perirenal,  184 

petrificum  ossificans,  180 

renal,  183 

secondary  changes  in,  179 

subcutaneous,  182 

synovial,  182 

telangiectaticum,  179 

trauma  as  cause,  181 

uterine,  184 
Lipomatosis,      replacement, 

181 

Liquefaction  cysts,  32 
Liver,  adenoma  of,  multiple, 

686 
solitary,  68 1 

cavernous     angioma     of, 
232 

cirrhosis    of,     carcinoma- 
tous,  686 

hyperplasia  of,  epithelial, 

675 

multiple  nodular,  677 
melanoma     of,     primary, 

693 

regenerative  power  of,  676 
sarcoma  of,  69 

in     infants,    congenital 

(Pepper  type),  775 
tumors  of,  675.     See  also 

Tumors  of  liver. 


1044 


INDEX 


Liver-cells,  cancer  of,  mul- 
tiple, 684 

primary  massive,  682 
Lung,  cancer  of,  807.     See 

also  Cancer  of  lung. 
extension  to,  in  cancer  of 

breast,  529 

lymphosarcoma  of,  817 
sarcoma  of,  815.    See  also 

Sarcoma  of  lung. 
tumors  of,  807 
Lupus  cancer,  823 
Lusitanus'  theory  of  cancer, 

18 

Lutein-cell  tumors,  585 
Lymphadenia  ossium,  378 
Lymphadenitis,  chronic,  313 

hyperplastic,  350 
Lymphadenoma,    350,   352, 

367 

Lyfnphangiofibroma,  149 
Lymphangioma,  233 

cavernosum,  234,  237 

clinical  forms,  235 

cutis  circumscripta,  236 

cystic,  983 

cysticum,  238 

cystoides,  235 

development  of,  235 

histological  structure,  234 

mesenteric,  238 

of  eye,  237 

of  ovary,  239 

of  salivary  glands,  736 

origin  of,  235 

retro  peritoneal,  238 

simple,  236 

simplex,  234 

tuberosum,  303 

multiplex,  236,  328 
Lymphangitis      carcinoma- 

tosa,  306 

Lymphatic     extensions     in 
cancer  of  prostate,  783 

invasion  by  sarcoma,  80 
in  cancer  of  uterus,  559 

permeation,       metastasis 
from,  76 

tuberculosis,  366 
Lymphatics  involved  in  can- 
cer of  stomach,  668 

of  stomach,  647 
Lymph-epithelioma,  643 
Lymph-nodes,  endothelioma 

.of,  3«9,  335 
clinical  types,  336 
etiology,  341 
frequency,  336 
gross  anatomy,  337 
histogenesis,  339 
localized,  336 
metastases  in,  337 
structure,  338 
systemic  form,  336 

in  leukemia,  354 

in  lymphemia,  354 

metastases  in,  77 
Lymphogranuloma,  367 


Lymphoid  tissue,  tumors  of, 

348 

classification,  348 
Lymphoid-cell  leukemia,  362 
Lymphoma,  27,  348 
leukemic,  353 
malignant,  380 
simple,  350 

etiology,  352 
Lymphomatosis,      systemic 

aleukemic,  376 
Lymphomatous    tumors    of 

intestine,  260 
of  stomach,  260 
Lymphosarcoma,  348,  380 
aggressive  qualities,  383 
anatomic  features,  381 
clinical  features,  381 

subvarieties,  384 
congenital,  390 
cutaneous,  387 
duration,  382 
etiology,  388 
extension,  382 
histological  character,  383 
metastases  in,  387 
of  gastro-intestinal  tract, 

385 

of  intestine,  387 
of  kidney,  388 
of  larynx,  856 
of  lung,  817 
of  prostate,  789 
of  spleen,  primary,  391 
of  stomach,  386 
of  testis,  388,  804 

etiology,  804 
of  thymus  gland,  917 

structure,  919 
of  tongue,  387 
origin,  382 
primary  lesions,  383 

pharyngeal,  385 
regressive  changes  in,  383 
relation  of  syphilis  to,  246 
of  tuberculosis  to,  246 
retro  peritoneal,  387 
round-cell,  large,  382 
structure,  382 
tuberculosis  in,  389 
types,  382 


MACROCHEILIA,  238 
Macroglossia,  238 
Macromelia,  238 
Mai  perforant,  984 
Maladie  de  Reclus,  477,  489 

kystique,  485,  486 

noueuse,  486,  489 
Malignancy,    diagnosis    of, 

63 
effects  on  body,  65 

on  organism,  62 
formation    of    metastases 

in,  62 

general  intoxication  in,  63 
infiltrative  growth  in,  62 


Malignancy,  significance  of, 

62 
Malignant    adenoma,    453, 

455 
of  thyroid  gland,  898 

cystadenoma,  742 

lymphoma,  380 

neuroma,  431 

tumors.     See  Cancer. 
Marantic  type  of  cancer,  67 
Marchand's  atypical  chori- 

oma(i  575 
Mastitis,  chronic  glandular, 

489 

cyst  contents  in,  489 
development,  489 
of  benign   or  ma- 
lignant    process 
in,  491 

predisposition  to  can- 
cer in,  492 
progress,  489 
structure,  489 
treatment,  493 
interstitial,  488 
productive,  485 
etiology,  486 
glandular,  486 
interstitial,  486 
senile,  486 
cystic,  489 

Maxillae,  osteoma  of,  199 
Maxillary     antrum,     carci- 
noma of,  721 
cysts  of,  721 
epithelial  papilloma  of, 

721 

tumors  of,  720 
sinuses,  tumors  of,  720 
tumors  of  dental  origin, 

707 
Mediastinal  dermoid  cysts, 

969 

hpoma,  184 

tumors  in  Hodgkin's  dis- 
ease, 370 
Medullary  cancer  of  breast, 

532 
tumors  of  adrenal  gland, 

771 

chromaffin  cell,  776 
with  adrenalin  con- 
tent  and   neph- 
ritic   symptoms, 
776 

Medullocelles,  269 
Meiostagmin     reaction     in 

cancer,  92 

Melanocarcinoma,  872 
Melanoma,  871 

clinical  characters,  872 

course,  873 

diffuse,  of  meninges,  439 

histogenesis,  887 

histology,  874 

history,  871 

malignant  changes  in,  877 

modes  of  origin,  872 


INDEX 


1045 


Melanoma  of  adrenal  gland, 
778,  890 

of  brain,  885 

of  breast,  505 

of  glans  penis,  870 

of  intestine,  886 

of  liver,  primary,  693 

of  rectum,  674 

of  spinal  cord,  885 

of  uncertain  origin,  887 

orbital,  882 

etiology  of,  885 
structure  of,  884 

pigmentation  of,  879 
Melanosarcoma,  872 
Melanotic  whitlow,  873 
Meningeal  pseudoneo- 

plasms,  443 
Meninges,  diffuse  melanoma 

of,  439 

endothelioma  of,  315 
sarcoma  of,  424,  437 

diffuse,  424 

gross  anatomy,  424 

structure,  425 
sarcomatosis    of,    diffuse, 

438 

multiple,  438 
Meningitis  arenosa,  315 

serosa  circumscripta,  443 
Mesenteric  cysts,  975 
lymphangioma,  238 
Mesentery,  chylangioma  of, 

238 
Mesobranchial       dermoids, 

967 
Mesodermal  elements  in  te- 

ratoma  of  ovary,  618 
tumors  of  breast,  499 
Mesonephric  adenomyoma, 

214 

tumors,  610 
Mesothelioma,  768 
Metastasis,  76 
cerebral,    in     cancer     of 

breast,  531 
formation  of,  62 
from   lymphatic   permea- 
tion, 76 

implantation,  in  serous 
cystadenoma  of  ovary, 
588  _ 

in  chorio-adenoma,  569 
in  choriocarcinoma,  575 
in  primary  epithelial 

tumor  of  liver,  680 
in  syncytioma,  576 
in  teratoma  of  ovary,  618 
lymph-node,  77 
of  benign  tumor,  84 
ovarian,     in     cancer     of 

stomach,  649 
preservation  of  structural 

type  in,  86 
pulmonary          embolism 

from,  84 
paradoxic,  84 
secondary,  84 


Metastasis,  pulmonary  em- 
bolism from,  tertiary,  84 
susceptibility    of    tissues 

to,  86 
visceral,     in     cancer     of 

uterus,  561 
Microorganisms   in    cancer, 

.IJ5. 
Mikulicz's  disease,  371 

Miliary  carcinosis,  464 
Mixed  tumors,  962 
of  testis,  794 
special  forms,  965 
Mixed-cell  leukemia,  361 
Mole,  congenital,  874 
pigmented,  872 
of  adults,  875 
Mollities  ossium,  292 
Molluscum       contagiosum, 

451 

Monsters,  double,  955 
asymmetrical,  956 
symmetrical,  955 
Mouth,    cancer   of,    epider- 

moid,  840 
Mucoid  carcinoma  of  breast, 

513 
Mucous  adenocarcinoma  of 

cervix  uteri,  549 
degeneration    in    tumors, 

44 
glands,    bronchial   cancer 

arising  from,  8li 
Muller's    tailed    corpuscles, 

21 

Multicentric  growth  of  tu- 
mors, 36 
Multiple  adenocarcinoma  in 

sclerotic  kidneys,  746 
hemorrhagic  sarcoma,  252 
neurofibroma     of     spinal 

cord,  441 
sarcomatosis  of  meninges, 

438. 

Muscle  tissue  tumors,  27 
Muscles,  angioma  of,  225 
sarcoma  of,  258 
voluntary,  rhabdomyoma 

of,  222 

Mycetozoa  in  cancer,  116 
Myelogenous  lipoma,  184 

pseudoleukemia,  292 
Myeloid       pseudoleukemia, 

379 
Myeloma,  256 

endothelial,  323 

of  bone,  292 

albumosuria  in,  293 
classification,  298 
clinical  course,  293 
erythroblastic      origin, 

298 

etiology,  298 
gross  anatomy,  293 
histogenesis,  297 
structure,  295 

of  bone-marrow,  multiple, 
292 


Myoma,  27,  203 
malignum,  205 
of  alimentary  tract,  216 
of  bladder,  216 
of  kidney,  217 
of  skin,  216 
of  stomach,  216 
of  testes,  217,  802 
of  urinary  organs,  216 
of  uterus,  20 

degenerative      changes 
in,  210 

etiology,  212 

form,  208 

gross  appearance,  210 

location,  208 

microscopical  structure, 
211 

recurrent,  265 
Myosarcoma,  27,  207 
spindle-cell,    of   stomach, 

259 

Myositis  ossificans,  202 
Myxochondrocarcinoma    of 

salivary  glands,  735 
Myxochondroma,  188 
Myxoglioma,  401 
Myxoma,  27,  170 

anatomical        characters, 

-1?1 
clinical  course,  172 

forms,  173 
combined    with    lipoma, 

176 

congenital,  of  navel,  175 
etiology,  177 
fibromatosum  of  kidney, 

165 

location,  173 
matrix,  171 
of  bones,  174,  175 
of  heart,  175 
of  nervous  system,  173 
of  optic  nerve,  173 
of  renal  hilus,  766 
origin,  176  , 

primary,  170 
structure,  171,  176 
Myxosarcoma  of  navel,  175 
of  ovary,  262 
of  renal  hilus,  766 


NARES,  fibroma  of,  1 66 

melanoma  of,  723 
Nasal  glioma,  411 

polyp,  1 66 

sinuses,  tumors  of,  720 
Nasopharyngeal  fibroma,  ju- 
venile, 168 
course,  169 
Nature  of  cancer,   theories 

of,  94 
Navel,  congenital  myxoma 

of,  175  . 
Necrotic  tissue,  osteoma  of, 

202 


1046 


INDEX 


Neoplastic          hyperplasia, 

morphology  of,  41 
versus        inflammatory 

hyperplasia,  40 
Nephrogenic    origin,    intra- 

peritoneal  cysts  of,  976 
Nerve  nevus,  159 

optic,    neuromyxoma    of, 

434 
Nerve-trunks,  endothelioma 

of,  318 

neurofibroma  of,  155 
tumors  of,  427 
Nervous    system,    myxoma 

of,   173 

osteoma  in,  200 
tumors  of,  27 
Neurinoma,  155 
Neurocytoma,  414 
of  adrenal  gland,  772 

clinical  types,  774 
Neuro-epithelioma,  27,  399, 

405 

of  retina,  422 
Neurofibroma,  149          / 
acoustic,  432 
cirsoid,  156 
cutaneous,  153 
multiple,   of  spinal   cord, 

441 
of   deeper   nerve   trunks, 

155 

plexiform,  156 

visceral,  155 
Neurofibroma  tosis,  152 

visceral,  157 
Neurofibrosarcoma,  155 

clinical  course,  156 
Neuroglioma       of       pineal 

gland,  ependymal,  951 
Neuroma,  27,  427 

amyelinicum,  427 

ganglionare,  27,  427,  771 

ganglionic,  430 
etiology,  432 

malignant,  431 

myelinicum,  427 

plexiform,  427 

traumatic,  427 
Neuromyxoma      of      optic 

nerve,  434 

Neuropathic  papilloma,  159 
Nevus,  872 

bathing  trunk  type,  873 

cellular.  331 

congenital,  871 

linearis,  159 

lipomatodes,  873 

nerve,  159 

papillaris,  873 

pilosus,  873 

results  of  studies,  888 

spilus,  873 

unius  lateris,  159 

vascular,  224 

vasculosus       molluscifor- 
mis,  225 

verrucosus,  873 


Nevus  vinosus,  224 
Nipple,   Paget's  disease  of, 

826 

Nodes,  singer's,  847 
Nuclear  fluid  in  tumor-cells, 

46  ^ 
Nuclem,  46 

in  tumor-cells,  46 
Nucleus,     cystic     degenera- 
tion of,  in  tumors,  46 

fragmentation    of,    in  tu- 
mors, 46 


ODONTOMA,  718 

etiology,  719 

modes  of  origin,  720 

soft,  719 

Omental  cysts,  975 
Oncology,  general,  17 

special,  149 

Oophoroma  folliculare,  603 
Optic    nerve,    myxoma    of, 

173 

neuromyxoma  of,  434 
Orbit,  angioma  of,  231 

angiosarcoma  of,  885 

endothelioma  of,  318 

melanoma  of,  882 
etiology,  885 
structure,  884 

osteoma  of,  199 

perithelioma  of,  885 

teratomas  of,  970 
Orbitonasal     fissures,     der- 

moid  cysts  of,  970 
Organization,    influence    of, 

on  cancer,  100 
Osteitis  fibrosa,  292 
Osteochondroma,    multiple, 

190 
Osteochondromyxosarcoma 

of  breast,  505 
Osteochondrosarcoma,  188 

of  bladder,  866 
Osteodystrophia      juvenilis, 

292 

Osteogenic  sarcoma,  270 
course,  275 
sclerosing,  275,  278 
site  of  origin J  271 
structure  of,  £76 
Osteoid  chondroma,  190 
Osteoma,  27,  196 

dead,  200 

heteroplastic,  197 

in  nervous  system,  200 

hyperplastic,  197 

of  antra,  199 

of  eye,  202 

of  facial  bones,  199 

of  frontal  sinus,  200 

of  maxillae,  199 

of  necrotic  tissue,  202 

of  orbit,  199 

of  penis,  202 

of  skin,  202 

reticulated,  201 


Osteoma,  secondary,  200 
terminology,  196 
true,  199 

Osteomalacia,  senile,  292 
Osteophyte,  197 
Osteosarcoma,  269 
Ovarian  metastases  in  can- 
cer of  stomach,  649 
Ovarium  gyratum,  166 
Ovary,  adenocarcinoma  of, 

cystic,  597 
papillary  serous,  589 
pseudomucinous,  595 
adenofibroma  of,  597 
adenoma  of,  586 

everted  papillary,  597 
solid,  596 
superficial,  597 
testicular,  610 
adenomyoma  of,  610 
cancer  of,  597.     See  also 

Cancer  of  ovary. 
cavernous  angioma  of,  232 
chondrosarcoma  of,  262 
cystadenoma     of,      pseu- 
domucinous, 591 
serous,  586 
cystoma  of,  simple  serous, 

583 
cysts   of,    582.      See   also 

Cysts  of  ovary. 
dermoids    of,    613.      See 

also    Dermoid   cysts   of 

ovary. 
endothelioma  of,  309 

appearance,  333 

clinical  course,  333 

diagnosis,  333 

structure,  333 
fibroma  of,  166 
fibrosarcoma     mucocellu- 

lare  carcinomatodes  of, 

262,  603 

lymphangioma  of,  239 
myxosarcoma  of,  262 
perithelioma  of,  346 
round-cell  sarcoma  of,  261 
sarcoma  of,  260 
spindle-cell    sarcoma    of, 

261 
teratoma  of,  613.  See  also 

Teratoma. 

tumors  of,  adrenal,  610, 
762 

age  in  etiology,  606 

epithelial,  582 

etiology,  606 

histogenesis,  606 

origin,  608 


PACHYDERMATOCELE,  159 
Pachydermia,  159 

laryngis,  851 

Pachymeningitis     cervicalis 
hypertrophica,  443 

interna  sarcomatosa,  425 
Paget's  cells,  827 


INDEX 


1047 


Paget's    disease    of   nipple, 

826 

origin,  828 
structure,  827 
Pancreas,  adenoma  of,  702 
cancer  of,  702.     See  also 

Cancer  of  pancreas. 
sarcoma  of,  706 
tumors  of,  702 
Papillary      adenocarcinoma 
of  chroid  plexus,  418 
of  kidney,  742 

with    granular    cells, 

746 

adenoma  of  kidney,  739 
of  ovary,  everted,  597 
cancer,  464,  470 

of    kidney    with    clear 

cells,  743 

cystic  adenoma,  455 
endothelioma,  305 
epithelial  tumors,  899 
epithelioma  of  lip,  837 
fibroma,  149 
intracystic  fibre-adenoma 

of  breast,  496 
pseudomucinous    cystad- 

enoma,  592 
serous  adenocarcinoma  of 

ovary,  589 
Papilloma,  28,  446 
bronchial,  813 
clinical  course,  447 
development     of     malig- 
nancy in,  448 
neuropathic,  159 
of  bladder,  860 

allantoid  type,  863 
structure,  863 
of  breast,  505 
of  larynx,  847 

structure,  847 
of  maxillary  antrum,  epi- 
thelial, 721 
of  renal  pelvis  and  ureter, 

763 

of  tongue,  452 
of  ureter,  763 
structure  of,  448 
Papillomatosis,  diffuse  buc- 

cal,  452 
Paraffin  cancer  of  scrotum, 

870 

Paraganglioma,  777 
Paranuclein,  46 

in  tumor-cells,  46 
Parasites,  scope  of  relation 

to  cancer,   122 
Parasitic  fetus,  958 
theory  of  cancer,  113 

theoretic     objections 

to,  120 
Parathyroid  gland,  cysts  of, 

910 

tumors  of,  909 
Parenchymatous  goiter,  894 

acquired,  895 
Parosteal  exostosis,  198 


Parosteal  sarcoma,  275 
Parovarium,  tumors  of,  609 
Pars  intermedia,  tumors  of, 

938 

Pavement  tumors,  28 
Pelvic     connective     tissue, 
dermoid  cysts  of,  978 

lipoma,  184 
Pelvis  spinosa,  185 
Penis,  epithelioma  of,  866 
course,  869 

established  disease,  867 
extensions,  868 
initial  lesion,  867 
structure,  869 

osteoma  of,  202 

tumors  of,  866 
Pepper's  type  of  congenital 

sarcoma  of  adrenal  gland 

and  liver  in  infants,  775 
Peptic  ulcer,  cancer  follow- 
ing, 630 
Peribronchial     sarcoma     of 

lung,  817 

Peri-endothelioma,  345 
Periosteal  sarcoma,  270 
Periosteum,  fibroma  of,  163 
Peripheral  nervous  system, 

tumors  of,   152 
Perirenal  lipoma,  184 
Perithelioma,  304,  317,  341 

clinical  types,  344 

gross  appearance,  343 

of  bones,  345 

of  breast,  345 

of  carotid  gland,  346 

of  cervix  uteri,  550 

of  kidney,  346 
'   of  ovary,  346 

of  pia  mater,  344 

of    subcutaneous    tissue, 

344 

orbital,  885 
secondary,  342 
structure,  343 
Peritoneal        endothelioma, 

320 
invasion     in     cancer     of 

breast,  530 
teratoid  tumors,  976 
Peritoneum,  cysts  of,  975 

dermoid,  975 
Perivascular   endothelioma, 

30.5,  339  . 

Petrified  epithelioma,  820 

Phagocytosis      by      tumor- 
cells,  47 

Pharyngeal   dermoid   cysts, 

970 
teratoma,  970 

Pharynx,       lymphosarcoma 
of,  primary,  385 

Phosphorus  in  tumors,  90 

Physaliden  of  Virchow,  43, 
187 

Pia  mater,  perithelioma  of, 

344 
Pial  glioma,  414 


Pigmented  mole,  872 

of  adults,  875 
Pineal  gland,  948 

cysts  of,  949 

general  pathology,  948 

glioma  of,   ependymal, 
.950 

histology,  948 

neuroglioma    of,    epen- 
dymal, 951 

teratoma  of,  949 

tumors  of,  948 
classification,  949 
clinical  features,  951 
occurrence,  948 
structure,  951 
symptomatology,  951 
Pituitary   gland,    adenocar- 
carcinoma   of,  932 
metastases,  933 
structure,  933 

adenosarcoma  of,  934 

anatomy,  925 

angiosarcoma  of,  934 

cancer  of,  atypical,  934 

functional    changes   in, 
928 

histology  of,  927 

hyperplasia  of,  diffuse, 

93° 
posterior    lobe,    glioma 

of,  939 

lipoma  of,  939 
tumors  of,  924 
anatomy,  929 
cephalic,  939 
dystrophic,  940 
etiology,  924 
miscellaneous,  939 
relation  of  type  with 
symptom  complex, 

945 

symptomatology,  939 
glandules,   accessory,   an- 
atomy of,  927 
Placenta,  angioma  of,  232 

myxoma  of,  173 
Plasma-cell  leukemia,  364 
tumors,     extramedullary, 

388 
Plastin,  46 

in  tumor-cells,  46 
Pleura,  endothelioma  of,  319 
involvement  in  cancer  of 

breast,  529 

Plexiform  angioma,  224 
endothelioma,  305,  339 
epithelioma,  475 
fibroma  of  spermatic  cord, 

80 1 

neurofibroma,  156 
neuroma,  427 
Polyp,  choanal,  167 

nasal,  1 66 

Polyposis,  intestinal,  673 
cancer  following,  662 
Porphyry  spleen,  368 
Port-wine  stain,  224 


1048 


INDEX 


Post-generation  of  embryos 

957 

Postnatal  tumors,  26 
Precancerous     changes 
cervix  uteri,  550 
_  in  corpus  uteri,  556 
diseases,  476 
lesions,  475 
Pregnancy,  effect  of,  144 

on  cancer  of  uterus,  560 
Presarcomatous  lesions,  246 
Presternal  dermoid  cysts 

970 
Primary    acinar    carcinoma 

of  breast,  522 
splenomegaly,  313 
Prostate,      adenocarcinoma 

of,  787 

adenoma  of,  786 
cancer  of,  781.     See  also 

Cancer  of  prostate. 
epithelioma  of,  squamous 

788 

hypertrophy  of,  459,  779 
adenomatous,  780 
carcinomatous,  780 
etiology,  780 
productive     inflamma- 
tion in,  779 
structure,  779 
lymphosarcoma  of,  789 
rhabdomyosarcoma       of, 

789 
sarcoma  of,  788 

spindle-cell,  789 
tumors  of,  779 
Proteins,    tumor,    constitu- 
tion of,  89 
febrile    destruction    of, 

66 

toxic  destruction  of,  66 
Protozoa  in  cancer,  115 
Pruritus  in  cancer  of  vulva, 

563 

Psammocarcinoma,  591 
Psammoma,  305 
endothelial,  of  skin,  331 
of  spinal  cord,  440 
Pseudoleukemia,  366,  367 
gastro-intestinal,  378 
myelogenous,  292 
myeloid,  379 
true,  376 

blood  in,  377 
clinical  features,  377 
general  features,  376 
histology,  376 

Pseudomucinous    adenocar- 
cinoma of  ovary,  595 
cystadenoma  of  ovary,59i 
Pseudomyxoma      peritonei, 

464,  595 
rseudoneoplasms,      menm- 

geal,  443 

Psoriasis  preputialis,  867 
Pulmonary    alveoli,    cancer 

arising  from,  812 
Pulp  tumors,  29 


Pylorus,     sclerosing     fibro 
•    carcinoma  of,  639 


RADICULODENTAL  cysts, 
Rankenneurome,  156 
Ransohoff's  test  in  cancer 

93.  . 

Rapidity  of  growth  in  ma 

lignancy,  62 
Rat,  experimental  cancer  o 

stomach  in,   133 
Rathke's  pouch,  927 
Recklinghausen's       disease 

153 

Rectum,  melanoma  of,  674 
Recurrent  myoma  of  uterus 

265 
Regeneration    of    blood    in 

cancer,  69 
Regenerative    hypertrophy 

cancer  from,  478 
Regressive       changes       in 

tumor-cells,  43 
Renaissance  period,  cancer 

in,  1 8 

Renal  hilus,  lipoma  of,  766 
myxoma  of,  766 
myxosarcoma  of,  766 
sarcoma  of,  diffuse,  767 
tumors  of,  766 
lipoma,  183 
pelvis,   epithelial    tumors 

of,  763 
epithelioma    of,    papil- 
lary, 763 
papilloma  of,  763 
sarcoma  of,  diffuse,  767 
Replacement      lipomatosis, 

181 
Respiratory     tract,     chon- 

droma  of,   192 
Retention  cysts,  32 
Reticulated        epithelioma, 

histogenesis,  833 
of  skin,  830 
osteoma,  201 
Reticulosplenome  nodulaire, 

391 

Reticulum-cell  sarcoma,  340 
Retina,  glioma  of,  421 
etiology,  423 
structure,  422 
neuro-epithelioma  of,  422 
Retrograde  transport  in  dis- 
semination of  tumors,  83 
^.etroperitoneal     dermoids, 

977 

lymphangioma,  238 
lymphosarcoma,  387 
teratoids,  977 
tumors  of  adrenal  rests, 

lateral,  762 

lhabdomyoma,  27,  203,  217 
appearance,  217 
clinical  forms,  220 
course,  219 
form,  217 


Rhabdomyoma,  miscellane- 
ous, 222 
of  bladder,  866 
of  heart,  congenital,  222 
of  testis,  221 
of  urinary  bladder,  220 
of       voluntary      muscle, 

222 

structure,  217 
uteri,  220 
Rhabdomyosarcoma          of 

prostate,  789 
Ribbert's         chromatopho- 

roma,  872 
Riedel's  struma,  908 
Rodent  ulcer,  830 
crateriform,  831 
histogenesis,  833 
structure,  832 

Round-cell   cancer  of  sali- 
vary glands,  727 
sarcoma,  243,  244 
of  breast,  503 
of  lung,  817 
of  ovary,  261 


SABER-SHEATH  veins  in  tu- 
mors, 57 
Sacral  cystic  lymphangioma, 

983 

hygroma,  239,  983 
mixed  tumors,  congenital, 

origin  of,  984 
teratomas,  982 
Sacrococcygeal       dermoids, 

979 

mixed  tumors,  979 
teratoid  tumors,  981 
teratomas,  979 
Salivary    glands,    adenoma 

of,  725 
cancer  of,  725 

round-cell,  727 
chondroma  of,  193 
lymphangioma  of,  736 
myxochondrocarcinoma 

of,  735 
tumors    of,    epithelial, 

725 

mixed,  727 
Sarcoma,  20,  27 
alveolar,  983 
alveolare       epithelioides, 

335 

benign  giant-cell,  of  bone, 
280 

capsular,  275 

character  of  growth,  241 

clinical  types,  249 

deciduocellulare,  566 

endometrial,  structure, 
267 

endothelioma  and,  com- 
bination of,  311 

epithelioides,  303 

etiology,  245 

fasciculatum,  250 


INDEX 


1049 


Sarcoma,  fibroblastic,  249 
general  characters,  240 
giant-cell,  250 

benign,  of  bone,  280 
of  tendon-sheaths  and 

aponeuroses,  256 
gross  anatomy,  240 
Hodgkin's,  373 
invasion  of  lymphatics  by, 

80 

lamellosum,  250 
multiple  hemorrhagic,  252 
histological        struc- 
ture, 253 
of  adrenal    gland    in  in- 
fants,    congeni- 
tal (Pepper 
type),  7.75 
with   cranial   met- 
astases    (Hutch- 
inson  type),  774 
of  bladder,. 865 
of  bone,  244,  269 
classification,  270 
duration,  277 

of  life  in,  277 
etiology,  289 
giant-cell,  benign,  280 

structure,  282 
prognosis,  287 
historical,  269 
prognosis,  284 
rapidity  of  growth,  285 
spindle-cell,  277 
prognosis,  287 
telangiectatic,  273,  278 

prognosis,  287 
trauma  in,  289 
treatment,  288 
of  bone-marrow,  269 

primary  multiple,  293 
of    brain    and    meninges, 

424 

diffuse,  424 
gross  anatomy,  424 
structure,  425 
of  breast,  pure,  503 

spindle-cell,  504 
round-cell,  503 
of  esophagus,  258 
of  gall-bladder,  697 
of  heart,  primary,  176 
of  intestine,  260 
of  larynx,  856 
of  liver,  692 

and  adrenal  in  infants, 
congenital        (Pepper's 
type),  775 
of  lung,  815 

classification,  816 
diffuse  spindle-cell,  816 
peribronchial,  817 
round-cell,  817 
of  muscles,  258 
of  ovary,  260 

round-cell,  261 
of  pancreas,  706 
of  prostate,  788 


Sarcoma  of  prostate,  spindle- 
cell,  789 
of  renal  hilus,  diffuse,  767 

pelvis,  diffuse,  767 
of  seminal  vesicles,  789 
of  skin,  252 
of  spinal  cord  and  men- 
inges, 437 
central,  440 
metastatic,  442 
solitary,  438 
of  spleen,  390 
endothelial,  390 
spindle-cell,  390 
of  stomach,  259 

miscellaneous,  260 
of  testis,  795,  802 
of  thymus  gland,  921 
of  thyroid  gland,  906 
of  uterine  mucosa,  266 
of  uterus,  263 
classification,  264 
etiology,  266 
histogenesis,  266 
metastases  in,  263 
mural,  263 
structure,  264 
osteogenic,  270 
course,  275 
sclerosing,  278 
site  of  origin,  271 
structure  of,  276 
parosteal,  275 
periosteal,  270 
radiare,  250 
reticulum-cell,  340 
round-cell,  243,  244 
sclerosing  osteogenic,  275 
spindle-cell,  249.    See  also 

Spindle-cell  sarcoma. 
stroma  of,  244 
structure,  242 
telangiectatic,     of    bone, 

278 

trabeculare,  250 
Sarcomatoid    structures    in 
cancer  of  cervix  uteri,  550 
Sarcomatosis   of    meninges, 

diffuse,  438 
multiple,  438 
Sarcomatous  struma,  934 
Sarcome  angioplastique,  797 
Scapula,  chondroma  of,  190 
Schimmelbusch's       disease, 

489 
Scirrhous  cancer  of  breast, 

534  . 

of  cervix  uteri,  549 
of  prostate,  788 
of  stomach,  clinical  fea- 
tures, 659 
diffuse,  637 
Scirrhus  pustuleux,  534 
Sclerosing  fibrocarcinoma  of 
stomach,    clinical    fea- 
tures, 659 

osteogenic  sarcoma,  275, 
278 


Sclerosing  pyloric  fibrocar- 
cinoma of  stomach,  639 

Sclerosis,  multiple  adeno- 
carcinoma  of  kidneys  in, 
746 

Scrotum,  cancer  of,  870 
paraffin,  870 

Sebaceous  cysts  of  breast, 

505 

Secondary  osteoma,  200 
Seminal    vesicles,    sarcoma 

of,  789 

Seminome,  795 
Senile  involution  of  breasts, 
487 

osteomalacia,  292 
Sennert's  theory  of  cancer, 

18 

Serology,  89 

Serous    adenocarcinoma    of 
ovary,  papillary,  589 

cavities,   invasion  of,  by 
cancer,  80 

cystadenoma  of  ovary,  586 

cysts,  975 

membranes,  endothehoma 

of,  319 

Simple  cystoma,  582 
lymphoma,  350 
etiology,  352 
mixed  tumors,  28 
Singer's  nodes,  847 
Skin,    acanthoma    of,    818. 
See  also  Acanthoma  of 
skin. 
angio-endothelioma       of, 

331 

cancer  of,  epidermoid,  818 
cysts    of,    atheromatous, 

965  . 

epithelial,  965 
endothelial  psammoma  of, 

331 

endothelioma  of,  309,  328 
epithelioma   of,   adenoid, 

834 

cystic,  834 
simple,  835 
basal-cell,  830 
reticulated,  830 
invasion     in     cancer     of 

breast,  525 

lesions  in  Hodgkin's  dis- 
ease, 371 
myoma  of,  216 
osteoma  of,  202 
sarcoma  of,  252 
spindle-cell    sarcoma    of, 

255 
Skull      changes     in      brain 

tumors,  398 
Small    alveolar    carcinoma, 

47.1  . 

cystic  adenocarcinoma  ot 

breast,  517 
duct       carcinoma      of 

breast,  517 
Solid  ovarian  adenoma,  596 


1050 


INDEX 


Solitary    diffuse    endotheli- 
oma  of  bones,  326  . 

Soot-wart,  870 
Spermatic  cord,  fibrolipoma 

of,  80 1 
fibroma    of,    plexiform, 

801 

tumors  of,  adrenal,  762 
Spina  bifida  occulta,  984 
tumors  associated  with, 

983 
Spinal   cord  and   meninges, 

sarcoma  of,  437 
angioma  of,  441 
degeneration      of,      in 

brain  tumors,  398 
glioma  of,  411 
lipoma  of,  441 
melanoma  of,  885 
neurofibroma  of,  multi- 
ple, 441 

psammoma  of,  440 
sarcoma  of,  central,  440 

metastatic,  442 

solitary,  438 
tumors    of,    436.      See 
also  Tumors  of  spi- 
nal cord. 

secondary  changes  in, 

442 

symptomatology,  443 
xanthochromia       in, 

442 
membranes,    relation     of 

tumors  to,  444 
Spindle-cell  myosarcoma  of 

stomach,  259 
sarcoma,  249 

blood-vessels  of,  250 
diagnosis,  250 
histogenesis,  251 
of  bone,  277 
of  breast,  pure,  504 
of  intestine,  260 
of  lung,  diffuse,  816 
of  ovary,  261 
of  prostate,  789 
of  skin,  254 
etiology,  256 
histogenesis,  255 
structure,  254 
of  spleen,  390 
rate  of  growth,  249 
secondary    changes   in, 

250 

structure,  249 
Spirochetae  in  cancer,  116 
Spleen,    lesions    in,    in    leu- 
kemia, 354 

lymphosarcoma    of,     pri- 
mary, 391 
porphyry,  368 
sarcoma  of,  390 
endothelial,  390 
spindle-cell,  390 
Splenic    Hodgkin's    disease 

368 
Splenomegaly,  primary,  31^ 


Spontaneous    cure     in     tu- 
mors, 60 

regression   in   tumors,   40 
Spotted  kidneys,  741 
Squamous    epithelioma    of 

prostate,  788 
Squamous-cell      cancer      of 

choroid  plexus,  419 
of  large  intestine,  674 
Stain,  port-wine,  224 
Stammler's  reaction  in  can- 
cer, 93 
Stenosing  fibrocarcinoma  of 

large  intestine,  670 
Sterility  in  etiology  of  uter- 
ine tumor,  212 
Sternberg's  disease,  367 
Stomach,      adenocarcinoma 

of,  627 

occurrence,  656 
adenoma  of,  simple,  629 
athletic,  652 
cancer  of,  625.     See  also 

Cancer  of  stomach. 
endothelioma  of,  335 
fibrocarcinoma     of,     dif- 
fuse, 639 

sclerosing,  clinical   fea- 
tures, 659 
pyloric,  639 
leather-bottle,     in    linitis 

plastica,  644 
lymphatics  of,  647 
lymphomatous  tumors  of, 

260 

lymphosarcoma  of,  386 
myoma  of,  216 
sarcoma  of,  259 

miscellaneous,  260 
spindle-cell     myosarcoma 

of,  259 
tumors     of,    lymphomat- 
ous, 259 

ulcerocancer  of,  658 
Stools,  blood  in,  in  cancer,  72 
Stroma  of  tumors,  53 

regressive    changes    in, 

55 

reactions,       experimental 

analysis  of,  55 
Struma  adrenalis,  461 

colloid,  460 

hypophysis,  461 

ovarii,  615,  621 

postbranchialis,  901 

Riedel's,  908 

sarcomatous,  934 

suprarenalis,  183,  758 
Strumae  suprarenales  aber- 

ratae  renalis,  738 
Subcutaneous  lipoma,  182 

tissues,    perithelioma    of, 

344 

Sublingual  dermoids,  967 
Submaxillary  gland,  epithe- 
lial tumors  of,  737 
Superficial       adenoma       ol 
ovary,  597 


Sweat-glands,     tumors     of, 

836 
Syncytial  endometritis,  566, 

575,  577 

wandering  cells,  568 
Syncytioma,  575 
clinical  course,  578 
metastases  in,  576 
Synovial  lipoma,  182 
Syphilis,  relation  of,  to  lym- 
phosarcoma, 246 
to  tumors,  123,  124 
Syringomyelia       associated 

with  gliosis,  412 
Systemic  aleukemic  lympho- 
matosis,  376 


TAIL,  false,  984 
Teeth,  tumors  of,  707 
Telangiectasis,  224 
Telangiectatic     angio-endo- 
thelioma  of  bones,  323 
bone-sarcoma,  273 
sarcoma,  224 

of  bone,  273,  278 
prognosis,  286 
Tendon-sheaths,     giant-cell 

sarcoma  of,  256 
Teratoblastomas,  962 
Teratogenic         termination 

period,  954,  973 
Teratoid  chondroma,  193 
Teratoids,  959 
cervical,  969 
intracranial,  974 
of  breast,  mixed,  499 
of  hypophyseal  duct,  935 
of  testis,  794 
peritoneal,  976 
retro  peritoneal,  977 
sacrococcygeal,  981 
Teratology,  954 
Teratoma,  28,  959,  975 
abdominal  fetal,  977 
causes,  961 
cervical,  969 
intracranial,  974 
morphogenesis,  960 
of  orbit,  970 
of  ovary,  613 
anatomy,  613 
atrophic  bidermal,  619 
clinical  course,  613 
contents,  615 
dermoids    and,    differ- 
entiation, 615 
etiology,  623 
mesodermal      elements 

in,  618 

metastases  in,  618 
multiple,  619 
prognosis,  613 
relation  to  simple  tu- 
mors, 622 
with  cystoma,  614 
of  pineal  gland,  949 
of  testis,  790 


INDEX 


1051 


Teratoma   of   testis,   adult, 

clinical  course,  794 
derivatives,  790 
historical  note,  790 
metastases  in,  800 
relation   to   miscellane- 
ous tumors,  801 
structure,  797 
varieties,  790 
pharyngeal,  970 
sacral,  982 
sacrococcygeal,  979 
source,  960 
special  forms,  965 
tridermal,  977 
Teratomatous  glioma,  415 
Testicular       adenoma       of 

ovary,  610 

Testis,  adenoma  of,  802 
cancer      of,      embryonal, 
with  lymphoid  stroma, 

795 

chondroma  of,  801 
chorioma  of,  797 
embryoma  of,  adult,  790 

complex,  790 
endothelioma  of,  308 
fibroma  of,  165,  801 
interstitial  cells  of,  hyper- 

plasia  of,  803 
lymphosarcoma    of,    388, 
804 

etiology,  804 
myoma  of,  217,  802 
rhabdomyoma  of,  221 
sarcoma  of,  795,  802 
teratoma    of,    790.      See 

also  Teratoma  of  testis. 
tumors  of,   adrenal,   762, 
803 

embryoid,  794 

embryonal,  795 

miscellaneous,    relation 
to  teratoma,  801 

mixed,  794 

teratoid,  794 

Theory  of  cell  autonomy,  97 
Thiersch's  theory  of  cancer, 

23 
Thoracic  duct,  invasion  of, 

by  cancer,  79 
Thoracopagi,  955 
Thymoma,  917 

interpretation,  922 
Thymus    gland,     anatomy, 

912 

cancer  of,  920 
cysts  of,  915 
gemeral  pathology,  914 
hypertrophy  of,  simple, 

914 
lymphosarcoma  of,  917 

structure,  919 
sarcoma  of,  921 
tumors  of,  912 
classification,  917 
clinical  course,  923 
primary,  916 


Thyroglossal  duct,  cysts  of, 

969 
Thyroid  gland,  adenocarci- 

noma  of,  898 
small  alveolar,   large 

cell,  901 

adenoma  of,  fetal,  895 
interacinous,  894 
malignant,  898 
cancer  of,  901 .    See  also 
Cancer      of      thyroid 
gland. 

cysts  of,  910 
granuloma   of,    benign, 

908 

hypertrophy    of,     con- 
genital, 459 
sarcoma  of,  906 
tumors  of,  891 

papillary     epithelial, 

899 

structure,  900 

Tibia,  adamantinoma  of ,  7 1 5 
Tissue    tension     theory    of 

cancer,  98 
Tongue,   cancer   of,  epider- 

moid,  840 
cavernous,     angioma    of, 

231 

lymphosarcoma  of,  387 
papilloma  of,  452 
Trachea,  exostosis  of,  198 
Transplantable          tumors, 

adaptation  of,  139 
fate  of,  139 
nature    and    origin    of, 

136 

problems  of,  136 
Transplantation  of  tumors, 

134 

acquired  resistance  to, 
144 

between  animals  of  dif- 
ferent species,  134 

between  lower  animals 
of  same  species,  135 

between  man  and  man, 

134 
between  related  species 

of  lower  animals,  134 
hypersusceptibility    to, 

H7 

influence  of  variations 
in  soil,  140 

natural  resistance,  143 

nature  of  factors  in  re- 
sistance, 145 

passive    resistance    to, 

H5 

uniformity    of    technic 

in,   140 

Transplanted     tumors,     in- 
fluence of  diet  on,  140 

resistance  to,  143 

spontaneous  absorption 
of,  141 

structural  changes  in, 
141 


Trauma   in  etiology  of  tu- 
mors,  109,   no 
frequency,  112 
mechanism,  in 
medicolegal    aspects, 

112 

Traumatic  exostoses,  198 
neuroma,  427 
tumors,  26 

Tridermal  teratomas,  977 
True  fibroneuroma,  427 
osteoma,  199 
pseudoleukemia,  376 
Tuberculosis     cutis     verru- 

cosa,  823 

Hodgkin's  disease  and,  375 
in  lymphosarcoma,  389 
lymphatic,  366 
relation    of,    to    lympho- 
sarcoma, 246 
to  tumors,  123,  124 
Tuberculum  impar,  910 
Tubo-ovarian  cysts,  584 
Tubular  acanthoma,  819 
adenocarcinoma    of    kid- 
neys, 750 
adenoma,  455 

of  kidney,  741 
carcinoma,  471 
epidermoid        carcinoma, 

474 
Tumeur  a  medullocelles,  269 

a  myeloplacques,  269 
Tumor-cells,    anaplasia    of, 

101 

miscellaneous,  peculiari- 
ties of,  46 

phagocytosis  by,  47 
regressive  changes  in,  43 
Tumor-like    hyperplasia    of 

endothelium,  313 
Tumors,     adrenal,    hepatic, 

762 
of        female        genital 

organs,  762 
of  spermatic  cord  and 

testis,  762 
rest,  755 

carcinomatous,  759 
gross  appearance,  757 
lateral       retroperito- 

neal,  762 
occurrence,  756 
peritheliomatous,  759 
renal     tumors     and, 
differentiation,  760 
sarcomatous,  759 
structure,  758 
trabecular,  759 
adult,  26,  48 
alveolar,  346 
amitosis  in,  39 
amyloid,  167 
associated  with  spina  bi- 

fida,  983 

autogenous  antigen  of, 
complement  deviation 
with,  91 


1052 


INDEX 


Tumors,  benign,  malignant 
transformation  in,  64 
metastasis  of,  84 
blood-vessel  lesions  in,  57 
cell  division  in,  38 
central  growth  in,  31 
chemistry  of,  89 
classification,  26 
collateral  hypertrophy  in, 

37. 

colloid  degeneration  of,  45 
color  of  tissue,  29 
complex  tissue  type,  28 
congenital,  26 
connective-tissue  type,  27 
consistence,  30 
course,  59 
cystic,  464 

of  carcinomatous  struc- 
ture, 464 
cysts  in,  31 
definition,  25 
desmoid,  164 
effects  on  body,  65 
emaciation  from,  65 
embryonal,  26,  49 
encephalpid,  511 
endothelial  type,  27 
epithelial  type,  28 

general  pathology,  446 
etiological     classification, 

26 

etiology  of,  special,  109 
expansive  growth,  25 
experimental    production 

of,  126 
by  x-ray,  132 
chronic  inflammation 

in,  131 

effect    of   extract    of 
human  tumors,  132 

study  of,  118 
extensive  growth,  25 
fats  in,  90 

fatty  degeneration  in,  43 
febrile  destruction  of  pro- 
teins in,  66 
ferments  in,  67,  90 

heterolytic  action  of,  67 
functional  activity  in,  53 
gametoid  mitosis  in,  39 
general  morphology,  29 
glandular,  28 
glycogenic     degeneration 

of,  44 

growth  of,  31,  48 
hereditary,  26 
histioid,  48 
histological  classification, 

26,  27 

histopathology,  34 
homologous,  48 
homotypic,  48 
hyaline  changes  in,  45 
hydropic  degeneration  in, 

43 
infiltrative     growth,     25, 

31 


Tumors,  inflammatory  reac- 
tion in,  50 

intermittent     periods    of 
growth  of,  59 

lactic  acid  in,  89 

local    circumscription   of, 

29 
extension  of,  50 

lutein-cell,  585 

lymphomatous,    of   intes- 
tine, 260 
of  stomach,  260 

malignancy     in,      signifi- 
cance of,  62 

markings  of,  30 

maxillary,   of  dental   ori- 
gin, 707 

mesonephric,  610 

mixed,  962 

sacral    congenital,    ori- 
gin, 984 
special  forms,  965 

modes  of  origin,  36 

mucous  degeneration   in, 

44. 

multicentric  growth  of,  36 
muscle  tissue  type,  27 
natural  limit  in  course  of, 

59 

nervous  system  type,  27 
nomenclature,  26 
of  adrenal  gland,  768 
classification,  768 
medullary,  771 

chromaffin  cell,  776 
with  adrenalin  con- 
tent  and    neph- 
ritic   symptoms, 
776 

of  bile-ducts,  689 
of  bladder,  epithelial,  860 

miscellaneous,  865 
of  brain,  393 

age  incidence,  393 
anatomical      classifica- 
tion, 398 

choked  disk  in,  398 
circulatory         disturb- 
ances in,  398 
destruction  of  tissue  in, 

397. 

duration,  396 
edema  in,  397 
general  considerations, 

.393 
distribution,  395 

heredity  in,  393 

meningeal       complica- 
tions, 398 

occurrence,  393 

operability,  395 

relative  frequency,  394 

secondary     effects    of, 
3?6 

sex  in,  393 

skull  changes  in,  398 

spinal    cord    degenera- 
tion in,  398 


Tumors  of  brain,  trauma  in 

etiology,  393 
of      breast,      ectodermal 

mixed,  500 
epithelial,  484 
mesodermal,  499 
miscellaneous,  505 
mixed,  494 
teratoid  mixed,  499 
of     choroid     plexus    and 

ependyma,  415 
etiology,  416 
gross    appearance, 

416 

structure,  416 
of  epoophoron,  609 
of      extrarenal      adrenal 

rests,  761 
of  Fallopian  tubes,  612 

adrenal,  762 

of  Gasserian  ganglion,  434 
of  hypophyseal  duct,  935 
of  hypophysis,  924 
of    infundibular    ependy- 
ma, 420 

of  intestine,  multiple  be- 
nign   embryonal   carci- 
noid,  663 
of  kidney,  738 

adrenal  tumors  and,  dif- 
ferentiation, 760 
epithelial,  738 

classification,  739 
of    lacrimal    gland,    319, 

725 

of  larynx,  847 
benign,  850 
of  liver,  675 

classification,  675 
primary  epithelial,  678 
anatomical    varie- 
ties, 681 
clinical  course,  680 

varieties,  68 1 
etiology,  678 
histogenesis,  679 
metastases  in,  68 1 
relation  to  cirrho- 
sis, 678 
of  lung,  807 
of  lymphoid  tissue,  348 

classification,  348 
of  maxillary  and  nasal  si- 
nuses, 720 
of  nerve  trunks,  427 
of    ovary,    adrenal,    610, 

762 

age  in  etiology,  606 
epithelial,  582 
etiology,  606 
histogenesis,  606 
origin,  608 
simple,  relation  to  tera- 

toma,  622 
of  pancreas,  702 
of  parathyroid  gland,  909 
of  parovarium,  609 
of  pars  intermedia,  938 


INDEX 


1053 


Tumors  of  penis,  866 

of  peripheral  nervous  sys- 
tem,  152 

of  pineal  gland,  948 
classification,  949 
clinical  features,  951 
occurrence,  948 
structure,  951 
symptomatology,  951 

of  pituitary  gland,  924 
anatomy,  929 
cephalic,  939 
dystrophic,  940 
etiology,  924 
miscellaneous,  939 
relation  of  type  with 
symptom  complex, 

945 

symptomatology,  939 
of  placenta,  232 
of  prostate,  779 
of  renal  hilus,  766 

pelvis  and  ureter,  epi- 
thelial, 763 

of    salivary    gland,    epi- 
thelial, 725 
mixed,      anatomy, 

..734 
clinical     course, 

733 

etiology,  733 
structure,  735 
mixed,  727 

of  spinal  cord  and  mem- 
branes, 436 
age    incidence    in, 

,437, 

classification,  437 

duration,  445 
etiology,  436 
trauma  in  etiology 
of,  436 

extradural,  444 

extramedullary,  444 

intramedullary,  444 

level  of,  443 

relation  of,  to  cord, 
membranes,  and 
vertebrae,  444 

secondary  changes  in, 
442 

symptomatology, 

443 

vertebral,  445 
xanthochromia       in, 

442 
of  stomach,  lymphomat- 

ous,  260 
of     submaxillary     gland, 

epithelial,  737 
of  sweat-glands,  836 
of  teeth,  707 
of  testis,  790 
adrenal,  803 
embryoid,  794 
embryonal,  795 
mixed,  794 
teratoid,  794 


Tumors  of   thymus   gland, 

912 

classification,  917 
clinical  course,  923 
primary,  916 
of  thyroid  gland,  891 

epithelial     papillary, 

899 

structure,  900 
of  uterus,  adrenal,  762 
of  vulva,  epithelial,  562 
parasitic  theory  of,  classi- 
fication by,  125 
pavement,  28 
peripheral  growth  of,  31 
plasma-cell,     extramedul- 
lary, 388 
post-natal,  26 
precancerous      stage      of 

growth,  34 

progressive  growth,  25,  59 
proteins,  constitution  of, 

89 

pulp,  29 

rate  of  growth,  59 
recurrence  of,  86 
regional  classification,  26 
relation    of   blood-vessels 

to,  56 
retrograde    transport    in 

dissemination  of,  83 
saber-sheath  veins  in,  57 
sacrococcygeal,        mixed, 

979 

simple  mixed,  28 
spontaneous  cure  in,  60 

regression  in,  40 
stroma  of,  53 

retrogressive      changes 

in,  55 

structure,  48 
teratoid.     See  Teratoids. 
texture  of,  30 
total  quantity  of  blood  in, 

69 

toxic  destruction  of  pro- 
tein tissues  in,  66 
transplantable,      adapta- 
tion of,   139 
fate  of,  139 
nature    and    origin    of, 

136 

problems  of,  136 
transplantation  of,  134 
acquired  resistance  to, 

144 

between  animals  of  dif- 
ferent species,  134 
between  lower  animals 

of  same  species,  135 
between  man  and  man, 

134 
between  related  species 

of  lower  animals,  134 
hypersusceptibility    to, 

147 

influence  of  variations 
in  soil,   140 


Tumors,  transplantation  of, 
natural       resistance, 

143 

nature  of  factors  in  re- 
sistance, 145 
passive    resistance    to, 

uniformity    of    technic 

in,   140 
transplanted,  influence  of 

diet  on,   140 
resistance  to,  143 
spontaneous  absorption 

of,  141 
structural    changes    in, 

141 
trauma  in  etiology  of,  109, 

no 

frequency,  112 
mechanism,  in 
medicolegal    aspects, 

112 

traumatic,  26 
ulceration  in,  33 
unicentric  growth  of,  36 

ULCER,    peptic,  cancer   fol- 
lowing, 630 
rodent,  830 

crateriform,  831 
histogenesis,  833 
structure,  832 
Ulceration  in  tumors,  33 
Ulcerative    infiltrating   epi- 

thelioma  of  lip,  837 
Ulcerocancer    of    stomach, 

658 

Unicentric    growth    of    tu- 
mors, 30 
Urea,     percentage     of,     in 

cancer,  72 
Ureter,  cancer  of,  primary, 

865  ^ 

epithelial  tumors  of,  763 
epithelioma  of,  papillary, 

763 

papilloma  of,  763 
Urethra,  cancer  of,  870 
Uric  acid  increase  in  cancer, 

72 
Urinary    bladder,     rhabdo- 

myoma  of,  220 
organs,  myoma  of,  216 
Urine,  changes  in,  in  cancer, 

Urobilin  in  urine  in  cancer, 

74. 
Uterine  fibromyoma,  207 

lipoma,  184 

mucosa,  sarcoma  of,  266 
Uterus,      adeno-acanthoma 
of,  547 

cancer  of,  267,  543.     See 
also  Cancer  of  uterus. 

chondroma  of,  192 

endothelioma  of,  334 

myoma  of,  208 


1054 


INDEX 


Uterus,  myoma  of,  degenera- 
tive changes  in,  210- 

etiology,  212 

form,  208 

gross  appearance,  210 

location,  208 

microscopical  structure, 
211 

recurrent,  265 
rhabdomyoma  of,  220 
sarcoma  of,  263 

classification,  264 

etiology,  266 

metastases  in,  263 

mural,  263 

structure,  264 
tumors  of,  adrenal,  762 


VAGINA,  epidermoid  cancer 

of,  564 

Varicosities,  chronic,  224 
Vascular  nevus,  224 
Verruca  plana  juvenilis,  448 

vulgaris,  448 


Vertebral  tumors  of  spinal 

cord,  445 

Villous  duct  cancer,  510 
Virchow's    physaliden,    43, 
187 

theory  of  cancer,  22 
Visceral  metastases  in  can- 
cer of  uterus,  561 

neurofibroma,  155 

neurofibromatosis,  157 
Vocal  cords,  acanthoma  of, 

855 
Vulva,  epidermoid  cancer  of, 

562 
tumors  of,  epithelial,  562 


WANDERING  cells,  syncytial, 

568 
Warts,  cutaneous,  448 

soot-,  870 
Wassermann      reaction      in 

cancer,  91 
Whitlow,  melanotic,  873 


XANTHELASMA,  162 
Xanthochromia     in     spinal 

cord  tumors,  442 
Xanthoma,  162 

diabeticorum,  162 

generalized,  162 

multiplex,  162 

palpebrarum,  162,  163 

planum,  162 

structure  of,  163 

tuberosum,  162 

vulgare,  162 
Xanthomatosis,  163 
Xanthosarcoma,  256 
Xeroderma      pigmentosum, 

822 
x-ray  carcinoma,  102 

dermatitis,     cancer    and, 

823 

clinical  course,  824 
structure,  824 

experimental     production 
of  tumors  by,   132 

ZONA  glomerulosa,  758 


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